Obesity: Epidemiology, Pathophysiology, and Prevention

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3802_C000.fm Page i Tuesday, January 30, 2007 9:37 AM

CRC Series in Modern Nutrition Science

Obesity Epidemiology, Pathophysiology, and Prevention

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CRC Series in Modern Nutrition Science Series Editor Stacey J. Bell Ideasphere, Inc. Grand Rapids, Michigan

Phytopharmaceuticals in Cancer Chemoprevention Edited by Debasis Bagchi and Harry G. Preuss Handbook of Minerals as Nutritional Supplements Robert A. DiSilvestro Intestinal Failure and Rehabilitation: A Clinical Guide Edited by Laura E. Matarese, Ezra Steiger, and Douglas L. Seidner Nutrition and Wound Healing Edited by Joseph A. Molnar A Clinical Guide for Management of Overweight and Obese Children and Adults Edited by Caroline M. Apovian and Carine M. Lenders Obesity: Epidemiology, Pathophysiology, and Prevention Edited by Debasis Bagchi and Harry G. Preuss

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CRC Series in Modern Nutrition Science

Obesity Epidemiology, Pathophysiology, and Prevention EDITED BY

Debasis Bagchi Harry G. Preuss

Boca Raton London New York

CRC Press is an imprint of the Taylor & Francis Group, an informa business

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CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2007 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8493-3802-6 (Hardcover) International Standard Book Number-13: 978-0-8493-3802-1 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable eﬀorts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microﬁlming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http:// www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-proﬁt organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identiﬁcation and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Obesity : epidemiology, pathophysiology, and prevention / edited by Debasis Bagchi and Harry G. Preuss. p. ; cm. -- (CRC series in modern nutrition science) “A CRC title.” Includes bibliographical references and index. ISBN-13: 978-0-8493-3802-1 (hardcover : alk. paper) ISBN-10: 0-8493-3802-6 (hardcover : alk. paper) 1. Obesity--Epidemiology. 2. Obesity--Pathophysiology. I. Bagchi, Debasis. II. Preuss, Harry G. III. Series. [DNLM: 1. Obesity--therapy. 2. Dietary Supplements. 3. Obesity--physiopathology. 4. Weight Loss--drug eﬀects. WD 210 O1121949 2007] RC645.O23O2465 2007 616.3’98--dc22 Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com

2006102265

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Dedication Dedicated to my beloved father, the late Tarak Chandra Bagchi, and my beloved father-in-law, the late Nakuleshwar Bardhan. –Debasis Bagchi Dedicated to my teachers, especially the late Rachel B. Lott (third grade), the late MSG Thomas Hannon (CCD), and the late Dr. Robert F. Pitts (postdoctoral training). They along with many others prepared me for my career. –Harry G. Preuss

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Contents Preface .............................................................................................................................................. xi Editors ............................................................................................................................................ xiii Contributors......................................................................................................................................xv

PART I Introduction 1

Epidemiology of Obesity .......................................................................................................3 Giovanna Turconi and Hellas Cena

2

Epidemiology of Obesity: A Global Burden for the New Millennium..............................21 Gopal C. Pain

PART II Pathophysiology of Obesity 3

Environmental Estrogens, Endocrine Disruption, and Obesity...........................................33 Frederick S. vom Saal, James R. Kirkpatrick, and Benjamin L. Coe

4

Cigarette Smoking, Inﬂammation, and Obesity ..................................................................43 Saibal K. Biswas, Ian L. Megson, Catherine A. Shaw, and Irfan Rahman

5

Disordered Eating as a Correlate in the Development of Obesity .....................................63 Gwendolyn W. Pla

6

Role of Neurotransmitters in Obesity Regulation...............................................................71 Sunny E. Ohia and Catherine A. Opere

7

Neurobiology of Obesity .....................................................................................................81 Nina Eikelis

8

Leptin as a Vasoactive Adipokine: Link Between Metabolism and Vasculature ...............93 Anne Bouloumié, Cyrile Anne Curat, Alexandra Miranville, Karine Lolmède, and Coralie Sengenès

9

Overview of Ghrelin, Appetite, and Energy Balance........................................................105 Rafael Fernández-Fernández and Manuel Tena-Sempere

10

Molecular Genetics of Obesity Syndrome: Role of DNA Methylation ...........................115 Rama S. Dwivedi, Atul Sahai, and Bernard L. Mirkin vii

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PART III Obesity and Degenerative Diseases 11

Oxidative Stress Status in Humans with Metabolic Syndrome ........................................123 Chung-Yen Chen and Jeffrey B. Blumberg

12

Obesity and Type 2 Diabetes.............................................................................................139 Subhashini Yaturu and Sushil K. Jain

13

Angiogenesis-Targeted Redox-Based Therapeutics ..........................................................155 Shampa Chatterjee, Debasis Bagchi, Manashi Bagchi, and Chandan K. Sen

14

Obesity as an Occult Risk Factor for Drug and Chemical Toxicities ..............................165 George B. Corcoran

PART IV Novel Concept in Obesity Drug Development 15

Adipose Drug Targets for Obesity Treatment ...................................................................177 Olivier Boss, Lorenz Lehr, and Jean-Paul Giacobino

PART V Safety of Obesity Drugs 16

Safety of Obesity Drugs ....................................................................................................199 Alok K. Gupta and Frank L. Greenway

PART VI Natural, Nutritional, and Physical Approaches to Weight Management 17

The Fundamental Role of Physical Activity and Exercise in Weight Management ........219 Dawn Blatt and Cheri L. Gostic

18

Nutritional and Dietary Approaches for Weight Management: An Overview .................233 Sanjiv Agarwal

19

Gender Differences in Body Fat Utilization during Weight Gain, Loss, or Maintenance.......................................................................239 Gabriel Keith Harris and David J. Baer

20

Appetite, Body Weight, Health Implications of a Low-Glycemic-Load Diet..................245 Stacey J. Bell, Wendy Van Ausdal, and Greg Grochoski

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Contents

21

ix

Beyond Obesity Prevention: The Anti-Aging Effects of Caloric Restriction...................265 Kurt W. Saupe and Jacob D. Mulligan

22

Dietary Supplement Carbohydrate Digestion Inhibitors: A Review of the Literature .....279 Jay Udani, Mary Hardy, and Ben Kavoussi

23

Vegetarian Diets in the Prevention and Treatment of Obesity .........................................299 Kathryn T. Knecht, Hien T. Bui, Don K. Tran, and Joan Sabaté

24

The Atkins Paradigm .........................................................................................................315 Ariel Robarge and Bernard W. Downs

25

Polyphenols from Fruits and Vegetables in Weight Management and Obesity Control .....321 Dilip Ghosh and Margot A. Skinner

26

Chromium (III) in Promoting Weight Loss and Lean Body Mass...................................339 Manashi Bagchi, Harry G. Preuss, Shirley Zafra-Stone, and Debasis Bagchi

27

An Overview on (–)-Hydroxycitric Acid in Obesity Regulation......................................349 Shirley Zafra-Stone, Manashi Bagchi, Harry G. Preuss, Gary J. Grover, and Debasis Bagchi

28

A Review of the Safety and Efﬁcacy of Citrus aurantium in Weight Management .......371 Sidney J. Stohs and Michael Shara

29

Conjugated Linoleic Acid and Weight Control: From the Biomedical Immune Viewpoint .........................................................................383 Zwe-Ling Kong

30

The Role of Tea in Weight Management ..........................................................................401 Chithan Kandaswami

31

Laboratory and Clinical Studies of Chitosan ....................................................................413 Harry G. Preuss, Debasis Bagchi, and Gilbert R. Kaats

32

Phaseolus vulgaris and α-Amylase Inhibition..................................................................423 Dennis E. Meiss

33

Glucomannan in Weight Loss: A Review of the Evidence...............................................433 Barbara Swanson and Joyce K. Keithley

34

Role of Caralluma ﬁmbriata in Weight Management ......................................................443 Ramasamy V. Venkatesh and Ramaswamy Rajendran

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Role of Medium-Chain Triglycerides in Weight Management.........................................451 Mary G. Enig

36

Anti-Obesity by Marine Lipids .........................................................................................463 Kazuo Miyashita

37

Dairy Foods, Calcium, and Weight Management .............................................................477 Michael B. Zemel

38

Lessons from the Use of Ephedra Products as Dietary Supplements ..............................495 Madhusudan G. Soni, Kantha Shelke, and Rakesh Amin

39

Dietary Supplementation in Weight Loss: A Dietitian’s Perspective ...............................507 Betty Wedman-St. Louis

PART VII Child Obesity and Prevention 40

Treatment and Prevention of Childhood Obesity and Associated Metabolic Diseases..... 515 Michael I. Goran, Jaimie N. Davies, and Louise A. Kelly

PART VIII Bariatric Surgery in Weight Management 41

Bariatric Surgery in Obesity and Reversal of Metabolic Disorders .................................531 Melania Manco

Index ..............................................................................................................................................545

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Preface The spread of obesity has been declared a worldwide epidemic by the World Health Organization (WHO). In fact, a new term, globesity, has been coined to describe the recent upsurge of overweight and obesity throughout the world’s population. How severe is the problem? According to WHO, more than 1 billion adults are overweight and at least 315 million are clinically obese. To make matters worse, the International Obesity Task Force estimates that 22 million of the world’s children under age of 5 are overweight or obese [1–4]. In addition to type 2 diabetes, obesity has also been linked to other broad-spectrum, degenerative diseases, including other metabolic disorders and certain forms of cancer. Among the children diagnosed with type 2 diabetes, 85% are obese [2]. It has been reported that 80% of type 2 diabetes, 70% of cardiovascular diseases, and 42% of breast and colon cancers are related to obesity [1,2]. Obesity is the major factor behind 30% of gallbladder perturbations leading to surgery and 26% of incidences of high blood pressure. The unfortunate outcome of globesity has generated an unlimited array of weight-loss strategies [1,2]. Products and programs that induce rapid weight loss and disturb metabolic homeostasis dominate the focus of marketers and consumers alike; however, rapid weight loss is potentially unhealthy and frequently induces undesirable rebound weight gain consequences. In addition, many anti-obesity pharmaceuticals are accompanied by adverse reactions, making the cure worse than the disorder itself; thus, it is very important to develop a strategic therapeutic intervention using safe, novel, natural supplements supported by credible research. This book, intended for practicing medical professionals, clinical nutritionists, dietitians, and researchers, addresses many issues relevant to obesity: the molecular mechanisms and pathophysiology leading to obesity and metabolic disorders, the safety of obesity drugs, drug development strategies, the inﬂuences of physical activity and nutrition, and the beneﬁts of research-supported nutraceutical supplements. The forty-one chapters in this book have been written by experts in their ﬁelds. A worldrenowned nutritionist and a health professional have provided a world overview of the epidemiology of obesity in the ﬁrst part. Part II demonstrates the pathophysiology of obesity and correlates obesity with environmental estrogens, endocrine disruption, inﬂammatory responses, tobacco, disordered eating, and neurobiology and neurotransmitters. The signiﬁcance of the hunger hormone ghrelin, leptin, and the molecular genetics of obesity syndrome are discussed in subsequent chapters. Part III correlates obesity with diverse degenerative diseases, including metabolic syndrome, type 2 diabetes, and cancer. Dr. Olivier Boss, a lead researcher on adipose drug targets, addresses new concepts in obesity drug development in Part IV. Pennington Biomedical Research Center scientists discuss the safety of obesity drugs in Part V, and Part VI summarizes natural, nutritional, and physical approaches to weight management. The roles of physical activity, healthy dietary approaches, gender effects, and caloric restriction are thoroughly explored, and this part also provides a thorough discussion of carbohydrate blockers, polyphenolic compounds, trivalent chromium, Garcinia cambogia, (–)-hydroxycitric acid, Citrus aurantium, Caralluma ﬁmbriata, Phaseolus vulgaris, α-amylase inhibition, conjugated linoleic acid, tea, chitosan, glucomannan, marine lipids, calcium and dairy products, and medium-chain triglycerides. Also included is a chapter on the Atkins paradigm, a chapter on the banned weight-loss supplement ephedra (which ruled the market for at least a decade), and, ﬁnally, a chapter offering the reﬂections of a practicing dietitian regarding weight-loss supplements. Part VII examines the complicated problem of childhood obesity, including metabolic acidosis, and provides an intervention strategy. Part VIII demonstrates how bariatric surgery can help in weight management and reversing metabolic disorders. Finally, we extend our special thanks to all the authors for their invaluable contributions.

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REFERENCES 1. Worldwide Obesity: Trends Global Obesity Trends, Globesity the Growing Epidemic of Chronic Overweight, 2006, http://www.annecollins.com/obesity/worldwide-obesity.htm. 2. Obesity Statistics: Weight Statistics — Adults, Children, Obesity-Related Diseases, 2006, http://www.annecollins.com/obesity/statistics-obesity.htm. 3. WHO, World Health Statistics, World Health Organization, Geneva, 2006, pp. 42–48. 4. NCHS, Health, United States 2005, National Center for Health Statistics, Hyattsville, MD, 2005.

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Editors Debasis Bagchi, Ph.D., FACN, CNS, MAIChE, received his Ph.D. in medicinal chemistry in 1982. He is a professor of toxicology in the Department of Pharmacy Sciences at Creighton University Medical Center, Omaha, Nebraska. Dr. Bagchi is also the senior vice president of research and development at InterHealth Nutraceuticals, Inc., in Benicia, California. Dr. Bagchi is the vice president of the American College of Nutrtion and chair-elect of the Nutraceuticals and Functional Foods division of the Institute of Food Technologists (IFT). His research interests include free radicals, human diseases, carcinogenesis pathophysiology, mechanistic aspects of cytoprotection by antioxidants, regulatory pathways in obesity, and gene expression. Dr. Bagchi has written 225 papers that have been published in peer-reviewed journals. He has delivered invited lectures and served as session chairperson for various national and international scientiﬁc conferences, organized workshops, and group discussion sessions. Dr. Bagchi is a fellow of the American College of Nutrition, member of the Society of Toxicology, member of the New York Academy of Sciences, fellow of the Nutrition Research Academy, and member of the TCE Stakeholder Committee of the Wright Patterson Air Force Base, Ohio. Dr. Bagchi is a member of the Study Section and Peer Review Committee of the National Institutes of Health, Bethesda, Maryland, and serves as a reviewer of U.S. Army research grants on Gulf War Illness. Dr. Bagchi is also serving as editorial board member of numerous peer-reviewed journals, including Antioxidants and Redox Signaling, Toxicology Letters, The Original Internist, Research Communications in Pharmacology and Toxicology, and the International Journal of Geriatric Urology and Nephrology. Dr. Bagchi has received research funding from various institutions and agencies, including the U.S. Air Force Ofﬁce of Scientiﬁc Research; National Institutes of Health (NIH); National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI); American Heart Association; Nebraska State Department of Health, Biomedical Research Support Grant; Health Future Foundation; The Procter & Gamble Company; and Abbott Laboratories. Harry G. Preuss, M.D., MACN, CNS, received his B.A. and M.D. from Cornell University, trained for 3 years in internal medicine at Vanderbilt University Medical Center under Dr. David E. Rogers, studied for 2 years as a fellow in renal physiology at Cornell University Medical Center under Dr. Robert F. Pitts, and spent 2 years in clinical and research training in nephrology at Georgetown University Medical Center under Dr. George E. Schreiner. During his training years, he was a special research fellow of the National Institutes of Health (NIH) and an established investigator of the American Heart Association. Following 5 years as an assistant and associate (tenured) professor of medicine at the University of Pittsburgh Medical Center, he returned to Georgetown Medical Center and is now a professor of physiology, medicine, and pathology (tenured). He subsequently performed a 6-month sabbatical in molecular biology at the NIH in the laboratories of Dr. Maurice Burg. His bibliography includes over 300 medical papers and more than 200 abstracts. Dr. Preuss has edited or co-edited seven books and three symposia published in wellestablished journals. He is the co-author of three books written for the lay public: The Prostate Cure, Maitake Magic, and the recently published The Natural Fat-Loss Pharmacy. He is currently an advisory editor for six journals. In 1976, Dr. Preuss was elected to membership in the American Society of Clinical Investigations. His previous government appointments included 4 years on the Advisory Council for the National Institute on Aging, 2 years on the Advisory Council of the director of the NIH, and 2 years on the Advisory Council for the Ofﬁce of Alternative Medicine of the NIH. He has been a member of many other peer research review committees for the NIH

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and American Heart Association and is now a member of the National Cholesterol Education Program of the NHLBI. Dr. Preuss was elected the ninth Master of the American College of Nutrition (ACN). He is a former chairman of two ACN councils: the Cardiovascular and Aging Council and the Council on Dietary Supplements, Nutraceuticals, and Functional Foods. After a brief stint on the Board of Directors of the ACN, Dr. Preuss spent 3 years as secretary–treasurer and 3 consecutive years as vice president, president-elect, and president. He is currently chairman of the Nutritional Policy Institute of the ACN. Dr. Preuss is a member of the board of directors for the American Association for Health Freedom (AAHF) and was their treasurer. Dr. Preuss wrote the nutrition section for the Encyclopedia Americana and for seven years was president of the Certiﬁcation Board for Nutrition Specialists (CBNS) that gives the CNS certiﬁcation. He is cochairman of the Institutional Review Board (IRB) at Georgetown University, which reviews all clinical protocols at Georgetown University Medical Center. His research centers on the use of dietary supplements and nutraceuticals to favorably inﬂuence or even prevent a variety of medical perturbations, especially those related to obesity, insulin resistance, and cardiovascular perturbations. Lately, he has also researched the ability of many oils and fats to overcome various infections, including those resistant to antibiotics.

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Contributors Sanjiv Agarwal ConAgra Foods, Inc. Omaha, Nebraska

Olivier Boss Sirtris Pharmaceuticals, Inc. Cambridge, Massachusetts

Rakesh Amin Amin Law, LLC Chicago, Illinois

Anne Bouloumié AVENIR INSERM U586, Obesity Research Unit Paul Sabatier University Louis Bugnard Institute IFR31 Toulouse, France

David J. Baer Diet and Human Performance Laboratory Beltsville Human Nutrition Research Center Beltsville, Maryland Debasis Bagchi Department of Pharmacy Sciences Creighton University Medical Center Omaha, Nebraska; InterHealth Research Center Benicia, California Manashi Bagchi InterHealth Research Center Benicia, California Stacey J. Bell IdeaSphere, Inc. Grand Rapids, Michigan Saibal K. Biswas Department of Biochemistry Dr. Ambedkar College Deeksha Bhoomi, Nagpur, India Dawn Blatt Division of Rehabilitation Sciences School of Health Technology and Management Stony Brook University Stony Brook, New York Jeffrey B. Blumberg Antioxidants Research Laboratory Jean Mayer U.S.D.A. Human Nutrition Research Center on Aging Tufts University Boston, Massachusetts

Hien T. Bui School of Pharmacy Loma Linda University Loma Linda, California Hellas Cena Department of Applied Health Sciences Section of Human Nutrition and Dietetics Faculty of Medicine University of Pavia Pavia, Italy Shampa Chatterjee University of Pennsylvania School of Medicine Philadelphia, Pennsylvania Chung-Yen Chen Antioxidant Research Laboratory Jean Mayer U.S.D.A. Human Nutrition Research Center on Aging Tufts University Boston, Massachusetts Benjamin L. Coe Division of Biological Sciences University of Missouri–Columbia Columbia, Missouri George B. Corcoran Department of Pharmaceutical Sciences Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit, Michigan

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Cyrile Anne Curat Cardiovascular Physiology Institute Frankfurt/Main, Germany Jaimie N. Davies Department of Preventive Medicine Keck School of Medicine University of Southern California Los Angeles, California Bernard W. Downs Allied Nutraceutical Research Lederach, Pennsylvania Rama S. Dwivedi Department of Pediatrics and Molecular Pharmacology and Biological Chemistry Children’s Memorial Research Center The Feinberg School of Medicine Northwestern University Chicago, Illinois

Michael I. Goran Department of Preventive Medicine Keck School of Medicine University of Southern California Los Angeles, California Cheri L. Gostic Division of Rehabilitation Sciences School of Health Technology and Management Stony Brook University Stony Brook, New York Frank L. Greenway Medical Director and Professor Pennington Biomedical Research Center Louisiana State University System Baton Rouge, Louisiana Greg Grochoski Research and Development IdeaSphere, Inc. Grand Rapids, Michigan

Nina Eikelis Human Neurotransmitter Laboratory Baker Heart Research Institute Melbourne, Australia

Gary J. Grover Euroﬁns Scientiﬁc Dayton, New Jersey

Mary G. Enig Nutritional Sciences Division Enig Associates, Inc. Silver Spring, Maryland

Alok K. Gupta Pennington Biomedical Research Center Louisiana State University System Baton Rouge, Louisiana

Rafael Fernández-Fernández Department of Cell Biology, Physiology, and Immunology University of Córdoba Córdoba, Spain Dilip Ghosh Health and Food Group The Horticulture and Food Research Institute of New Zealand Ltd. Auckland, New Zealand

Mary Hardy Integrative Medicine Group, Cedars-Sinai Medical Center UCLA Center for Dietary Supplement Research in Botanicals UCLA Center for Human Nutrition Department of Medicine, David Geffen/UCLA School of Medicine UCLA Collaborative Centers for Integrative Medicine Los Angeles, California

Jean-Paul Giacobino Growth and Development Laboratory Rangos Research Center Pittsburgh, Pennsylvania

Gabriel Keith Harris Diet and Human Performance Laboratory Beltsville Human Nutrition Research Center Beltsville, Maryland

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Contributors

Sushil K. Jain Department of Pediatrics Louisiana State University Health Sciences Center Shreveport, Louisiana Gilbert R. Kaats Health and Research Foundation San Antonio, Texas Chithan Kandaswami ADVOCARE International Carrollton, Texas Ben Kavoussi Medicus Research, LLC Northridge, California Joyce K. Keithley Adult Health Nursing Rush University College of Nursing Chicago, Illinois Louise A. Kelly Department of Preventive Medicine Keck School of Medicine University of Southern California Los Angeles, California James R. Kirkpatrick Division of Biological Sciences University of Missouri–Columbia Columbia, Missouri Kathryn T. Knecht Department of Pharmaceutical Science School of Pharmacy Loma Linda University Loma Linda, California Zwe-Ling Kong Cellular Immunology Lab Department of Food Science National Taiwan Ocean University Taiwan, Republic of China

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Lorenz Lehr Department of Cell Physiology and Metabolism University of Geneva Medical School Geneva, Switzerland Karine Lolmède Cardio-Thoracic and Vascular Department University Vita-Salute San Raffaele Milano, Italy Melania Manco Liver Unit Bambino Gesù Paediatric Hospital and Research Institute Rome, Italy Ian L. Megson Free Radical Research Facility Department of Diabetes UHI Millennium Institute Inverness, United Kingdom Dennis E. Meiss ProThera®, Inc. Reno, Nevada Alexandra Miranville Cardiovascular Physiology Institute Frankfurt/Main, Germany Bernard L. Mirkin Department of Pediatrics and Molecular Pharmacology and Biological Chemistry Children’s Memorial Research Center The Feinberg School of Medicine Northwestern University Chicago, Illinois Kazuo Miyashita Hokkaido University Hakodate, Japan Jacob D. Mulligan Departments of Medicine University of Wisconsin–Madison Madison, Wisconsin

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Sunny E. Ohia Department of Pharmacological and Pharmaceutical Sciences College of Pharmacy University of Houston Houston, Texas Catherine A. Opere Department of Pharmacy Sciences School of Pharmacy and Health Professions Creighton University Medical Center Omaha, Nebraska Gopal C. Pain National Consultant of India World Health Organization New Delhi, India Gwendolyn W. Pla Department of Nutritional Sciences Howard University Washington, D.C. Harry G. Preuss Georgetown University Medical Center Washington, D.C. Irfan Rahman Department of Environmental Medicine Division of Lung Biology and Disease University of Rochester Medical Center Rochester, New York Ramaswamy Rajendran Green Chem Bangalore, India Ariel Robarge Department of Nutrition Rothman Institute Philadelphia, Pennsylvania Joan Sabaté Department of Nutrition School of Public Health Loma Linda University Loma Linda, California

Atul Sahai National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda, Maryland Kurt W. Saupe Departments of Medicine and Physiology University of Wisconsin–Madison Madison, Wisconsin Chandan K. Sen The Ohio State University Medical Center Columbus, Ohio Coralie Sengenès AVENIR INSERM U586, Obesity Research Unit Paul Sabatier University Louis Bugnard Institute IFR31 Toulouse, France Michael Shara School of Pharmacy and Health Professions Creighton University Medical Center Omaha, Nebraska Catherine A. Shaw Centre for Cardiovascular Sciences Queen’s Medical Research Institute University of Edinburgh Edinburgh, United Kingdom Kantha Shelke Corvus Blue, LLC Chicago, Illinois Food Processing & Wellness Foods magazine Itasca, Illinois Margot A. Skinner Health and Food Group The Horticulture and Food Research Institute of New Zealand Ltd. Auckland, New Zealand Madhusudan G. Soni Soni and Associates Vero Beach, Florida

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Contributors

Sidney J. Stohs ADVOCARE International Carrollton, Texas Barbara Swanson Adult Health Nursing Rush University College of Nursing Chicago, Illinois Manuel Tena-Sempere Department of Cell Biology, Physiology, and Immunology University of Córdoba Córdoba, Spain Don K. Tran School of Pharmacy Loma Linda University Loma Linda, California Giovanna Turconi Department of Applied Health Sciences Section of Human Nutrition and Dietetics Faculty of Medicine University of Pavia Pavia, Italy Jay Udani David Geffen/UCLA School of Medicine Integrative Medicine Program, Northridge Hospital Medicus Research, LLC Northridge, California

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Wendy Van Ausdal IdeaSphere, Inc. American Fork, Utah Ramasamy V. Venkatesh Gencor Paciﬁc Limited Discovery Bay, Hong Kong Frederick S. vom Saal Division of Biological Sciences University of Missouri–Columbia Columbia, Missouri Betty Wedman-St. Louis New York Chiropractic College and University of Phoenix Licensed Nutritionist and Environmental Health Specialist St. Petersburg, Florida Subhashini Yaturu Overton Brooks Veterans Administration Medical Center Louisiana State University Health Sciences Center Shreveport, Louisiana Shirley Zafra-Stone InterHealth Research Center Benicia, California Michael B. Zemel The University of Tennessee Nutrition Institute The University of Tennessee Knoxville, Tennessee

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Part I Introduction

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1 Epidemiology of Obesity Giovanna Turconi and Hellas Cena CONTENTS Introduction ........................................................................................................................................3 Prevalence of Obesity in the Adult Population .................................................................................5 Europe .........................................................................................................................................6 United States ...............................................................................................................................8 Latin America and Caribbean...................................................................................................10 Africa ........................................................................................................................................10 Japan, China, and Western Paciﬁc Countries...........................................................................10 Prevalence of Obesity in Children and Adolescents .......................................................................11 Europe .......................................................................................................................................11 United States .............................................................................................................................13 Australia and China ..................................................................................................................14 Health Consequences of Obesity and Morbidity ............................................................................14 Beneﬁts of Weight Loss...................................................................................................................14 Economic Costs of Obesity .............................................................................................................15 The Need for Action ........................................................................................................................16 References ........................................................................................................................................17

INTRODUCTION Obesity is a complex, multifactorial, chronic disease involving environmental (social and cultural), genetic, physiologic, metabolic, behavioral, and psychological components. It has been increasing at an alarming rate throughout the world over the past two decades to the extent that it is now a pandemic, affecting millions of people globally, and it is the second leading cause of preventable death in the United States. The World Health Organization (WHO) has estimated that more than 300 million people are obese worldwide [1]. Obesity is deﬁned as a condition of excess body fat, and it is associated with a large number of debilitating and life-threatening disorders, such as major increases in associated cardiovascular, metabolic, and other noncommunicable diseases [2]. It also contributes to increased mortality rates from all causes, including cardiovascular diseases (CVDs) and cancer. The obesity prevalence rate increase is evident in Westernized countries, where obesity has been present for decades, but today it is also particularly noticeable in less developed countries that previously had not experienced problems with overweight and obesity. For example, the prevalence of obesity has increased by about 10 to 40% in the majority of European countries in the last decade, and it currently affects nearly one third of the adult American population, as well as three quarters of the adult population living in urban areas of Western Samoa in the Paciﬁc [3]. Obesity in the developing world reﬂects the profound changes in society over the past 20 to 30 years that have created an environment that promotes a sedentary lifestyle and the consumption of a high-fat, energy-dense diet, collectively known as the nutrition transition. As poor countries

3

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From least to most developed countries: overweight is on the rise Percentage of population 25

20

Underweight Overweight

15

10

5

0 Global

Least developed countries

Developing countries

Economies in transition

Developed market economy countries

As countries develop, they face many of the problems common in industrialized nations. Obesity is one of the most worrisome.

FIGURE 1.1 From least to most developed countries, overweight is on the rise. As countries develop, they face many of the problems common to industrialized nations. Obesity is one of the most worrisome. (From FAO, The Developing World’s New Burden: Obesity, Food and Agriculture Organization, United Nations, Geneva, Switzerland, 2002, http://www.fao.org/FOCUS/E/obesity/obes2.htm.)

become more prosperous, they acquire some of the beneﬁts as well as some of the problems of industrialized nations, including obesity (Figure 1.1) [4]. Because the direct measurement of body fat is difﬁcult, the body mass index (BMI), a simple weight-to-height ratio (kg/m2), is typically used to classify overweight and obese adults. Consistent with this, the WHO has recently published international standards for classifying overweight and obesity in adults (Table 1.1). Obesity is deﬁned as a BMI ≥ 30 kg/m2, but it can be further subdivided on the basis of the severity of the obesity [1].

TABLE 1.1 WHO Standard Classification of Obesity Classification Normal range Overweight Obesity class I Obesity class II Obesity class III

BMI (kg/m2)

Risk of Comorbidities

18.5–24.9 25.0–29.9 30.0–34.9 35.0–39.9 ≥40

Average Mildly increased Moderate Severe Very severe

Source: WHO, Obesity: Preventing and Managing the Global Epidemic, Report of a WHO Consultation, World Health Organization, Geneva, Switzerland, 2000, p. 256.

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TABLE 1.2 Sex-Specific Waist Circumferences for Increased Risk and Substantially Increased Risk of Metabolic Complications Associated with Obesity in Caucasians Risk of Obesity-Associated Metabolic Complications

Men Women

Increased

Substantially Increased

≥94 cm ≥80 cm

≥102 cm ≥88 cm

Note: The ﬁgures are population-speciﬁc and the relative risk also depends on levels of obesity (BMI) and other risk factors for CVD and NIDDM. Source: WHO, Obesity: Preventing and Managing the Global Epidemic, Report of a WHO Consultation, World Health Organization, Geneva, Switzerland, 2000, p. 256.

Although the BMI provides a simple, convenient measurement of obesity, a more important aspect of obesity is the regional distribution of excess body fat. Visceral or intraabdominal obesity, in contrast to subcutaneous or lower body obesity, carries the greatest risk of a number of chronicdegenerative diseases, including CVD and non-insulin-dependent diabetes mellitus (NIDDM). The importance of central obesity is clear in populations (e.g., Asian) that tend to have relatively low BMI values but high levels of abdominal fat and are particularly prone to NIDDM, hypertension, and CVD. Methods for evaluating abdominal fat include measuring waist circumference. Changes in waist circumference reﬂect changes in risk for CVD and other chronic diseases. As with the BMI, cut-off values have been set to identify increased risk, but for waist circumference these must be sex and population speciﬁc (Table 1.2) [1]. We must still recognize that overweight and obesity are part of a continuum and that health risks increase with increasing weight in the individual. It has been estimated that the costs of obesity account for up to 8% of the total healthcare costs in Western countries, and they represent an enormous burden with regard to individual illness, disability, and early mortality as well as in terms of the costs to employers, taxpayers, and society. The mortality associated with excess weight increases as the degree of obesity and overweight increases. One study estimated that between 280,000 and 325,000 deaths annually in the United States could be attributed to overweight and obesity [5]. More than 80% of these deaths occur among people with a BMI > 30 kg/m2. The increase in deaths due to obesity has been documented in a number of studies from around the world (Table 1.3) [6–10].

PREVALENCE OF OBESITY IN THE ADULT POPULATION It should be noted that it is often difﬁcult to make a direct comparison of the prevalence of obesity among countries due to the inconsistent classiﬁcations used to deﬁne obesity. This problem may be overcome with the adoption in future surveys of the WHO standardized classiﬁcations for obesity. From available data, the worldwide prevalence of obesity has been found to range from less than

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TABLE 1.3 All-Cause and Disease-Specific Cause of Death from Several Epidemiological Studies in Relation to Body Mass Index All-Cause Mortality (Deaths/1000 Patient-Years) Study and BMI Criteria (kg/m2)

Male

Female

Nurses Health Study (ages 30–55 years, with 16 years’ follow-up) [7] 19.0–21.9 — 2.46 22.0–24.9 — 2.46 25.0–26.9 — 2.61 27–28.9 — 3.35 29–31.9 — 3.90 >32 — 4.64 British Regional Heart Study (ages 40–59 years, with 13.8 years’ follow-up) [8] 20–21.9 12.6 — 22–23.9 11.5 — 24–25.9 11.8 — 26–27.9 11.8 — 28–29.9 13.3 — >30 16.8 — Gothenberg Birth Cohort (ages 47–55 years, with 19.7 years’ follow-up) [9] 20.0–22.5 15.5 — 22.5–25.0 13.9 — 25.0–27.5 14.3 — 27.5–30 16.6 — >30 21.1 — Cancer Prevention Study II (ages 65–74 years) [10] 22.0–23.4 8.54 23.5–24.9 8.98 25.0–26.4 9.41 26.5–27.9 10.38 28.0–29.9 12.70 30.0–31.9 13.70 32.0–34.9 17.98 >35 27.67

4.98 5.95 5.98 6.36 7.96 8.36 11.11 12.99

Source: Caterson, J.D. et al., Circulation, 110, e476–e483, 2004. With permission.

5% in rural China, Japan, and some African countries to levels as high as 75% of the adult population in urban Samoa. Table 1.4 [3] provides examples of secular trends of obesity for various countries. Obesity levels also vary depending on ethnic origin. In the United States, particularly among women, large differences exist in the prevalence of obesity among populations of different ethnic origins within the same country.

EUROPE Obesity is relatively common in Europe, especially among women and in Southern and Eastern European countries. A marked trend toward increasing levels of adult overweight and obesity can be found throughout Europe, although prevalence rates differ. Current prevalence data from a report

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TABLE 1.4 Secular Trends of Obesity Worldwide (BMI > 30) Country

Year

Ages

Men

Women

Australia Brazil

1989 1975 1989 1991 1989 1991 1992 1988 1989 1992 1980 1986–1987 1991–1992 1995 1987–1988 1982 1987 1993 1994 1992 1998 1990–1993

20–69 25–64

9.3 3.1 5.9 15 0.29 0.36 1.20 16 13 21 6 7 13 15 0.9 0.9 1.3 1.8 32 10 13.5

11.1 8.2 13.3 15 0.89 0.86 1.64 20 21 27 8 12 15 16.5 — 2.6 2.8 2.6 44 10 11.7

18 12 8 10 11.6 12.0 19.7 16 17.7 41.5 38.8 58.4

28 18 44 11 16.1 14.8 24.7 21 37.0 59.2 59.1 76.8

Canada China

Czech Republic East Germany England

Ghana Japan

Kuwait Quebec Saudi Arabia Urban Rural South Africa Cape Peninsular The Netherlands United States

West Germany Western Samoa (rural) Western Samoa (urban)

1990 1994 1973 1978 1991 1991 1978 1991 1978 1991

18–74 20–45

20–65 25–65 16–64

20+ 20+

18+ 20–64 15+

15–64 20–59 20–74

25–69 25–69 25–69

Source: WHO, Obesity: Preventing and Managing the Global Epidemic, Report of WHO Consultation on Obesity, World Health Organization, Geneva, 1998.

by the International Obesity Task Force (IOTF) suggest that the obesity prevalence in European countries ranges from 10 to 27% for men and up to 38% for women [11]. Finland, Germany, Greece, Cyprus, the Czech Republic, Slovakia, and Malta all have overweight rates that bypass those of the United States. When judged on obesity alone, at least nine European countries have male obesity rates above 20%, including Greece and Cyprus (27%). The prevalence of obesity has increased by about 10 to 40% in most of the European countries in the last decade. In France, obesity rose from 8.0% to 11.3% in women and from 8.4% to 11.4% in men, based on self-reported surveys conducted between 1997 and 2003. In The Netherlands, obesity rose gradually from 6.2% to 9.3% in women and from 4.9% to 8.5% in men from the late 1970s to the mid-1990s. The most

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FIGURE 1.2 Prevalence of adult obesity in Europe (BMI ≥ 30 kg/m2). (From Rigby, N. and James, P., Waiting for a Green Light for Health? Europe at the Crossroads for Diet and Disease, IOTF Position Paper, International Obesity Task Force, London, 2003, http://www.iotf.org/media/euobesity2.pdf.)

dramatic increase was recorded in the United Kingdom, where the obesity rate rose from 13.2% to 22.2% in men and from 16.4% to 23.0% in women in just 10 years, up to 2003. Compare these rates to an obesity rate of 6 to 7% in 1980 [11]. Figure 1.2 shows the prevalence of adult obesity in Europe reported by the IOTF in 2003 [12].

UNITED STATES National survey data from the United States show that the prevalence of overweight and obesity among adults remained relatively constant over the 20-year period from 1960 to 1980. It began to increase around the mid-1980s, and the past 25 years have witnessed a dramatic increase. In 1985, only a few states participated in and provided obesity data to the Behavioral Risk Factor Surveillance System (BRFSS) of the Centers for Disease Control and Prevention (CDC). In 1991, 4 states reported obesity prevalence rates of 15 to 19%, and no states had rates at or above 20%. In 2004, 7 states had obesity prevalence rates of 15 to 19%, 33 states had rates of 20 to 24%, and 9 states had rates higher than 25% (no data for one state). A recent IOTF report [11] shows that obesity stands at 28% in men and 34% in women, although this rate rises to as high as 50% among black women and includes a very signiﬁcant component of morbid obesity. The data shown in Figure 1.3 [13] were collected through the CDC’s BRFSS. Each year, state health departments use standard procedures to collect data through a series of monthly telephone interviews with U.S. adults. Prevalence estimates generated for the maps may vary slightly from those generated for the states by the BRFSS, as slightly different analytic methods are used. It must be noted that overweight and obesity in the United States occur at higher rates among racial or ethnic minority populations, such as African-Americans and Hispanic-Americans, compared with Caucasian Americans. Asian-Americans have a relatively low prevalence for obesity. Women and persons of low socioeconomic status within minority populations appear to be particularly

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9 Obesity Trends* Among U.S. Adults BRFSS, 1991, 1996, 2004

(*BMI ≥30, or about 30 lb overweight for 5ʼ4” person) 1991

1996

2004

No Data

<10%

10% – 14%

15% – 19%

20% – 24%

≥25%

FIGURE 1.3 Trends in U.S. obesity from 1991 to 2004. (From CDC, Overweight and Obesity: Obesity Trends—U.S. Obesity Trends 1985–2004, Centers for Disease Control and Prevention, Washington, D.C., 2005, http://www.cdc.gov/nccdphp/dnpa/obesity/trend/maps/index.htm.)

affected by overweight and obesity. Cultural factors that inﬂuence dietary and exercise behaviors are reported to play a major role in the development of excess weight in minority groups [14]. The prevalence of overweight and obesity increased over the last decade among the various racial and ethnic groups, as shown in Table 1.5 [15]. Mexican-American and black (non-Hispanic) adults in the United States are considerably more overweight and obese than Caucasian (non-Hispanic) adults. The American Indian population also has high prevalence rates of overweight (where overweight is deﬁned as a BMI of ≥27.8 for men and ≥27.3 for women). The highest rates for American Indians are 80% for women and 67% for men in Arizona, according to researchers of

TABLE 1.5 Increase in Overweight and Obesity Prevalence Among U.S. Adults by Racial and Ethnic Group Prevalence (%) Overweight (BMI ≥ 25) Racial/Ethnic Group Black (non-Hispanic) Mexican-American Caucasian (non-Hispanic)

Obesity (BMI ≥ 30)

1988 to 1994

1999 to 2000

1988 to 1994

1999 to 2000

62.5 67.4 52.6

69.6 73.4 62.3

30.2 28.4 21.2

39.9 34.4 28.7

Note: Ages 20 and older for 1999 to 2000 and ages 20 to 74 for 1988 to 1994. Source: Flegal, K.M. et al., JAMA, 288(14), 1723–1727, 2002. With permission.

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the 1995 Strong Heart Study. For women, the black (non-Hispanic) population has the highest prevalence of overweight (78.0%) and obesity (50.8%). For men, the Mexican-American population has the highest prevalence of overweight (74.4%) and obesity (29.4%). The prevalence of overweight, obesity, and severe obesity (BMI of 40 or more) has increased for both men and women in the various racial and ethnic groups in the United States over the last decade [14].

LATIN AMERICA

AND

CARIBBEAN

Evidence of the impact of the nutrition transition is clear in the growing levels of obesity throughout this region. Obesity rates are reported to vary for men from 7% in Peru and Brazil to more than 20% in Paraguay, but among women rates rise to as high as 36% in Paraguay [16]. Obesity is a signiﬁcant problem in the Caribbean and affects women more than men. Abdominal obesity, using WHO waist circumference limits, ranged from 3% of men in St. Lucia to 8% in Barbados, but among women it was found to be as high as 34% in Jamaica, 41% in St. Lucia, and 45% in Barbados [17]. Brazil is the only Latin American country to have a nationally representative survey conducted in the last 10 years. The Brazilian PNSN survey indicated that obesity is prevalent in Brazil and is rising, especially among lower income groups. The problem of dietary deﬁcit appears to be rapidly shifting to one of dietary excess [3].

AFRICA In contrast to most Western countries, the emphasis in Africa has been on undernutrition and food security rather than overweight and obesity, so few data exist with regard to their current prevalence. Regional studies do, however, indicate a growing prevalence of overweight and obesity in certain socioeconomic groups. Wide disparities in levels of obesity can be found. The highest rates occur in South Africa, where mean BMI values for men and women are 22.9 kg/m2 and 27.1 kg/m2, respectively, but levels of central obesity among women have been assessed at 42% [18]. The South African Health Review 2000 reported obesity rates ranging from 8% among black men to 20% among Caucasian men, but among women the rates ranged from 20% for Indian/Asian women to 30.5% for black women. In North Africa, the prevalence of obesity among women is high. Half of all women are overweight (BMI > 25), with rates of 50.9% in Tunisia and 51.3% in Morocco. Obesity rates (BMI > 30) among this population of women are 23% in Tunisia and 18% in Morocco, a threefold increase over 20 years [19]. In parts of Sub-Saharan Africa, obesity often exists alongside undernutrition [20].

JAPAN, CHINA,

AND

WESTERN PACIFIC COUNTRIES

In Japan, obesity in men has doubled since 1982, whereas its rise in women has been restricted to the younger age group (20 to 29 years), for which it has increased 1.8 times since 1976 [3]. Using the obesity cut-off of a BMI > 25 as the standard, adult obesity in Japan would average 20%, rising to 30% in men over 30 years old and in women over 40 years old, thus representing a three- to fourfold increase over the last 40 years [21]. Obesity is increasing in China and is more common in urban areas and among women. Between 1992 and 2002, the prevalence of overweight and obesity increased in all gender and age groups and in all geographic areas. The Chinese obesity standard shows an increase from 20.0% to 29.9%. The annual increase rate was highest in men ages 18 to 44 years and women ages 45 to 59 years (approximately 1.6% and 1.0%, respectively). In general, male subjects, urban residents, and high-income groups had a greater increase [22]. Obesity is not new to the Paciﬁc and has long been regarded by Polynesian and Micronesian societies of this region as a symbol of high social status and prosperity. The prevalence has risen dramatically, however, in the last 20 years. The link between obesity and type 2 diabetes is most manifest in this region, which has some of the highest levels of adult obesity. Obesity prevalence rates of between 60 and 80% can be found among men and women in some islands, including

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Samoa and Nauru. In Tonga, 60% of the adult population is obese, and recently 12% of men and nearly 18% of women were identiﬁed with type 2 diabetes, a doubling of the rate over 25 years. A further 20% were found to be at risk due to elevated blood sugar levels [23].

PREVALENCE OF OBESITY IN CHILDREN AND ADOLESCENTS EUROPE Recent concern has focused on child and adolescent obesity, which is a rapidly growing problem in many countries. The concern is not only that young people who are already overweight and obese are destined to remain so throughout their adult lives with heightened risks to health, but also that youngsters are already developing diseases of old age, such as type 2 diabetes. Surveys show overweight and obesity levels among children in Southern Europe to be higher than their Northern European counterparts as the traditional Mediterranean diet gives way to more processed foods rich in fat, sugar, and salt. The 2005 IOTF European Union platform brieﬁng paper [11] shows that the Mediterranean islands of Malta, Sicily, Gibraltar, and Crete, as well as the countries of Spain, Portugal, and Italy, have reported overweight and obesity levels exceeding 30% among children ages 7 to 11, as illustrated in Figure 1.4 [11]. In addition, England, Ireland, Cyprus, and

Percentage of adolescents ages 7 to 11 obese or overweight Malta Sicily Spain Gibraltar Crete Portugal Italy England Ireland (Republic) Cyprus Sweden Greece France Switzerland Bulgaria Poland Czech Republic Hungary Germany Denmark Netherlands 0

10 obese

20

30

40

oveweight

FIGURE 1.4 Overweight and obesity in adolescents ages 7 to 11. (From Lobstein, T. et al., EU Platform on Diet, Physical Activity and Health, IOTF EU Platform Brieﬁng Paper, in collaboration with EASO, International Obesity Task Force, London, 2005, http://ec.europa.eu/comm/health/ph_determinants/life_style/nutrition/documents/iotf_en.pdf.)

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Percentage of schoolchildren ages 13 to 17 obese or overweight Crete England Italy Cyprus Ireland (Republic) Greece Bulgaria Spain Denmark Hungary Ireland (Northern) Poland Finalnd Czech Republic Germany Netherlands Slovakia 0

10 obese

20

30

40

oveweight

FIGURE 1.5 Overweight and obesity in children ages 13 to 17. (From Lobstein, T. et al., EU Platform on Diet, Physical Activity and Health, IOTF EU Platform Brieﬁng Paper, in collaboration with EASO, International Obesity Task Force, London, 2005, http://ec.europa.eu/comm/health/ph_determinants/life_style/nutrition/documents/iotf_en.pdf.)

Greece reported levels above 20%, while France, Switzerland, Poland, the Czech Republic, Hungary, Germany, Denmark, The Netherlands, and even Bulgaria reported overweight and obesity levels of 10 to 20% among this same age group [11]. For teenagers (ages 13 to 17), seven countries reported overweight and obesity levels above 20%, with Crete peaking at 35%, as shown in Figure 1.5 [11]. The data in both Figure 1.4 and Figure 1.5 are from available surveys, so comparisons require caution as the survey years may differ. The IOTF’s international standard for analyzing childhood overweight and obesity data has been widely adopted [24]. It provides growth curves that relate cut-off points for different age groups to the adult categories for overweight (BMI ≥ 25 kg/m2) and obesity (BMI ≥ 30 kg/m2). The IOTF method allows more realistic comparisons to be made among data from different countries, whereas other assessment standards often relate to centiles, which indicate arbitrary positions above a BMI centile value for overweight and obesity. Childhood overweight and obesity are accelerating rapidly in some countries. The rise has been particularly marked in recent years. IOTF estimates [11] prepared for WHO suggest that one out of ﬁve children in Europe is overweight. An additional 400,000 children each year are becoming overweight, and at least 3 million are obese. Annual increases in prevalence of around 0.2% during the 1970s rose to 0.6% during the 1980s and up to 0.8% in the early 1990s, reaching as high as 2.0% in some cases by the 2000s.

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TABLE 1.6 Increase in Obesity Prevalence (%) Among U.S. Children (Ages 6 to 11) Years

Boys

Girls

1999 to 2000 1988 to 1994 1971 to 1974

16.0 11.6 4.3

14.5 11.0 3.6

Source: Ogden, C.L. et al., JAMA, 288, 1728–1732, 2002. With permission.

TABLE 1.7 Increase in Obesity Prevalence (%) Among U.S. Adolescents (Ages 12 to 19) Years 1999 to 2000 1988 to 1994 1971 to 1974

Males

Females

15.5 11.3 6.1

15.5 9.7 6.2

Source: Ogden, C.L. et al., JAMA, 288, 1728– 1732, 2002. With permission.

UNITED STATES Overweight and obesity for children and adolescents are deﬁned as being at or above the 85th and 95th percentiles, respectively, of the gender-speciﬁc BMI for age growth charts. Approximately 30.3% of children (ages 6 to 11) are overweight, and 15.3% are obese. Among adolescents (ages 12 to 19), 30.4% are overweight and 15.5% are obese. Overweight prevalence is higher in boys (32.7%) than girls (27.8%). In adolescents, overweight prevalence is about the same for females (30.2%) and males (30.5%). The prevalence of obesity quadrupled over 25 years among children, as shown in Table 1.6 [25,26], and more than doubled over 25 years among adolescent males and females, as shown in Table 1.7 [25,26]. With regard to race and ethnicity, African-American, Hispanic-American, and Native American children and adolescents have particularly high obesity prevalence rates. Overweight and obesity prevalence for children and adolescents is presented by racial group in Table 1.8 [25,26]. Among female youth, the highest overweight and obesity prevalence rates are found in black (non-Hispanic) girls (ages 6 to 11; 37.6% and 22.2%, respectively) and black (non-Hispanic) adolescent females (ages 12 to 19; 45.5% and 26.6%, respectively). Among male youth, the highest overweight and obesity prevalence rates are found in MexicanAmerican boys (ages 6 to 11; 43.0% and 27.3%, respectively) and Mexican-American adolescent males (ages 12 to 19; 44.2% and 27.5%, respectively). Overweight prevalence rates for Native American children and adolescents (ages 5 to 17) were reported in a 1999 study to be 39.0% for males and 38.0% for females in the Aberdeen area Indian Health Service. Asian-American adolescents (ages 13 to 18) were reported to have an overweight prevalence of 20.6% in the 1996 National Longitudinal Study of Adolescent Health. Asian-American and Hispanic-American adolescents born in the United States from immigrant parents are more than twice as likely to be overweight as foreign-born adolescents who move to the United States.

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TABLE 1.8 Overweight (85th Percentile) and Obesity (95th Percentile) Prevalence for Children and Adolescents by Racial Group Children (Ages 6 to 11) Prevalence (%) Race Black (non-Hispanic) Mexican American Caucasian (non-Hispanic)

Adolescents (Ages 12 to 19) Prevalence (%)

Overweight

Obesity

Overweight

Obesity

35.9 39.3 26.2

19.5 23.7 11.8

40.4 43.8 26.5

23.6 23.4 12.7

Source: Ogden, C.L. et al., JAMA, 288, 1728–1732, 2002. With permission.

AUSTRALIA

AND

CHINA

In Australia, between 1985 and 1995, the prevalence of obesity among children ages 7 to 15 years increased 4.6-fold among girls and 3.4-fold among boys [27]. Countries undergoing rapid urbanization and economic development are experiencing double challenges: They have to ﬁght both childhood undernutrition and a growing tide of obesity [28–30]. For example, in China, the prevalence of overweight and obesity among children ages 7 to 9 years increased from 1% to 2% in 1985 to 17% among girls and 25% among boys in 2000 [30]. In addition, obesity prevalence varies across socioeconomic strata. In developed countries, children of low socioeconomic status are more affected than their wealthy counterparts [31–33]. The opposite is observed in developing countries, where children in the upper socioeconomic status are more likely than poor children to be obese [34,35].

HEALTH CONSEQUENCES OF OBESITY AND MORBIDITY Obesity has a great number of negative health, social, and economic consequences, as evidenced by the higher mortality and morbidity rates among overweight and obese individuals than lean people. Obese subjects have a 50 to 100% increased risk of premature death from all causes compared to individuals with a healthy weight. The health consequences of obesity range from a number of nonfatal complaints that impact the quality of life, such as respiratory difﬁculties, musculoskeletal disorders, skin problems, and infertility, to complaints that lead to an increased risk of premature death, including NIDDM, gallbladder disease, cardiovascular problems (hypertension, stroke, and coronary heart disease), and certain cancers. Hypertension, diabetes, and raised serum cholesterol are between two and six times more prevalent among heavier women. Severe obesity is associated with a 12-fold increase in mortality in 25 to 35 year olds when compared to lean individuals. The psychological consequences of obesity can range from lowered self-esteem to clinical depression; the rates of anxiety and depression are three to four times higher among obese individuals [3]. In addition to its physical consequences, obesity creates a massive social burden in that negative attitudes toward the obese can lead to discrimination in many areas of their lives, including health care and employment [3].

BENEFITS OF WEIGHT LOSS Modest weight reduction can signiﬁcantly reduce the risk of these serious health conditions. Weight loss in overweight and obese individuals improves physical, metabolic, and endocrinological complications, often dramatically. Weight loss in obese persons can also improve depression, anxiety, psychosocial functioning, mood, and quality of life. In a 12-year study in the United States,

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TABLE 1.9 Benefits of Weight Loss Obesity Comorbidity

Weight Loss

Benefits of Weight Loss

Mortality

10 kg

Diabetes

10 kg

>20% reduction in total mortality >30% reduction in diabetes-related death Reduction in obesity-related cancer death 50% reduction in fasting glucose

Blood pressure

10 kg

Blood lipids

10 kg

Blood clotting indices

—

Physical complication

5–10 kg

Ovarian function

>5%

10-mmHg reduction in systolic pressure 20-mmHg reduction in diastolic pressure 10% reduction in TOT cholesterol 15% reduction in LDL cholesterol 30% reduction in triglycerides 8% increase in HDL cholesterol Reduced red cell aggregability Improved ﬁbrinolytic capacity Improved back and joint pain Improved lung function Decreased breathlessness Reduced frequency of sleep apnea Improved ovarian function

Source: WHO, Obesity: Preventing and Managing the Global Epidemic, Report of WHO Consultation on Obesity, World Health Organization, Geneva, 1998.

intentional weight loss of 0.5 to 9.0 kg in overweight women with existing obesity-related disease led to a 20% reduction in total mortality, a 40 to 50% reduction in mortality from obesity-related cancers, and a 30 to 40% reduction in diabetes-related deaths [3]. Table 1.9 shows the major beneﬁts of weight loss on health status.

ECONOMIC COSTS OF OBESITY Often overshadowed by the health and social consequences of obesity is the economic cost to society and to the individual. The direct costs of diagnosis, treatment, and management of obesity within national healthcare systems have been assessed in only a few countries to date. Although the methodology varied considerably between studies, making it difﬁcult to compare costs across countries and to extrapolate the results from one country to another, these estimates suggest that between 2 and 8% of the total healthcare costs in Western countries can be attributed to obesity [3]. This represents a major fraction of national healthcare budgets comparable with, for example, the total cost of cancer therapy. The potential impact on healthcare resources in the less-developed healthcare systems of developing countries is likely to be even more severe. In addition to the direct costs of obesity are costs in terms of the individual (including the intangible costs of poor health and reduced quality of life) and society (such as the indirect costs of loss of productivity due to sick-leave and premature pensions). Being able to determine the indirect costs of obesity that arise from, for example, the loss of wages and productivity would raise the total cost of obesity even higher. The IOTF is planning to investigate further the direct and indirect costs of obesity worldwide as part of its implementation plan. Data collected by the IOTF in 2002 are summarized in Table 1.10 [36]. Prevention is clearly more cost effective than treatment, both in terms of economic and personal costs.

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TABLE 1.10 Examples of Direct Costs in European Union Compared with the United States Country England (1995) France (1992) Germany (1996) Portugal (1996) The Netherlands (1981–1989) United States

Direct Costs in Euros (millions)

Percent of Health Expenditure (%)

816 (+3270 indirect) 640–1320 10,600 230 454

1.5 1.5 — 3.5 4.0

US$70,000

7.0

Note: Data not adjusted for inﬂation. Source: IOTF and EASO, Obesity in Europe: The Case for Action, International Obesity Task Force and European Association for the Study of Obesity, London, 2002 (http://www.iotf.org/media/euobesity.pdf).

THE NEED FOR ACTION Obesity is a serious medical condition that requires urgent attention throughout the world. Despite its high prevalence and our improved understanding of how the disease develops, only limited effective obesity management systems are in place in national healthcare services around the world. This is in contrast with other chronic diseases, such as diabetes and coronary heart disease, where integrated care is frequently provided. It is clear, therefore, that the rational development of coordinated healthcare services for the management of overweight and obese patients is needed in most countries. Primary healthcare services should play the dominant role, although hospital and specialist services are also required for dealing with more severe cases and the associated major life-threatening complications. There is an urgent need for expanded training of all healthcare workers to improve their levels of knowledge and skills with regard to obesity management strategies. The IOTF was established in May 1996 to tackle the emerging global epidemic of obesity. The IOTF is a part of the International Association for the Study of Obesity (IASO), an organization that represents 43 national obesity associations across the globe. The IOTF is composed of world experts in the ﬁeld of obesity and related diseases from around world, including China, Japan, Chile, Australia, Brazil, the United States, Canada, and Europe. The IOTF collaborates closely with the WHO and is engaged with other international health organizations and national governments to raise awareness and help develop solutions to the global epidemic of obesity. The IOTF aims to achieve taking action on the prevention and management of overweight and obesity and endeavors to create an environment that encourages and supports the development of appropriate public and health polices and programs for the prevention and management of obesity. The IOTF initiative on the prevention and management of obesity has four main goals: 1. Increase the awareness among governments, healthcare professionals, and the community that obesity is a serious medical condition and a major health problem with substantial economic costs. 2. Provide evidence and guidance for the development of better prevention and management strategies. 3. Secure the commitment of policymakers to take action. 4. Foster development of national, regional, and international structures that will enable and support the implementation of taking action on the problems of overweight and obesity. Management strategies are shown in Figure 1.6.

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A systematic approach to management based on BMI and other risk factors Assess overall health risk from BMI and other risk factors (e.g., waist circumference) BMI

OVERALL HEALTH RISK Additional risk factors? NO

BMI 18.5– 24.9

MANAGEMENT STRATEGIES

YES

Healthy diet and advice on preventing weight gain.

Average

Increased

Elevated waist circumference: institute weight management. Family history of obesity: prevent weight gain >3 kg. Smoking: stop with dietary advice. Lipids high: dietary advice. Hypertensive: diet, exercise, weight maintenance. Glucose intolerance: exercise, diet, weight maintenance. Weight maintenance, healthy diet, exercise.

BMI Increased 25–29.9 Moderate

BMI Moderate 30–34.9

Goal of 5–10% weight loss without risk appropriate. Severe

BMI 35–39.9

Severe

BMI ≥40

Very severe

Goal for diet, exercise, behavior: primarily geared to risk management. Weight loss needed if risk not reduced substantially within 3 months, then aim for 5–10 kg over 24 weeks by mild energy deficit. If not achieving this weight reduction at 24 weeks and risks persist, test usefulness of drug to reduce risk by weight management.

Consider very low calorie diet and drug therapy if diet, exercise, and lifestyle program is unsuccessful after 12 weeks in reducing all risk factors. Useful therapy including drugs to achieve >10% weight loss.

Very severe

Refer to specialist for separate management and consideration of surgery if conventional treatment fails. Aim for 20–30% weight reduction.

FIGURE 1.6 A systematic approach to management based on BMI and other risk factors. (From WHO, Obesity: Preventing and Managing the Global Epidemic, Report of WHO Consultation on Obesity, World Health Organization, Geneva, 1998.)

In 1997, the WHO, together with the IOTF, held an expert consultation on obesity to review the extent of the obesity problem and examine the need to develop public health policies and programs to tackle the global problem of obesity. The consultation resulted in the publication of the interim report Obesity: Preventing and Managing the Global Epidemic [3] and the subsequent WHO Technical Report Series 894. The IOTF has identiﬁed a number of areas where our understanding of overweight and obesity must be improved. Speciﬁc working groups have examined the following issues: childhood obesity, economic costs of obesity, management of obesity, public health approaches to the prevention of obesity, and, ﬁnally, the training of health professionals.

REFERENCES [1]

WHO, Obesity: Preventing and Managing the Global Epidemic, Report of WHO Consultation on Obesity, Technical Report Series No. 894, World Health Organization, Geneva, Switzerland, 2000, p. 256. [2] Must, A. et al., The disease burden associated with overweight and obesity, JAMA, 282, 1523–1529, 1999. [3] WHO, Obesity: Preventing and Managing the Global Epidemic, Report of WHO Consultation on Obesity, World Health Organization, Geneva, 1998. [4] FAO, The Developing World’s New Burden: Obesity, Food and Agriculture Organization, United Nations, Geneva, Switzerland, 2002, http://www.fao.org/FOCUS/E/obesity/obes2.htm.

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[9]

[10] [11]

[12]

[13]

[14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27]

[28] [29]

Allison, D.B. et al., Annual deaths attributable to obesity in the United States, JAMA, 282, 1530–1538, 1999. Caterson, J.D. et al., AHA Conf. Proc., Obesity: a worldwide epidemic related to heart disease and stroke; Group III: worldwide comorbidities of obesity, Circulation, 110, e476–e483, 2004. Manson, J.E. et al., Body weight and mortality among women, N. Engl. J. Med., 333, 677–685, 1995. Shaper, A.G., Wannamethee, S.G., and Walker, M., Body weight: implications for the prevention of coronary heart disease, stroke, and diabetes mellitus in a cohort study of middle-aged men, Br. Med. J., 314, 1311–1317, 1997. Rosengren, A., Wedel, J., and Wilhelmsen, L., Body weight and weight gain during adult life in men in relationship to coronary heart disease and mortality: a prospective population study, Eur. Heart J., 20, 269–277, 1999. Calle, E.E. et al., Body mass index and mortality in a prospective cohort of U.S. adults, N. Engl. J. Med., 341, 1097–1105, 1999. Lobstein, T., Rigby, N., and Leach, R., EU Platform on Diet, Physical Activity and Health, IOTF EU Platform Brieﬁng Paper, in collaboration with the European Association for the Study of Obesity, International Obesity Task Force, London, 2005, http://ec.europa.eu/comm/health/ph_determinants/ life_style/nutrition/documents/iotf_en.pdf. Rigby, N. and James, P., Waiting for a Green Light for Health? Europe at the Crossroads for Diet and Disease, IOTF Position Paper, International Obesity Task Force, London, 2003, http://www.iotf. org/media/euobesity2.pdf. CDC, Overweight and Obesity: Obesity Trends—U.S. Obesity Trends 1985–2004, Centers for Disease Control and Prevention, Washington, D.C., 2005, http://www.cdc.gov/nccdphp/dnpa/obesity/trend/ maps/index.htm. AOA, Obesity in Minority Populations, AOA Fact Sheet, American Obesity Association, Washington, D.C., 2002, http://www.obesity.org/subs/fastfacts/Obesity_Minority_Pop.shtml. Flegal, K.M. et al., Prevalence and trends in obesity among U.S. adults, 1999–2000, JAMA, 288(14), 1723–1727, 2002. Filozof, C. et al., Obesity prevalence and trends in Latin-American countries, Obes. Rev., 2, 99–106, 2001. Okosun, I.S. et al., Abdominal adiposity in six populations of West African descent: prevalence and population attributable fraction of hypertension, Obes. Res., 5, 453–462, 1999. Puoane, T. et al., Obesity in South Africa: the South African demographic and health survey, Obes. Res., 110, 1038–1048, 2002. Mokhtar, N. et al., Diet culture and obesity in northern Africa, J. Nutr., 131(3), 887S–892S, 2001. Maire, B. et al., Urbanization and nutritional transition in Sub-Saharan Africa: exempliﬁed by Congo and Senegal [in French], Rev. Epidemiol. Sante Publique, 4, 252–258, 1992. Kanazawa, M. et al., Criteria and classiﬁcation of obesity in Japan and Asia-Oceania, World Rev. Nutr. Diet., 94, 1–12, 2005. Wang, Y. et al., Is China facing an obesity epidemic and the consequences? The trends in obesity and chronic disease in China, Int. J. Obes. (Lond.), May 2, 2006 (Epub ahead of print). Colagiuri, S. et al., The prevalence of diabetes in the kingdom of Tonga, Diabetes Care, 8, 1378–1383, 2002. IOTF Childhood Obesity Working Group; Cole, T.J. et al., Establishing a standard deﬁnition for child overweight and obesity worldwide: international survey, Br. Med. J., 320, 1240–1243, 2000. Ogden, C.L. et al., Prevalence and trends in overweight among U.S. children and adolescents, 1999–2000, JAMA, 288(14), 1728–1732, 2002. AOA, Obesity in Youth, AOA Fact Sheet, American Obesity Association, Washington, D.C., 2002, http://www.obesity.org/subs/fastfacats/obesity_youth.shtml. Magarey, A.M., Daniels, L.A., and Boulton, T.J., Prevalence of overweight and obesity in Australian children and adolescents: reassessment of 1985 and 1995 data against new standard international deﬁnitions, Med. J. Aust., 174(11), 561–564, 2001. de Onis, M. and Blossner, M., Prevalence and trends of overweight among preschool children in developing countries, Am. J. Clin. Nutr., 72(4), 1032–1039, 2000. Ebbeling, C.B., Pawlak, D.B., and Ludwig, D.S., Childhood obesity: public-health crisis, common sense cure, Lancet, 360(9331), 473–482, 2002.

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[30] Wang, L. et al., Preventing chronic diseases in China, Lancet, 366, 1821–1824, 2005. [31] Stamatakis, E. et al., Overweight and obesity trends from 1974 to 2003 in English children: what is the role of socioeconomic factors?, Arch. Dis. Child., 90(10), 999–1004, 2005. [32] Strauss, R.S. and Pollack, H.A., Epidemic increase in childhood overweight, 1986–1998, JAMA, 286(22), 2845–2848, 2001. [33] Strauss, R.S., Childhood obesity, Pediatr. Clin. North Am., 49(1), 175–201, 2002. [34] Salmon, J. et al., Trends in children’s physical activity and weight status in high and low socioeconomic status areas of Melbourne, Victoria, 1985–2001, Aust. N.Z. J. Public Health, 29(4), 337–342, 2005. [35] Chhatwal, J., Verma, M., and Riar, S.K., Obesity among pre-adolescents and adolescents of a developing country (India), Asia Pac. J. Clin. Nutr., 13(3), 231–235, 2004. [36] IOTF/EASO, Obesity in Europe: The Case for Action, International Obesity Task Force and European Association for the Study of Obesity, London, 2002, http://www.iotf.org/media/euobesity.pdf.

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of Obesity: 2 Epidemiology A Global Burden for the New Millennium Gopal C. Pain CONTENTS Introduction ......................................................................................................................................21 Body Mass Index .............................................................................................................................21 Signiﬁcance of Waist Circumference and Waist-to-Hip Ratio........................................................22 Prevalence of Obesity ......................................................................................................................22 Childhood Obesity ...........................................................................................................................25 Obesity and Morbidity .....................................................................................................................25 Obesity and Mortality ......................................................................................................................25 Age and Sex .....................................................................................................................................27 Roles of Physical Inactivity and Eating Habits...............................................................................27 Conclusion........................................................................................................................................27 References ........................................................................................................................................28

INTRODUCTION Of the 1 billion overweight adults in the world, 300 million are clinically obese. This is an alarming situation, even in light of the limited availability of population-based data. Even in Asian and African countries experiencing acute starvation and underweight, obesity is still a problem. Obesity and overweight are major risk factors for chronic diseases, including type 2 diabetes, coronary heart disease, hypertension, stroke, and certain forms of cancer. An attempt has been made to review the epidemiology of obesity. Obesity in general occurs from excess fat deposition and insufﬁcient energy expenditure. Body weight is usually measurable, and this approach is the one primarily used in clinical practice. Ideal or desirable body weights have been developed by the Metropolitan Insurance Company using weights associated with the lowest mortality so as to achieve maximum life span. The tables that were prepared indicated that the average weight for height at age 30 was ideal in terms of mortality [1]. In clinical practice, overweight is described as weighing 10% more than the desirable weight.

BODY MASS INDEX Though not a direct measure of obesity, the widely accepted means of assessing obesity is the body mass index (BMI). A very good correlation has been found between BMI and the percentage of body fat in a population. Table 2.1 provides the World Health Organization (WHO) classiﬁcation of adults according to the BMI: BMI =

kg Body weight in kg = m2 (Height in m)2 21

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TABLE 2.1 WHO Classification of Adults According to BMI Classification Underweight Normal range Overweight Preobese Obese class I Obese class II Obese class III

BMI

Risk of Comorbidities

<18.50 18.50–24.99

Low (but risk of other clinical problems increased) Average

25.00–29.99 30.00–34.99 35.00–39.99 >40.00

Increased Moderate Severe Very severe

The BMI fails to distinguish general body obesity from abdominal obesity. The latter is more serious and is related to osteoarthritis; breast, colon, and prostate cancers; decreased glucose tolerance; and elevated low-density lipoprotein (LDL) cholesterol and triglycerides (together with smoking and high blood pressure). In an analysis carried out by the World Health Report 2002, approximately 58% of diabetes, 21% of ischemic heart disease, and 4 to 42% of certain cancers globally were attributable to BMIs above 21 kg/m2 [2]. The BMI does not distinguish between weight associated with muscles and weight associated with fat; therefore, the BMI may not correspond to the same degree of fatness across a population.

SIGNIFICANCE OF WAIST CIRCUMFERENCE AND WAIST-TO-HIP RATIO A waist-to-hip ratio greater than 1.0 in men and 0.85 in women indicates abdominal fat accumulation [3], but waist circumference alone provides a good indication of abdominal fat distribution that is associated with ill health [4,5]. Table 2.2 shows the correlations among sex-speciﬁc waist circumference, obesity, and the risk of metabolic dysfunctions and complications. A strong association exists between upper body (android) obesity and the development of type 2 diabetes mellitus [6]. Accumulation of abdominal fat is an important risk factor indicator, and in this respect waist circumference has an advantage over the BMI [7]. Table 2.3 highlights the relationship between waist measurement and the odds ratio for risk factors.

PREVALENCE OF OBESITY The prevalence of obesity is increasing worldwide at an alarming rate and is now a problem for both developed and developing countries. Even India, where a third of the population falls below the poverty line, has experienced steady growth in its relatively afﬂuent urban middle class population to 200 million, of which 40 to 50 million are overweight [8]. Starvation and malnutrition

TABLE 2.2 Sex-Specific Waist Circumference and Risk of Metabolic Complications Associated with Obesity Waist Circumference (cm) Risk of Metabolic Complications Increased Substantially increased

Men

Women

>94 (≈37 in.) >102 (≈40 in.)

>80 (≈32 in.) >88 (≈35 in.)

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TABLE 2.3 Relationship Between Waist Measurement and Odds Ratio for Risk Factors Men

Waist measurement (cm) Odds ratio for risk factors

Women

At Risk

High Risk

At Risk

High Risk

94–102 2.2 (1.8–2.8)

>102 4.6 (3.5–6.0)

80–88 0.6 (1.3–2.1)

>88 2.6 (2.0–3.2)

Risk factors: >6.5 mmol/L total cholesterol; <0.9 mmol/L HDL cholesterol; >160 systolic or >95 mmHg diastolic blood pressure.

TABLE 2.4 Obesity Prevalence in Some African Countries and Populations

Country or Population Mauritius Cape Peninsula, South Africa (blacks) United Republic of Tanzania

Prevalence of Obesity (%)

Year

Age Group

Men

1992 1990 1986–1989

25–74 15–64 35–64

5 8 0.6

Women

Ref.

15 44 3.6

Hodge et al. [11] Steyn et al. [10] Berrios et al. [12]

TABLE 2.5 Obesity Prevalence in Selected European Countries Prevalence of Obesity (%)

Country

Year

Age Group

Men

Women

Ref.

England

1995

16–64

15

16.5

1991–1993 1992 1995

20–75 25–65 20–29

14 20.5 8.4

11 26.8 8.3

Prescott-Clarke and Primatesta [13] Seidell and Rissanen [14] Hoffmeister et al. [15] Seidell [16]

Finland Former Federal Republic of Germany Netherlands

coexist with obesity in many developing countries. In spite of the limited availability of populationbased data and differing deﬁnitions of obesity and age standardization, WHO has provided a clear global picture of the increased prevalence of obesity [9]. Table 2.4, Table 2.5, Table 2.6, Table 2.7, Table 2.8, and Table 2.9 provide data on the prevalence of obesity (BMI ≥ 30) in various countries as suggested by WHO. Table 2.8 provides insight into the prevalence of overweight (BMI ≥ 25), obese, and severely obese (BMI ≥ 40) persons in the United States, and Table 2.9 shows the overall global obesity prevalence in WHO regions. The most comprehensive data on obesity in Europe are those of the WHO MONICA study [17]. It has been observed that over the last 10 years the prevalence of obesity has increased by 10 to 40% in European countries. According to the Centers for Disease Control and Prevention (CDC), over half of the U.S. population is overweight (approximately 127 million), nearly one third is obese (60 million), and about 15 million are severely obese. Emerging evidence suggests that overweight and obesity have reached epidemic proportions globally.

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TABLE 2.6 Obesity Prevalence in Selected Mediterranean Countries

Year

Age Group

Men

Women

Ref.

1994 1990–1993 1992

18+ 15+ 17+

32 16 16

41 24 38

Al-Isa [18] Al-Nuaim et al. [19] Musaiger [20]

Country Kuwait Saudi Arabia United Arab Emirates

Prevalence of Obesity (%)

TABLE 2.7 Obesity Prevalence in Selected Western Pacific Countries Prevalence of Obesity (%)

Country

Year

Age Group

Men

Women

Ref.

Australia China Japan New Zealand

1989 1992 1993 1989

25–64 20–45 20+ 18–64

11.5 1.20 1.7 10

13.2 1.64 2.7 13

Bennett and Magnus [21] WHO [pers. comm.] WHO [pers. comm.] Ball et al. [22]

TABLE 2.8 Overweight, Obese, and Severely Obese Prevalence in the United States Prevalence

Men Women Adolescents (ages 12–19) Children (ages 6–11) U.S. population

Overweight (BMI ≥ 25 kg/m2)

Obese (BMI ≥ 30 kg/m2)

Severely Obese (BMI ≥ 40 kg/m2)

67.0% 62.0% 30.4% 30.3% 127 million

27.7% 34.0% 15.5% 15.3% 60 million

3.1% 6.3% Not determined Not determined 15 million

Source: WHO, Controlling the Global Obesity Epidemic, World Health Organization, Geneva, 2003, www.who.int/nutrition/topics/obesity/en/.

TABLE 2.9 Obesity Prevalence in WHO Global Regions Obese Adults (BMI ≥ 30 kg/m2) WHO Region The Americas Europe Western Pacific Eastern Mediterranean Global population

Prevalence (%)

Number of People (Millions)

20.9 16.7 3.8 10.0 8.9

109.0 106.5 42.5 24.9 315.0

Source: Worldwide Obesity: Trends Global Obesity Trends, Globesity the Growing Epidemic of Chronic Overweight, 2006, http://www.annecollins.com/obesity/worldwide-obesity.htm.

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Papua New Guinea Bangladesh Philippines Burkina Faso Singapore Togo Tunisia Rwanda India Indonesia Belize Jordan Tahiti Nicaragua Brazil Saint Lucia United Kingdom Yogoslavia Antigua Zambia Venezuela Italy Panama Peru Barbados Honduras Lesotho Bolivia Trinidad & Tobago Iran (Islamic Republic of) Mauritius Canada Jamaica Chile 0

2

4 6 8 Percentage of obese preschool children

10

FIGURE 2.1 Prevalence of obese preschool children (0 to 59 months) in selected countries and territories.

CHILDHOOD OBESITY So far, no agreement has been reached with regard to the classiﬁcation of overweight and obesity in children and about a globally applicable reference population, yet an attempt has been made by WHO to compile data on the global prevalence of obesity in childhood [25]. Children were deﬁned as obese when they exceeded the National Center for Health Statistics (NCHS) median weight for height plus two standard deviations or Z-scores. According to Martorell [26], the prevalence of obesity in the reference population was 2.3%. With the exception of Pakistan, where 2.6% of children were obese, obesity was rare in South Asia (including India) and in Thailand. Figure 2.1 clearly illustrates that the prevalence of obesity is high in most of the developing and developed parts of the world.

OBESITY AND MORBIDITY According to Jung [27], obesity results in a multiplicity of problems, and a weight loss of 10 kg can have beneﬁcial health effects (see Table 2.10 and Table 2.11).

OBESITY AND MORTALITY A close relationship exists between obesity and mortality. In the Nurses’ Health Study, Manson et al. [28] demonstrated an almost linear and continuous relationship between BMI and premature

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TABLE 2.10 Morbidity and Obesity Aspect Cardiovascular system

Respiratory system

Gastrointestinal system

Metabolic system

Neurology

Effect of Obesity Hypertension Coronary heart disease Cerebrovascular disease Varicose veins Deep venous thrombosis Hypertension

Aspect

Effect of Obesity

Breast

Breast cancer Male gynecomastia

Uterus

Endometrial cancer Cervical cancer

Urological

Breathlessness Sleep apnea Hypoventilation syndrome

Prostate cancer Stress incontinence

Skin

Hiatus hernia Gallstones and cholelithiasis Fatty liver and cirrhosis Hemorrhoids Hernia Cancer (colorectal)

Sweat rashes Fungal infections Lymphoedema Cellulitis Acanthosis nigracans

Orthopedic

Osteoarthritis Gout

Endocrine system

Reduced growth hormone and IGF1 Reduced prolactin response Hyperdynamic ACTH response to CRH Increased urinary free cortisol Altered sex hormones

Pregnancy

Obstetric complications Cesarean operation Large babies Neural tube defects

Hyperlipidemia Insulin resistance Diabetes mellitus Polycystic ovarian syndrome Hyperandrogenization Menstrual irregularities Nerve entrapment

TABLE 2.11 Benefits of a 10-kg Weight Loss Mortality

20–25% reduction in total mortality 30–40% reduction in diabetes-related deaths 40–50% reduction in obesity-related cancer deaths

Blood pressure

10-mmHg reduction in systolic pressure 20-mmHg reduction in diastolic pressure

Angina

Symptoms reduced by 91% 33% increase in exercise tolerance

Lipids

10% reduction in total cholesterol 15% reduction in LDL cholesterol 30% reduction in triglycerides 8% increase in HDL cholesterol

Diabetes

>50% reduction in risk of developing diabetes 30–50% reduction in fasting blood glucose 15% reduction in HbA1c

mortality (Figure 2.2). After removing confounding variables such as smoking and subclinical disease, it was found that the relative risk of premature mortality gradually increases with increasing BMI. After the analysis of numerous data, the American Institute of Nutrition concluded that the lowest mortality risk is associated with a BMI between 18 and 25 kg/m2 [29].

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2.5 All women

Women who never smoked

2.0

Risk

Women who never smoked and recently had stable weight 1.5

1.0

0.5

<19.0

19.0-21.9

22.0-24.9

25-26.9 27-28.9 Body mass index (BMI)

<29-31.9

≥ 32.0

FIGURE 2.2 Relationship between BMI and relative risk of premature mortality. (Adapted from Gill, T.P., Br. Med. Bull., 53, 359–388, 1997. With permission.)

AGE AND SEX No age or sex is exempt from obesity. One third of obese infants grow up to be obese adults [30]. Women generally have a higher rate of obesity than men, although men have higher rates of overweight. The BMI increases with successive pregnancies, but in developing countries, where repeated pregnancies occur, weight loss instead of weight gain is found [9].

ROLES OF PHYSICAL INACTIVITY AND EATING HABITS Sedentary lifestyles in conjunction with physical inactivity lead to obesity [31]; for example, afﬂuence allows watching television for many hours a day and a sedentary life that lead to obesity. A diet high in sweets, reﬁned foods, and fats causes obesity, as does a diet of greater energy intake than energy expenditure. It has been found that a child whose energy requirement is 2000 kcal/day and who consumes an extra 100 kcal/day will gain about 5 kg a year [32]. Obesity is a consequence of excess energy intake over a prolonged period. No single factor leading to obesity can be identiﬁed. Multifactorial causes are responsible: genetic, environmental, psychological, and managerial. A well-disciplined life with regular physical exercise and a balanced diet lowers the chances of gaining excess weight. Health education in this respect is an important factor.

CONCLUSION Global obesity is a major challenge to health professionals and society. The epidemiological data are alarming, and the obesity epidemic must be properly monitored and controlled with immediate effect. Physical inactivity, sedentary lifestyles, overindulgence, and genetic predisposition are some of the factors responsible for obesity; thus, it is a global task to educate people about the importance and signiﬁcance of caloric restriction, healthy lifestyles, and proper nutrition in conjunction with increased physical activity and routine exercise to combat obesity.

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[12]

[13] [14] [15] [16] [17] [18] [19]

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Jung, R.T., Obesity as a disease, Br. Med. Bull., 53, 307–321, 1997. Manson, J.E., Stampfer, M.J., Hennekens, C.H., and Willett, W.C., Body weight and longevity: a reassessment, JAMA, 257, 353, 1987. AIN, Report of the American Institute of Nutrition (AIN) steering committee on healthy weight, J. Nutr., 124, 2240, 1994. Hager, A., Adipose tissue cellularity in childhood in relation to the development of obesity, Br. Med. Bull., 37, 287, 1981. WHO, Diet, Nutrition, and the Prevention of Chronic Diseases, Report of a Joint WHO/FAO Expert Consultation, WHO Technical Report Series No. 916, World Health Organization, Geneva, 2003. Children in the Tropics, International Children’s Centre, Paris, 1984.

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Part II Pathophysiology of Obesity

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Estrogens, 3 Environmental Endocrine Disruption, and Obesity Frederick S. vom Saal, James R. Kirkpatrick, and Benjamin L. Coe CONTENTS Mechanisms Mediating Responses to Estrogenic Endocrine Disrupting Chemicals .....................33 Estrogenic Chemicals: Organizational Effects During Development and Activational Effects in Adulthood....................................................................34 Estrogen and Obesity .......................................................................................................................35 Fetal Basis of Adult Disease ....................................................................................................35 Estrogen and the Differentiation and Regulation of Adipose Tissue ......................................36 The Estrogenic Chemical Bisphenol A and Obesity.......................................................................37 The Endocrine Disruptor Tributyltin and Obesity ..........................................................................37 Conclusions ......................................................................................................................................38 Acknowledgment..............................................................................................................................38 References ........................................................................................................................................38

MECHANISMS MEDIATING RESPONSES TO ESTROGENIC ENDOCRINE DISRUPTING CHEMICALS Since the early 1990s [1], evidence has accumulated that chemicals used in a wide range of household products, such as building materials, plastics, cleaning ﬂuids, cosmetics, and pesticides have the capacity to disrupt the chemical messengers by which cells communicate [2–4]. These chemicals are referred to as endocrine disruptors, even though their effects may include disruption of signaling molecules not labeled as hormones, such as neurotransmitters. Of the different types of environmental chemicals that disrupt endocrine function, the most well known are those categorized as environmental estrogens. These chemicals have the capacity to bind to classical nuclear estrogen receptors (both the alpha and beta forms) associated with speciﬁc genes. These estrogenic chemicals thus act as ligands that initiate or inhibit transcription of estrogen-responsive genes; however, it is now clear that, although generally classiﬁed as estrogenic, the speciﬁc responses that each chemical causes may differ from those caused by the most potent endogenous estrogen, estradiol. In addition, speciﬁc responses caused by estrogenic chemicals and estradiol may vary among tissues in the same species. Some estrogenic endocrine-disrupting chemicals are thus categorized as selective estrogen receptor modulators (SERMs) [5]. Recent research has also demonstrated that estradiol and estrogenic chemicals can cause effects by activating enzymes that mediate responses initiated by receptors associated with the cell membrane [6–9]. These responses are very rapid compared to those initiated by binding to nuclear receptors, and they also appear to occur in response to extremely low doses within the range of human exposure [5]. 33

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ESTROGENIC CHEMICALS: ORGANIZATIONAL EFFECTS DURING DEVELOPMENT AND ACTIVATIONAL EFFECTS IN ADULTHOOD Estrogens and other sex hormones regulate the functioning of tissues in adults. These effects occur when the hormone is present and do not occur after the hormone is withdrawn; they are termed activational effects. However, when exposure occurs during the time in development when cells are differentiating (referred to as critical periods), estrogens and other hormones cause permanent changes referred to as organizational effects. Extensive research is currently directed at elucidating the mechanisms by which genes are programmed during cell differentiation under the inﬂuence of hormones such as estradiol, as well as endocrine-disrupting chemicals. The mechanisms that determine which genes in a cell are able to be transcribed, as well as the level at which transcription occurs, involve epigenetic modiﬁcations of DNA as well as the associated histone proteins. A schematic depicting the imprinting mechanisms that determine whether speciﬁc genes are silenced or activated is shown in Figure 3.1 [10]. Data indicate that it is via these epigenetic changes that estrogenic endocrine-disrupting chemicals program gene activity during critical periods in development, with long-term consequences that impact the health status of the individual throughout the remainder of life [11].

FIGURE 3.1 Schematic diagram showing the “epigenetic” chemical modiﬁcations of histone proteins by the removal of acetyl groups and cytosine bases by the addition of methyl groups, resulting in repression of transcription. Epigenetic changes that occur early in development are transmitted to daughter cells during mitosis and thus can permanently alter gene transcription in tissues. (Adapted from Weinhold, B., Environ. Health Perspect., 114(3), A160, 2006.)

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ESTROGEN AND OBESITY The typical view of estrogen is that it is associated with a reduction in food intake and body weight in adults and that the loss of ovarian estrogen secretion associated with menopause in women results in weight gain. Evidence is accumulating, however, that during critical periods in development estrogenic chemicals can have unexpected effects on the differentiation of adipocytes as well as postnatal growth [12]. Speciﬁcally, the hypothesis that the programming of obesity is related to exposure to environmental estrogens during critical periods in organogenesis [13,14] may seem counterintuitive, as considerable experimental evidence suggests that in adult mice estradiol acts via estrogen receptor alpha (ERα) to have an inhibitory effect on adipocyte number and lipogenesis, and the removal of estrogen by ovariectomy or via a genetic mutation also causes impaired glucose tolerance and insulin resistance in addition to increased fat mass [15–18]. Estrogen has central effects on food consumption and energy expenditure that also contribute to its overall inhibitory effects on adipose deposition in adults; however, a maxim in developmental biology and pediatric medicine is that it is inappropriate to use effects in adults to predict effects during development.

FETAL BASIS

OF

ADULT DISEASE

The hypothesis that obesity is related to events that occur during early development is known as the fetal basis of adult disease hypothesis [19]. The incidence of metabolic syndrome, which includes obesity, type 2 diabetes, heart disease, and hypertension, has increased dramatically over the last few decades in the United States and in many other regions of the world [20]. The fetal basis of adult disease hypothesis proposes that metabolic syndrome is related to factors that inﬂuence growth in utero [21]. As indicated earlier, increasing experimental and epidemiological evidence suggests that fetal programming of genetic systems is a contributing factor [22]. This has led to the hypothesis that epigenetic changes associated with the increased use of manmade chemicals, such as chemicals used in the manufacture of plastic products, may interact with other factors that inﬂuence fetal and postnatal growth to contribute to the current obesity epidemic [23,24]. The hypothesis that epigenetic mechanisms are involved in the etiology of obesity relates to the general issue of developmental plasticity. The hypothesis is that individuals are adapted to function within a restricted range of potential responses throughout life as a consequence of their underlying genetic potential being acted on by environmental factors during the time in tissue differentiation when genetic programming occurs [25]. Thus, a fetus that develops in a uterine environment with reduced placental blood ﬂow and nutrient transport is thought to develop a thrifty phenotype, such that the mechanisms mediating weight homeostasis are permanently programmed for a lifetime of undernourishment. When exposed to modern fast foods and their excessive calories, these individuals are unable to regulate their body weight, resulting in weight gain. The question being posed here is whether, during fetal and neonatal life, environmental chemicals are playing a role in programming a phenotype that is prone to obesity. Restriction of placental blood ﬂow is one cause of reduced fetal growth, and light-at-term human babies are at higher risk for subsequent obesity, type 2 diabetes, and hypertension [26]. Convincing evidence supports the hypothesis that, during fetal life, environmental factors that inﬂuence fetal growth interact with factors that increase the rate of postnatal growth, resulting in obesity and type 2 diabetes. The interaction between prenatal and postnatal factors is supported by ﬁndings that the best predictor of insulin resistance in 8-year-old children is the combination of being light at birth associated with a high postnatal growth velocity. The phenomenon of restricted intrauterine growth followed by accelerated postnatal growth is referred to as centile crossing [20]. Recent evidence suggests that the age at which the rapid body weight increase occurs during postnatal life is a critical factor in the eventual health status of a person [19].

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ESTROGEN AND THE DIFFERENTIATION AND REGULATION OF ADIPOSE TISSUE Hormones are major regulators of adipose tissue and are critical for adipocyte development and function. An extensive array of hormones and growth factors modulate adipocyte development and activity, including growth hormone, thyroid hormone, catecholamines, glucagon, insulin and insulin-like growth factors, glucocorticoids, and, relevant to this proposal, estradiol and thus chemicals with estrogenic activity [14]. In humans, differentiation of preadipocytes into adipocytes begins prior to birth, but the majority of preadipocytes differentiate postnatally. Adipocyte number increases markedly between birth and 18 months of age, then continues to increase more slowly throughout early childhood [27]. The developmental sequence by which the adipocyte phenotype arises from undifferentiated connective tissue cells has been described in detail [28]. The adipocyte lineage arises from undifferentiated mesenchymal cells, which can also give rise to other connective tissue lineages. Mesenchymal cells become committed to an adipogenic lineage and give rise to preadipocytes, which can remain undifferentiated and quiescent, proliferate but remain undifferentiated, or differentiate as a post-mitotic adipocyte. While preadipocytes in mice do not begin to differentiate into adipocytes prior to birth [29], mouse preadipocytes develop from mesenchymal cells and proliferate during fetal life, and, as discussed further below, they express estrogen receptors [12]. Mouse preadipocytes continue to proliferate rapidly at birth, but then the majority enters the differentiation pathway neonatally to give rise to post-mitotic adipocytes. By approximately 3 weeks of age, the basic adult number of adipocytes has been established in most mouse strains [30]. A preadipocyte population still remains in adults and can give rise to new adipocytes at any time during life in both mice and humans [31]. The genes critical for inducing adipocyte differentiation, as well as their temporal sequence of expression during adipocyte differentiation, are being actively investigated [32]. For example, it is known that CCAAT/enhancer-binding proteins (C/EBPs), such as C/EBPα, along with peroxisome proliferator-activated receptor γ (PPARγ) play critical roles in adipocyte differentiation from the preadipocyte to the fully functional, post-mitotic adipocyte [33], and that the transcription factor CREB plays an important role in regulating these genes [34]. In humans, C/EBPα mRNA levels in adipocyte tissue are elevated in those with an obese relative to lean phenotype [35]. PPARγ is expressed in adult adipocytes. PPARγ and C/EBPα are regulators of lipogenesis in addition to regulating adipocyte differentiation [33]. PPARγ activators result in increased fat deposition, and an increase in PPARγ should be associated with an increase in adipocyte number [36]. A critical question to consider when postulating potential effects on adipocyte number and subsequent function generated during development is whether such effects would be permanent or transitory and reversible once the stimulus inducing the change in adipocyte is removed. Although obesity typically involves adipocyte hypertrophy, adipocyte hyperplasia is also seen in certain types of human obesity, and similar results have been obtained in rodents with various types of obesity resulting from dietary modiﬁcation or gene knockouts [28,30]. In summary, the fetal period is a time in the mouse when changes in circulating estrogen (either exogenous or endogenous) could result in changes in adipose tissue function during later life and changes in the methylation pattern of genes in one potential mechanism. This prediction is consistent with evidence from other systems that exposure to sex hormones and estrogenic endocrine-disrupting chemicals during fetal life can have latent effects on the functioning of tissues after birth [14,37]. In recent years, the focus on obesity has involved the “big two” factors thought to be primarily responsible for the dramatic increase in obesity over the last two decades: reduced physical activity and overconsumption of junk food associated with food marketing practices [24]. It seems likely, however, that environmental factors are also involved, and sorting out which factors are most important has not received much attention. Thus, the role of environmental estrogens in the human obesity epidemic has not been investigated in epidemiologic studies, although data from studies with experimental animals as well as cell culture studies indicate that such studies are needed.

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Estrogen is known to play an important role in regulating adipose deposition in males, and estrogen regulates key developmental events in adipogenesis [18]; thus, although the factors regulating whether preadipocytes proliferate or differentiate are not well understood, estrogen appears to be one factor involved in their development. Adipose tissue expresses both ERα and ERβ. ERα is expressed in adipocytes, preadipocytes, and stromal vascular cells, indicating that almost all cells in adipose tissue are potentially estrogen responsive [38,39]. Estrogens appear to play a crucial role in the establishment of adult adipocyte number, although the effects of estrogens on adipose tissue are complex and may vary with cell type. A number of papers have shown that estradiol increases proliferation in preconﬂuent 3T3-L1 preadipocyte cells or in human or rat preadipocytes in vitro [40-42]. Estradiol treatment of cultured preadipocytes induces increased release of mitogenic substances into the media [43]. Adipocyte hyperplasia is a particular problem because the increased adipocyte population appears to make it very difﬁcult to ever overcome the obesity and maintain a normal weight. It is thus possible that during fetal life exposure to estrogenic chemicals may facilitate a particularly intractable type of obesity, and this may occur via epigenetic programming of genes during critical periods in development which results in permanent changes in gene activity [12].

THE ESTROGENIC CHEMICAL BISPHENOL A AND OBESITY Bisphenol A (BPA) is one of the highest volume chemicals in worldwide production, with production capacity exceeding 6 billion pounds per year [44] for use in manufacturing polycarbonate plastic, the resin that lines metal cans, and as an additive in many other types of plastic. All human fetuses that have been examined have measurable blood levels of BPA [5,45,46], and mean or median levels found in humans are higher than levels in fetal mice in response to maternal doses that increase postnatal growth [47]. Exposure to BPA during gestation and lactation has been shown to result in a wide range of effects observed during postnatal life in mice, rats, and a wide range of other vertebrates and invertebrate species [4,48]. We initially reported [49] and other studies have conﬁrmed [2,50–53] that prenatal exposure to very low doses of BPA increases the rate of postnatal growth in mice and rats. In addition, neonatal exposure to a low dose (≤1 µg/kg/day) of the estrogenic drug diethylstilbestrol (DES) stimulated a subsequent increase in body weight, an increase in body fat, and other effects in mice [13,54]. Related to these ﬁndings is the report that a high dose of BPA (2 µg/mL) accelerated the conversion of mouse 3T3-L1 ﬁbroblast cells into adipocytes and also increased lipoprotein lipase activity and triacylglycerol accumulation; BPA resulted in the presence of larger lipid droplets in the differentiated cells [55]. Insulin and BPA interacted synergistically to further accelerate these processes. In a related study, BPA stimulated an increase in the glucose transporter GLUT4 and glucose uptake into 3T3-F442A adiposities in cell culture [56]. In a separate study, upregulation of GLUT4 increased basal and insulin-induced glucose uptake into adipocytes [57]. In addition, very low doses of BPA stimulated the rapid secretion of insulin in mouse pancreatic β cells in primary culture through a nonclassical, nongenomic, estrogen-response system. In contrast, prolonged exposure to a low oral dose of BPA (10 µg/kg/day) resulted in stimulation of insulin secretion in adult mice that was mediated by the classical nuclear estrogen receptors; the prolonged hypersecretion of insulin was followed by insulin resistance [9].

THE ENDOCRINE DISRUPTOR TRIBUTYLTIN AND OBESITY Recent publications have implicated some other environmental chemicals with changes in adipocyte function. For example, organotin compounds were used for many years to protect the bottoms of boats, and these persistent compounds remain a health problem even though their use has been restricted in recent years. In addition, organotin compounds are used as stabilizers in polyvinyl-

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chloride (PVC) plastic, which is used to manufacture the pipes that carry water into homes, and organotin compounds leach out of PVC into water [58–60]. Tributyltin (TBT) is an organotin compound and is an endocrine-disrupting chemical that results in imposex in gastropod mollusks. This is a condition in which abnormal masculinization of females occurs due to the inhibition of the estrogen-synthesizing enzyme aromatase, which results in an increase in testosterone; testosterone is the substrate that is aromatized by aromatase to form estradiol-17β [61]. TBT also inhibits aromatase activity in human granulose cells in culture [62]. TBT is a ligand for PPARγ as well as for retinoic X receptors (RXRs), which, along with estrogen receptors and PPARs, are members of the nuclear receptor superfamily. In mice, treatment of pregnant females with TBT stimulated adipocyte differentiation and increased fat mass in offspring (number and volume of adipocytes were not reported). This ﬁnding is thus consistent with other ﬁndings described earlier regarding PPARγ activation during adipogenesis and adds to other evidence that activation of RXRs is also involved [63].

CONCLUSIONS At this time, data are limited relating obesity with environmental chemicals and, speciﬁcally, environmental chemicals that are estrogenic or otherwise disrupt estrogen homeostasis; however, we now have increased awareness that energy expenditure and components of a person’s diet, although important, cannot alone explain the rate of increase in obesity that has been documented over the last two decades [23,24]. Although the contribution of environmental chemicals to the obesity epidemic remains a largely unexamined issue, the dramatic increase in the incidence of obesity has occurred in parallel with a dramatic increase in the use of plastic. Plastic materials contain many types of endocrine-disrupting compounds in addition to bisphenol A. The initial animal experiments showing a relationship between accelerated postnatal growth, insulin secretion and sensitivity, and bisphenol A provide a strong argument for further research into the possibility that developmental exposure to bisphenol A, as well as other endocrine-disrupting chemicals, is contributing to the development of obesity later in life.

ACKNOWLEDGMENT Support during the preparation of this chapter was provided by a grant from the National Institute of Environmental Health Sciences (ES11283) to FvS.

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Obesity: Epidemiology, Pathophysiology, and Prevention Gregoire, F.M., Smas, C.M., and Sul, H.S., Understanding adipocyte differentiation, Physiol. Rev., 78(3), 783–809, 1998. Zhang, J.W. et al., Role of CREB in transcriptional regulation of CCAAT/enhancer-binding protein beta gene during adipogenesis, J. Biol. Chem., 279(6), 4471–4478, 2004. Krempler, F. et al., Leptin, peroxisome proliferator-activated receptor-gamma, and CCAAT/enhancer binding protein-alpha mRNA expression in adipose tissue of humans and their relation to cardiovascular risk factors, Arterioscler. Thromb. Vasc. Biol., 20(2), 443–449, 2000. Yamauchi, T. et al., The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deﬁciency and PPARgamma agonist improve insulin resistance, J. Biol. Chem., 276(44), 41245–41254, 2001. vom Saal, F.S., Sexual differentiation in litter-bearing mammals: inﬂuence of sex of adjacent fetuses in utero, J. Anim. Sci., 67(7), 1824–1840, 1989. Naaz, A. et al., Effect of ovariectomy on adipose tissue of mice in the absence of estrogen receptor alpha (ERalpha): a potential role for estrogen receptor beta (ERbeta), Horm. Metab. Res., 34(11–12), 758–763, 2002. Joyner, J.M., Hutley, L.J., and Cameron, D.P., Estrogen receptors in human preadipocytes, Endocrine, 15(2), 225–230, 2001. Lea-Currie, Y.R., Monroe, D., and McIntosh, M.K., Dehydroepiandrosterone and related steroids alter 3T3-L1 preadipocyte proliferation and differentiation, Comp. Biochem. Physiol. C. Pharmacol. Toxicol. Endocrinol., 123(1), 17–25, 1999. Dieudonne, M.N. et al., Opposite effects of androgens and estrogens on adipogenesis in rat preadipocytes: evidence for sex- and site-related speciﬁcities and possible involvement of insulin-like growth factor 1 receptor and peroxisome proliferator-activated receptor gamma2, Endocrinology, 141(2), 649–656, 2000. Anderson, L.A. et al., The effects of androgens and estrogens on preadipocyte proliferation in human adipose tissue: inﬂuence of gender and site, J. Clin. Endocrinol. Metab., 86(10), 5045–5051, 2001. Cooper, S.C. and Roncari, D.A., 17-beta-estradiol increases mitogenic activity of medium from cultured preadipocytes of massively obese persons, J. Clin. Invest., 83(6), 1925–1929, 1989. Burridge, E., Bisphenol A: product proﬁle, European Chemical News, April 14–20, 2003, p. 17. Schonfelder, G. et al., Parent bisphenol A accumulation in human maternal–fetal–placental unit, Environ. Health Perspect., 110, A703–A707, 2002. Ikezuki, Y. et al., Determination of bisphenol A concentrations in human biological ﬂuids reveals signiﬁcant early prenatal exposure, Human Reprod., 17(11), 2839–2841, 2002. Zalko, D. et al., Biotransformations of bisphenol A in a mammalian model: answers and new questions raised by low-dose metabolic fate studies in pregnant CD-1 mice, Environ. Health Perspect., 111, 309–319, 2002. vom Saal, F.S. and Welshons, W.V., Large effects from small exposures. II. The importance of positive controls in low-dose research on bisphenol A, Environ. Res., 100(1), 50–76, 2006. Howdeshell, K.L. et al., Exposure to bisphenol A advances puberty, Nature, 401, 763–764, 1999. Akingbemi, B.T. et al., Inhibition of testicular steroidogenesis by the xenoestrogen bisphenol A is associated with reduced pituitary luteinizing hormone secretion and decreased steroidogenic enzyme gene expression in rat Leydig cells, Endocrinology, 145(2), 592–603, 2004. Nikaido, Y. et al., Effects of maternal xenoestrogen exposure on development of the reproductive tract and mammary gland in female CD-1 mouse offspring, Reprod. Toxicol., 18(6), 803–811, 2004. Rubin, B.S. et al., Perinatal exposure to low doses of bisphenol A affects body weight, patterns of estrous cyclicity, and plasma LH levels, Environ. Health Perspect., 109, 657–680, 2001. Takai, Y. et al., Preimplantation exposure to bisphenol A advances postnatal development, Reprod. Toxicol., 15, 71–74, 2000. Newbold, R.R. et al., Developmental exposure to diethylstilbestrol (DES) alters uterine response to estrogens in prepubescent mice: low versus high dose effects, Reprod. Toxicol., 18, 399–406, 2004. Masuno, H. et al., Bisphenol A in combination with insulin can accelerate the conversion of 3T3-L1 ﬁbroblasts to adipocytes, J. Lipid Res., 43, 676–684, 2002. Sakurai, K. et al., Bisphenol A affects glucose transport in mouse 3T3-F442A adipocytes, Br. J. Pharmacol., 141(2), 209–214, 2004.

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Deems, R.O. et al., Expression of human GLUT4 in mice results in increased insulin action, Diabetologia, 37, 1097–1104, 1994. Forsyth, D.S. et al., Speciation of organotins in poly(vinyl chloride) products, Food Addit. Contam., 10(5), 531–540, 1993. Sadiki, A. and Williams, D.T., Speciation of organotin and organolead compounds in drinking water by gas chromatography–atomic emission spectrometry, Chemosphere, 32(10), 1983–1992, 1996. Smith, M.D. et al., Poly(vinylchloride) formulations: acute toxicity to cultured human cell lines, J. Biomater. Sci. Polym. Ed., 7(5), 453–459, 1995. Matthiessen, P. and Gibbs, P., Critical appraisal of the evidence for tributyltin-mediated endocrine disruption in mollusks, Environ. Toxicol. Chem., 17, 47–43, 1998. Saitoh, M. et al., Tributyltin or triphenyltin inhibits aromatase activity in the human granulosa-like tumor cell line KGN, Biochem. Biophys. Res. Commun., 289(1), 198–204, 2001. Grun, F. et al., Endocrine disrupting organotin compounds are potent inducers of adipogenesis in vertebrates, Mol. Endocrinol., 20(9), 2141–2155, 2006.

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Smoking, 4 Cigarette Inflammation, and Obesity Saibal K. Biswas, Ian L. Megson, Catherine A. Shaw, and Irfan Rahman CONTENTS Introduction ......................................................................................................................................43 Energy Storage, Intake, and Expenditure ........................................................................................44 Cigarette Smoking, Appetite, and Energy Expenditure ...........................................................44 Smoking and Hormonal Mediators of Energy Homeostasis ...................................................45 Obesity, Metabolism, and Energy Expenditure: Signaling Molecules ....................................46 Cigarette-Smoke-Mediated Oxidative Stress and Obesity ..............................................................47 Role of iNOS in Obesity and Relation to Inﬂammation .........................................................49 Inﬂammation and Obesity ........................................................................................................50 Factors Overlapping Inﬂammation and Metabolic Disease ............................................................51 Oxidative/Nitrosative Stress in Cardiovascular Disease: Impact on Disease Progression and Inﬂuence of Obesity and Smoking as Risk Factors ..........................................52 Oxidative Stress and the Endothelium .....................................................................................52 Oxidative Stress, Hypertension, and Obesity...........................................................................53 Oxidative Stress, Lipid Peroxidation, and Inﬂammation in Atherogenesis.............................53 Impact of Smoking and Obesity on Plaque Progression and Rupture Leading to Thrombotic Events..........................................................................54 Phytochemical Treatment of Obesity and Related Diseases...........................................................55 Conclusions ......................................................................................................................................57 Acknowledgment..............................................................................................................................57 References ........................................................................................................................................57

INTRODUCTION Obesity has already reached epidemic proportions in many countries, including the United States, United Kingdom, and many developing economies, affecting approximately 33% of adults worldwide. The body mass index (BMI; the weight in kilograms divided by the square of the height in meters) is an indicator of obesity that is easy to calculate and is sufﬁciently correlated with direct anthropometric measures of body. A BMI greater than 28 is generally associated with a three- to fourfold increased risk of clinical conditions such as stroke, ischemic heart disease, or diabetes mellitus [1]. A central distribution of body fat (as determined by the ratio of waist circumference to hip circumference: 0.90 in women and 1.0 in men) is widely accepted to reﬂect so-called visceral fat, which is associated with a higher risk than a more peripheral distribution and may be a better indicator of the risk of morbidity than absolute fat mass. Childhood obesity increases the risk of subsequent morbidity, whether or not obesity persists into adulthood [1].

43

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Elevated Body Weight

General Body Weight (lean/obese)

• Triiodothyronine • Energy expenditure during exercise • Post-feeding thermic effect • Sympathetic and parasympathetic nervous tone

Reduced Body Weight • Triiodothyronine • Energy expenditure during exercise • Resting energy expenditure • Sympathetic nervous tone • Parasympathetic nervous tone

FIGURE 4.1 Metabolic alterations in adults due to weight gain or loss. Decreased body weight is associated with reduced energy expenditure during exercise, sympathetic nervous tones, and resting state energy expenditure. An almost opposite phenomenon is observed for increased body weight.

ENERGY STORAGE, INTAKE, AND EXPENDITURE Fat (or triglyceride) is the primary form in which potential chemical energy is stored in the body. The amount of triglyceride in adipose tissue is the cumulative sum of the differences between energy intake and energy expenditure. Although homeostatic mechanisms act to minimize the difference, imbalances over a long period can have a large-scale effect. The degree of control between energy intake and expenditure is achieved by coordinated effects mediated through endocrine and neural signals that arise from various tissues [2–6]. Such integration is central to the regulation of body fat stores (Figure 4.1). A large number of factors originating throughout the body relay afferent signals to a smaller number of functional centers in the central nervous system, which in turn signal the efferent pathways to regulate energy expenditure (e.g., through the sympathetic and parasympathetic nervous systems and thyroid hormones) and energy intake (through eating behavior) [7,8]. These factors can interact at many levels; for example, the effect of cholecystokinin on satiety is increased by estradiol and insulin and is dependent on parasympathetic afferent signals [9,10]. The release of insulin is increased by cholecystokinin and parasympathetic efferent activity and is inhibited by sympathetic efferent signals [11]. The redundancy of interactions within this system makes any pharmacological or surgical manipulation of a single component inadequate for long-term resolution of obesity. That body fat content can be regulated is evident from the responses of both lean and obese humans subjected to experimental manipulation of body weight, making it unlikely that behavior alone is the sole determinant of obesity. It has been observed that a decreased expenditure of energy and an increased propensity to store fat may precede the development of obesity, which suggests that the extra body fat in the obese person in some way corrects for low energy expenditure [8].

CIGARETTE SMOKING, APPETITE,

AND

ENERGY EXPENDITURE

Smoking is a behavior that is maintained by physical addiction, psychological dependence, and habit and is associated with a wide variety of health problems relating to the cardiovascular, neurological, and pulmonary systems. Nicotine, the addictive substance in cigarettes, has various mood-altering effects that contribute to and reinforce the highly controlled or compulsive pattern of drug use through smoking. The pharmacological and biochemical effects of nicotine are powerful, with smokers reporting a mixture of relaxing, mood-lifting, and pleasurable effects. Smoking is also associated with decreased food intake and lower body weight. Nicotine is considered the major appetite-suppressing component of tobacco. Leptin and insulin are endogenous hormones that decrease appetite and increase energy expenditure by affecting the neuropeptide levels in the hypothalamus. Nicotine administration has been found to reduce food intake and body weight. Acute (24-hr) administration of nicotine lowered the expression of orexigenic neuropeptides, such as neuropeptide Y, Agouti-related protein, and melanin-concentrating hormone; however, 3 days of nicotine treatment did not alter hypothalamic neuropeptide mRNA levels. Nicotine was not found to affect the intracellular signaling of leptin and insulin in the hypothalamus. These data indicate

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that the acute anorectic effect of smoking may be explained in part by the decreased levels of orexigenic neuropeptides in the hypothalamus. This effect is not likely due to enhanced leptin or insulin signal transduction in the hypothalamus; however, chronic cigarette smoking may have a differential effect on leptin and insulin signaling. Studies on the inﬂuence of cigarette smoking on resting energy expenditure (REE) in normalweight and obese smokers have indicated that REE increased in both obese and normal-weight smokers after smoking, but the increase was greater for normal-weight participants [12]; however, the reliability of the observed alterations is lower for both normal-weight and obese smokers. Although smokers have lower mean BMIs compared with non-smokers, they have a more metabolically adverse fat distribution proﬁle, with higher central adiposity [13]. Just how smoking affects fat distribution is not entirely clear. One theory is that smoking has some kind of antiestrogenic effect. Another suggestion is that cigarette smoking may have an effect on the uptake and storage of triglyceride fatty acids, increasing fat mass [13]. A precise explanation for the association may help to identify the mechanisms underlying the adverse health consequences of cigarette smoking and abdominal obesity. The strong negative correlation over time between smoking rates and obesity have led some to suggest that reduced smoking leads to weight gain [14].

SMOKING

AND

HORMONAL MEDIATORS

OF

ENERGY HOMEOSTASIS

Cigarette smoke is an admixture of many potent oxidants, carcinogens, mutagens, and chemicals that are major risk factors for the development of various metabolic disorders. Mainstream cigarette smoke contains over 5000 chemical species, including high concentrations of oxidants (1017/puff) [15]. The aqueous phase of cigarette smoke condensate may undergo redox recycling (due to the presence of free iron) in the lungs of smokers [16]. The tar component of cigarette smoke contains high levels of relatively stable radicals (e.g., semiquinone radicals). The tar component effectively chelates metals and can bind iron (released from activated macrophages) to produce tar–semiquinone and tar–Fe2+ adducts, which can generate millimolar levels of hydrogen peroxide (H2O2) over a prolonged period. Sidestream cigarette smoke contains more than 1015 reactive organic compounds per puff, as well as carbon monoxide, ammonia, formaldehyde, N-nitrosamines, benzo(a)pyrene, benzene, isoprene, ethane, pentane, nicotine, acrolein, acetaldehyde, and other genotoxic and carcinogenic organic compounds. Superoxide anion (O2•– ) and nitric oxide (NO) are the predominant free radicals of the gas phase of cigarette smoke. NO and O2•– quickly react to form more toxic peroxynitrite (ONOO–). The semiquinone radicals in the tar component of cigarette smoke can reduce oxygen to produce so-called reactive oxygen species (ROS), including O2•– , •OH, and H2O2 [17]. Oxidants present in cigarette smoke can stimulate alveolar macrophages to release a host of mediators, some of which are chemotactic and recruit neutrophils and other inﬂammatory cells into the lungs. Both neutrophils and macrophages can then generate ROS via activation of the NADPH oxidase complex system [18]. Cigarette-smoke-derived oxidants (inhaled or endogenously produced by inﬂammatory cells) may affect many obesity-related hormones such as leptin, adiponectin, and resistin that are produced by the adipose tissue [18]. Whereas leptin, a satiety hormone, regulates appetite and energy balance, adiponectin suppresses atherogenesis and ﬁbrotic diseases and might play a role as an antiinﬂammatory hormone. Increased resistin, on the other hand, might cause insulin resistance and thus could link obesity with type 2 diabetes [18]. Ghrelin, produced in the stomach, is involved in longterm regulation of energy metabolism. All of these hormones play an important role in energy homeostasis, glucose and lipid metabolism, reproduction, cardiovascular function, and immunity, and they also inﬂuence other organ systems, including the brain, liver, and skeletal muscle. Importantly, the functions of these enzymes are inﬂuenced by the cellular oxidant/antioxidant balance. In view of the local oxidative stress generated by adipocytes (discussed later) leading to activation of macrophages, this is still further evidence to support a crucial role for oxidative stress in the

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Brain

Hormonal Effects

Neuropeptide Y Metabolic Effects -NPY Secretion -Food intake -Body weight -Sympathetic tone -Energy expenditure

Leptin

Leptin

-Glucocorticoids -Insulin -TNFα/IL-1

-Catecholamines -T3/T4 -cAMP -Androgens -Fertility

Leptin Synthesis

Glucose & Insulin Homeostasis

Adipose Tissue

Pancreas Insulin Synthesis

Liver Glycogenesis

Smooth Muscles Glucose Uptake & Utilization

FIGURE 4.2 Effect of leptin on hypothalamus and peripheral organs such as liver, pancreas, and smooth muscles. Leptin released from the adipocytes triggers the brain to regulate a host of responses such as food intake, fertility, insulin secretion, and sympathetic tones and exerts peripheral responses on the liver, pancreas, and smooth muscles.

complications related to obesity. Smoking, which is known to directly activate and recruit macrophages and other leucocytes in various tissues, can thus further exaggerate the effect of oxidative stress in obesity. The adipocyte volume has been reported to be proportional to plasma insulin concentrations [10]. Insulin is transported to the central nervous system by a saturable transport system where it mediates reduction in food intake by inhibiting the expression of neuropeptide Y, enhancing the anorectic effects of cholecystokinin and inhibiting neuronal norepinephrine reuptake [3,19]. It has been recently shown that insulin reduces food intake through an effect on leptin-mediated signaling. Cholecystokinin is a duodenal peptide secreted in the presence of food and is known to reduce food intake [6].

OBESITY, METABOLISM,

AND

ENERGY EXPENDITURE: SIGNALING MOLECULES

Leptin is synthesized in and secreted from adipose tissue and is a potential afferent signal of fat stores (Figure 4.2). In humans, the gene responsible for leptin expression is referred to as LEP. It is anorectic and increases energy expenditure, resulting in reduced body fat and restoration of insulin-sensitive glucose disposal in leptin-deﬁcient (ob/ob) mice [20]. Plasma leptin concentrations have been reported to be in direct proportion to body fat mass in obese human subjects [21]. Various hormones inﬂuence the expression of leptin in adipose tissue [21–23]. Leptin probably contributes to energy homeostasis in part by decreasing neuropeptide Y mRNA [20] or by blocking its action as an appetite stimulant; however, transgenic mice lacking the neuropeptide Y gene still respond to the anorexigenic effects of leptin, suggesting that it may also act via mechanisms that are independent of neuropeptide Y [20]. Neuropeptide Y is a potent central appetite stimulant that links afferent signals of the nutritional status of the organism from the endocrine, gastrointestinal, and central and peripheral nervous systems to effectors of energy intake and expenditure (Figure 4.2). Exogenous administration of neuropeptide Y has been reported to exert coordinated effects on energy intake and output and favor weight gain.

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• Adiponectin • Leptin • TNFα • Resistin • Free fatty acids

47

Obesity

Normal

• Adiponectin • Leptin • TNFα • Resistin • Free fatty acids

PPAR Hypertrophy

Adipose tissue

Adipose tissue

Insulin sensitive

Insulin resistant

FIGURE 4.3 Adiponectin and related biochemical effects. Both cigarettes and adipocytes lead to inﬂammation through PPARγ activation leading to obesity via elevations in resistin, free fatty acids, leptin, and TNFα and decreased adiponectin. The adipocytes in turn become resistant to insulin.

Ghrelin, a 28-amino-acid peptide preprohormone, was discovered as an agent that stimulates the release of growth hormone (GH) from the anterior pituitary. Studies established that ghrelin stimulates food intake in rodents as well as in humans and is strongly involved in the regulation of energy homeostasis. It was subsequently determined that ghrelin, along with several other hormones, has signiﬁcant effects on appetite and energy balance [24]. Ghrelin increases adipose deposition by decreasing fat oxidation. Adiponectin, also known as adipocyte-complement-related protein (adipoQ), is an adipocytespeciﬁc secreted protein with roles in glucose and lipid homeostasis. Adiponectin is induced during adipocyte differentiation, and its secretion is stimulated by insulin. Administration of adiponectin leads to an insulin-independent decrease in plasma glucose. This is likely attributable to insulinsensitizing effects involving adiponectin regulation of triglyceride metabolism (Figure 4.3). The mechanism underlying the role of adiponectin in lipid oxidation may involve the regulation of production or activity of proteins associated with triglyceride metabolism, including CD36, acyl CoA oxidase, 5-activated protein kinase, and peroxisome proliferator-activated receptor γ (PPARγ) [25]. Inhalation of cigarette smoke may be associated with abnormal triglyceride metabolism and activation of PPARγ. A negative correlation between obesity and circulating adiponectin has been well established, and adiponectin concentrations increase concomitantly with weight loss [26]. Decreased adiponectin concentrations are associated with insulin resistance and hyperinsulinemia, and patients with type 2 diabetes are reported to have decreased circulating adiponectin.

CIGARETTE-SMOKE-MEDIATED OXIDATIVE STRESS AND OBESITY Oxidative stress due to increased ROS or reactive nitrogen species (RNS) plays a critical role in the pathogenesis of various diseases and their complications. Activation of various inﬂammatory cells consequent to smoking results in the release of a battery of cytokines, including proinﬂammatory tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β), both of which cause upregulation of adhesion proteins on the endothelium, increased permeability, and increased secretion of chemokines such as IL-8, macrophage inﬂammatory protein 2, or monocyte chemotactic protein 1 (MCP1) [27]. Chemokines and cytokines then act in concert to further promote the extravasation and accumulation or activation of leukocytes to produce ROS, such as superoxide anion and hydrogen peroxide (H2O2). The release of ROS is largely believed to contribute to cell and tissue damage associated with many chronic inﬂammatory diseases such as atherosclerosis, asthma, adult respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD). Chemokines released as a result of oxidative stress may in turn impinge on the fat cells and trigger

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Obesity

NADPH Oxidase Antioxidant Enzymes

ROS

Oxidative stress in peripheral tissues

Oxidative stress in white adipose tissues

Dysregulation of adipocytokines

-PAI-1, TNFα, MCP-1 -Adiponectin

METABOLIC SYNDROME FIGURE 4.4 Oxidative stress in the adipocytes, followed by inﬂammatory response, can lead to the development of various metabolic alterations such as diabetes and atherosclerosis.

a series of reactions leading to obesity or secondary complications of obesity. Growing evidence supports the notion that the condition of obesity may itself induce systemic oxidative stress, and increased oxidative stress in accumulated fat cells in turn may lead to dysregulation of adipocytokines and development of metabolic syndrome. Increased oxidative stress in accumulated fat, therefore, is potentially an important target for the development of new therapies. In studies involving obese mice, H2O2 production was found to be increased in adipose tissue but not in other tissues. These results suggested that adipose tissue may be the major source of the elevated plasma ROS in obese conditions (Figure 4.4). Oxidative stress is known to impair both insulin secretion by pancreatic β-cells and glucose transport in muscle and adipose tissue. Increased oxidative stress in vascular walls is involved in the pathogenesis of hypertension and atherosclerosis. An association between smoking and increased risk of coronary heart disease was ﬁrst reported in 1940 in an observational study by the Mayo Clinic [28]. Subsequently, numerous epidemiologic studies have conﬁrmed a strong and consistent association between cigarette smoking and morbidity and mortality associated with coronary heart disease [29]. In general, the relative risk of death due to coronary heart disease in smokers is two to four times greater than that in persons who have never smoked; thus, oxidative stress locally produced and disseminated to tissues seems to be involved in the pathogenesis and outcome of these diseases. Furthermore, increased ROS release and the resultant appearance of lipid peroxidation end-products in peripheral blood from accumulated fat in obesity may be involved in the induction of insulin resistance in skeletal muscle and adipose tissue, impaired insulin secretion by β-cells, and pathogenesis of various vascular diseases such as atherosclerosis and other cardiovascular disorders.

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The other abundant source of O2•– and H2O2 is the professional phagocytes (i.e., neutrophils and macrophages), which have long been known to express an NADPH oxidase that requires stimulation for assembly of its cytosolic components with the two subunits of the membrane ﬂavocytochrome (gp91phox and p22phox) to generate high levels of O2•– upon activation of the cell [30]. The recent recognition that many cells express homologs of the catalytic subunit of the NADPH oxidase gp91phox (now collectively known as NOX for NADPH oxidase and DUOX for dual oxidase) has raised questions about their mode of regulation to produce ROS either constitutively or in response to cytokines, growth factors, and calcium signals. Why, therefore, is oxidative stress only exhibited in accumulated fat and not more widespread in association with inﬂammatory cells? The answer to this question probably lies in the fact that mRNA expression levels of NADPH oxidase (NOX) subunits were increased only in white adipose tissue (WAT), and was associated with decreased mRNA expression levels of various antioxidant enzymes. A parallel increase in the expression of the transcription factor PU.1, which upregulates the transcription of the NADPH oxidase gene [31], was also recorded in adipose tissue of obese mice. Recently, it was reported that macrophages inﬁltrate the adipose tissues of obese individuals and are an important source of inﬂammatory cytokines, indicative of their activation in this setting [32,33]. Because activated macrophages are also known to produce ROS, it is possible that inﬁltrating macrophages are subject to augmentation of NOX and, consequently, increased ROS production in the adipose tissue of obese individuals. In this regard, a family of gp91phox homologs, termed NOX (NAD(P)H oxidase) proteins, has been reported to be expressed in non-phagocytic cells, not in macrophages [34]. Recent studies on adipocytes found that NOX4, a member of the NOX family, plays a role in the generation of H2O2 [35]. The expression of NOX4 was not detected in macrophages [36,37]. In contrast, expression of NOX4 in WAT, as well as gp91phox, and mRNA expression of NOX4 were significantly increased in the WAT of obese mice. These results suggest that adipose NOX is elevated and contributes to ROS production in accumulated fat. These observations are also supported by reports that ROS production was increased in 3T3-L1 adipocytes, in parallel with fat accumulation and by incubation with linoleic acid, in a NOX-dependent manner. In accumulated fat, therefore, elevated levels of fatty acids activate NADPH oxidase and hence induce ROS production, which in turn upregulates mRNA expression of NADPH oxidase, establishing a vicious cycle that augments oxidative stress in WAT and blood. It has also been reported that ROS increases the expression of monocyte chemotactic protein 1 (MCP1), a chemoattractant for monocytes and macrophages, in adipocytes. Byproducts of lipid peroxidation by ROS, such as trans-4-hydroxy-2-nonenal and malondialdehyde, are themselves potent chemoattractants [38]. Hence, it is possible that increased ROS production and MCP1 secretion from accumulated fat may trigger macrophage recruitment and inﬂammation of adipose tissue in obesity. Thus, oxidative stress (triggered endogenously by cigarette smoking) in the adipocytes, followed by inﬂammatory response, can lead to the development of various metabolic alterations such as diabetes, cancer, and atherosclerosis (Figure 4.4).

ROLE

OF INOS IN

OBESITY

AND

RELATION

TO INFLAMMATION

Nitric oxide (NO) free radical is synthesized by three different isoforms of NO synthase (NOS) and was originally discovered as an endothelium-derived relaxing factor (EDRF). Endothelial NOS (eNOS) and neuronal NOS (nNOS) are constitutively expressed and synthesize low levels of NO in response to a wide range of stimuli, including, in the case of eNOS, shear stress and insulin [39]. In contrast, inducible NOS (iNOS) is expressed upon stimulation by inﬂammatory cytokines and can produce up to 1000-fold more NO than eNOS [40], which, while important for the immune response, can have detrimental effects on different cell types, including vascular smooth muscle cells [41] and pancreatic β-cells [42]. Common vascular disease states including hypertension and atherosclerosis are associated with endothelial dysfunction, characterized by reduced bioactivity of NO [43]. Loss of the vasculoprotective effects of NO contributes to disease progression, but the mechanisms underlying endothelial

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dysfunction remain unclear. Increased superoxide production in animal models of vascular disease contributes to reduced NO bioavailability and endothelial dysfunction. In human blood vessels, the NAD(P)H oxidase system is an important source of superoxide anion under pathological conditions and is functionally related to clinical risk factors and systemic endothelial dysfunction. Furthermore, the C242T polymorphism in the NAD(P)H oxidase p22phox subunit is associated with signiﬁcantly reduced superoxide production in patients carrying the 242T allele, suggesting a role for genetic variation in modulating vascular superoxide production. In vessels from patients with diabetes mellitus, endothelial dysfunction, NAD(P)H oxidase activity, and protein subunits are signiﬁcantly increased compared with matched non-diabetic vessels [43]. Furthermore, the vascular endothelium in diabetic vessels is a net source of superoxide rather than NO production, due to the dysfunction of eNOS. This deﬁcit is dependent on the eNOS cofactor, tetrahydrobiopterin, and is in part mediated by protein kinase C signaling. These studies suggest an important role for both the NAD(P)H oxidases and endothelial NOS in the increased vascular superoxide production and endothelial dysfunction in human vascular disease states. It is well established that obesity is associated with a chronic inﬂammatory response characterized by abnormal cytokine production, increased acute phase reactants, and activation of inﬂammatory signaling pathways [44,45]. Recent studies have demonstrated that murine models of obesity are associated with inﬁltration of adipose tissue by macrophages and activation of several inﬂammatory genes [46]. The expression of iNOS may be one aspect of such inﬂammatory activation. iNOS expression is primarily regulated at a transcriptional level and, once expressed, the enzyme may generate large amounts of NO over long periods of time. In other models of increased iNOS-derived NO (e.g., sepsis), excessive NO may contribute to increased basal bioactive NO and blunt classic, calcium-dependent vasodilation (e.g., in response to acetylcholine) [46–48]. Thus, iNOS expression induced by cigarette smoke could potentially contribute to several of the obesity-associated abnormalities reported in this study. Evidence of a signiﬁcant increase rather than a reduction in basal NO in the early stages of obesity has been found using several different approaches. Supporting these reports is the observation of an increased vasoconstrictor response to the nonselective NOS inhibitor L-NMMA, an effect of obesity that was lost in iNOS knockout (KO) mice. A role for iNOS was further supported by the effect of the speciﬁc iNOS inhibitor 1400W to increase tone in the aorta of obese mice, whereas no effect was seen in lean mice. Evidence for an increase in whole-body NO production was seen in the elevated plasma nitrite levels in obese mice, an effect that was signiﬁcantly reduced in iNOS KO mice. Finally, iNOS expression was found to be signiﬁcantly increased in the aorta of obese mice. Earlier studies in vessels exposed to inﬂammatory cytokines rendered the mice septic by using injections of lipopolysaccharide [47], and iNOS gene transfer studies have all supported a role for iNOS-derived NO in causing vascular dysfunction during obesity [48].

INFLAMMATION

AND

OBESITY

Advances in adipose tissue research over the past decade have led to a better understanding of the mechanisms linking obesity with metabolic syndrome and related complications [49]. Biomarkers of inﬂammation, such as leukocyte count, tumor necrosis factor α (TNFα), interleukin 6 (IL-6), and Creactive protein, are all increased in obesity and insulin resistance and are useful in predicting the development of type 2 diabetes and cardiovascular disease. It is perhaps no coincidence that all of the above cited biomarkers of inﬂammation are also hallmarks of smoking-induced oxidative stress. Thus, it is reasonable to surmise that many of the detrimental effects of smoking and obesity are mediated via a common pathway that is characterized by inﬂammation. This interaction could explain the additive, if not synergistic, relationship between these factors in disease development and outcome. Although it is now established that adipocytes are active participants in the generation of the inﬂammatory state in obesity, the initiating steps in the pathway are not fully ascertained. Adipocytes secrete a variety of cytokines, including IL-6 and TNFα, that promote inﬂammation. Moreover,

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recent studies suggest that obesity is associated with an increased recruitment of macrophages in adipose tissue, which also participate in the inﬂammatory process through the expression and release of cytokines. An in-depth understanding of the role of adipose tissue in the activation of inﬂammatory pathways may identify novel treatment and prevention strategies aimed at reducing obesityassociated morbidity and mortality. Many questions still remain to be answered; for example, does obesity per se induce an inﬂammatory response, or is inﬂammation initiated as a secondary event by hyperlipidemia or hyperglycemia? Is inﬂammation the primary event linking obesity with insulin resistance, or does the inﬂammatory response begin only after the onset of resistance to insulin? How and why does the body initiate an inﬂammatory response to obesity? From the available reports, it is fairly clear that obesity promotes states of both chronic low-grade inﬂammation and insulin resistance, but how the inﬂammatory response begins is yet to be understood [50]. The answers to such questions are unlikely to be straightforward, but it has been suggested that the inﬂammatory response is initiated in the adipocytes, as they are the ﬁrst cells affected by the development of obesity, or in neighboring cells that may be affected by adipose hypertrophy. Recent reports suggest that obesity may elicit inﬂammatory pathways by inducing oxidative stress on the endoplasmic reticulum (ER) [50–53]. ROS are produced as inevitable byproducts of energy production within mitochondria during the course of normal metabolism. The production of O2•– by the mitochondrial respiratory chain occurs continuously during normal aerobic metabolism; a small, but signiﬁcant, percentage of all the electrons traveling down the mitochondrial respiratory chain never make it to the end but instead form O2•– . The autoxidation of ubisemiquinone in mitochondria as well as metal-catalyzed autoxidation of molecules generate O2•– through one-electron O2 reduction. In addition to mitochondria, cytochrome P450s and their reductases, the xanthine–xanthine oxidase system, and NOS are all capable of ROS generation. Under normal metabolic conditions, it has been estimated that each cell is exposed to ~1010 molecules of O2•– each day. This is particularly relevant to the adipose tissue, which undergoes alterations in tissue architecture, protein and lipid synthesis, and perturbations in intracellular nutrient and energy ﬂuxes. Studies involving both cultured cells and whole animals have revealed that ER stress leads to activation of Janus kinase (JAK) and thus contributes to insulin resistance [51]. Interestingly, ER stress is also known to activate I-kappaB kinase (IκBK, a cytosolic nuclear factor kappa-B [NFκB] modulator) and thus may represent a common mechanism for the activation of these important signaling pathways [54]. Another mechanism that may play a role in the initiation of inﬂammation in obesity is oxidative stress. Increased delivery of glucose to adipose tissue may increase glucose uptake by endothelial cells in the fat pad, leading to excess production of ROS in mitochondria, which inﬂicts oxidative damage and activates inﬂammatory signaling cascades inside endothelial cells [55]. Endothelial injury in the adipose tissue is likely to attract inﬂammatory cells such as monocytes and further exacerbate the local inﬂammation. Hyperglycemia has earlier been reported to also stimulate ROS production in adipocytes, which leads to increased production of proinﬂammatory cytokines [56].

FACTORS OVERLAPPING INFLAMMATION AND METABOLIC DISEASE The ﬁrst molecular link between inﬂammation and obesity — tTNFα —was established from the discovery that this inﬂammatory cytokine is overexpressed in the adipose tissues of rodent models of obesity [57]. TNFα was also found to be elevated in adipose tissue and muscle in obese humans [44,58]. Furthermore, transcriptional proﬁling studies have revealed that inﬂammatory and stressresponse genes are among the most abundantly regulated gene sets in adipose tissue of obese animals [59]. Finally, lipids themselves also participate in the coordinated regulation of inﬂammation and metabolism; elevated plasma lipid levels are characteristic of obesity, infection, and other

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inﬂammatory states. It is interesting to note that metabolic changes characteristic of the acute-phase response are also proatherogenic; thus, altered lipid metabolism that is beneﬁcial in the short term in ﬁghting against infection is harmful if maintained chronically. The critical importance of bioactive lipids is also evident in their regulation of lipid-targeted signaling pathways through fatty-acidbinding proteins (FABPs) and nuclear receptors. The coordination of inﬂammatory and metabolic pathways is highlighted by the overlapping biochemical characteristics and function of macrophages and adipocytes in obesity. Both macrophages and adipocytes can express similar sets of genes. Macrophages can express many of the adipocyte genes, such as the adipocyte/macrophage FABP aP2 (also known as FABP4) and PPARγ, and adipocytes can express many macrophage-derived proteins, such as TNFα, IL-6, and matrix metalloproteinases (MMPs) [60,61]. There is, therefore, considerable overlap in the functional capability of these two cell types. For example, macrophages can take up and store lipid to become atherosclerotic foam cells. Preadipocytes under some conditions can exhibit phagocytic and antimicrobial properties and may even differentiate into macrophages given the appropriate environment, suggesting a potentially immunological role for preadipocytes [62]. Furthermore, macrophages and adipocytes colocalize in adipose tissue in obesity. Macrophages in adipose tissue are likely to contribute to the production of inﬂammatory mediators either alone or in concert with adipocytes, suggesting a potentially important inﬂuence of macrophages in promoting insulin resistance; however, no direct evidence has been offered to establish this connection to date. In terms of the immune response, integration between macrophages and adipocytes appears interesting, given that both cell types participate in innate immune responses. Although it is still to be conﬁrmed that macrophages are drawn to adipose tissue in other inﬂammatory conditions, it is conceivable that macrophage accumulation in adipose tissue may be a feature not only of obesity but of other inﬂammatory conditions as well.

OXIDATIVE/NITROSATIVE STRESS IN CARDIOVASCULAR DISEASE: IMPACT ON DISEASE PROGRESSION AND INFLUENCE OF OBESITY AND SMOKING AS RISK FACTORS OXIDATIVE STRESS

AND THE

ENDOTHELIUM

The potential contribution of oxidative and nitrosative stress to the progression of cardiovascular disease is well recognized but highly complex. The monolayer of endothelial cells that lines all blood vessels is central to protection against cardiovascular diseases, including hypertension and atherosclerosis. In healthy vessels, the endothelium secretes various antiatherogenic molecules, including the powerful vasodilator NO, which help to control vascular tone, maintain the integrity of the vessel wall, and resist the adhesion of leucocytes and platelets. It is now widely accepted that a critical early event in atheroma formation is endothelial cell injury and damage, resulting in endothelial dysfunction. This can occur by several mechanisms: Chemical injury can be caused by oxidative stress, including the oxidation of low-density lipoproteins (LDLs) which results in the formation of damaging oxidized low-density lipoproteins (ox-LDLs), which can themselves cause further endothelial damage. Also, physical damage to the endothelium can occur from shear stress within vessels, with plaques tending to form in regions of low shear stress or at sites usually subjected to particularly turbulent blood ﬂow, such as bifurcation points in the arterial tree [63]. The consequences of an insult to the endothelium are several fold: First, the endothelium becomes dysfunctional, resulting in a decrease in the net production of NO by eNOS, thus promoting vasoconstriction and allowing the adhesion of circulating inﬂammatory cells. A decrease in the normal NO-producing capacity of the endothelium has been demonstrated in patients with risk factors for atherosclerosis, such as hypercholesterolemia, who have impaired endothelium-dependent vasodilatation of resistance vessels, which can be reversed by the delivery of exogenous NO [64]. Additionally, the insult to the endothelium triggers an inﬂammatory response.

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OXIDATIVE STRESS, HYPERTENSION,

AND

53

OBESITY

Hypertension, deﬁned as chronically elevated blood pressure, is a complex clinical condition that is recognized as an important risk factor for coronary artery disease. Many studies have indicated that endothelial dysfunction is a feature of hypertension, but there is still some debate as to whether it is a cause or an effect; however, there is an increasing body of evidence to support a role for increased angiotensin II-dependent ROS production from NAD(P)H oxidases, with an associated uncoupling of eNOS, leading to the generation of further ROS and formation of highly cytotoxic peroxynitrite. Taken together, these events result not only in the loss of vasodilatory effects of NO but also the perpetuation of further endothelial damage induced by oxidating and nitrosating species [65], perhaps contributing to the predisposition of hypertensives to other vascular diseases. Obesity, and particularly visceral obesity, is strongly associated with hypertension, mediated at least in part through overactivity of the sympathetic nervous system, leading to an increase in peripheral resistance and sodium and water retention [66]. It is understood that increased circulating levels of leptin, free fatty acids, and perhaps insulin all act to increase sympathetic outﬂow from the hypothalamus, particularly when associated with low levels of adiponectin and ghrelin, which normally act to suppress sympathetic activity and are antiinﬂammatory. An important impact of increased renal sympathetic drive is activation of the renin–angiotensin system, with the associated increase in oxidative stress and endothelial dysfunction [67] as discussed above. It is somewhat surprising and disappointing, therefore, that clinical trials of dietary antioxidants in hypertension have proved inconclusive, and it remains to be seen whether any more success will be achieved with phytochemicals in this arena, given their potential for a combined antioxidant/antiinﬂammatory effect.

OXIDATIVE STRESS, LIPID PEROXIDATION,

AND INFLAMMATION IN

ATHEROGENESIS

Atherosclerosis is characterized by the formation of lipid-rich plaques in the subendothelial space of conduit blood vessels [63,68–71] and is the process that underpins coronary artery disease, peripheral vascular disease, and some forms of stroke. The plaques consist of a necrotic core of lipid-laden inﬂammatory cells encapsulated by a ﬁbrous, collagen-rich cap made up of vascular smooth muscle cells (VSMCs) and extracellular matrix [72]. It is generally accepted that endothelial cell injury is a trigger for atherogenesis, leading to the expression of numerous inﬂammatory cytokines together with cell-surface adhesion molecules speciﬁc for monocytes. Adherent monocytes then translocate through the endothelial layer into the subendothelial space where they differentiate into macrophages that express scavenger receptors and secrete inﬂammatory cytokines. TNFα, for example, is essentially produced by monocytes and macrophages in response to oxidative stress, and, in turn, it is the strongest known paracrine activator of monocytes and macrophages [73]. Upon stimulation, these cells also secrete a variety of products including IL-6, stimulating the liver to produce the acute-phase reactant C-reactive protein (CRP) [74]. TNFα and CRP are both found in considerable quantities in atherosclerotic lesions, and they have also been associated with increased cardiovascular risk in numerous large population-based studies. Beside instigating endothelial injury, oxidative stress is an important mediator of lipid peroxidation, which is essential for the accumulation of LDL-derived lipids in macrophages that have inﬁltrated the blood vessel wall. Modiﬁcation of LDL can occur by various means, including acetylation, exposure to malondialdehyde (MDA), or ROS-mediated peroxidation that leads to recognition by scavenger receptors and accumulation in macrophages [75]. Peroxynitrite (ONOO–), formed by the rapid reaction of superoxide with NO, can also oxidize LDL [76–79] but might also have proatherogenic effects through modiﬁcation of the protein, lipid, and antioxidant composition of LDL, most notably by depleting the antioxidant vitamin E content of the particle via the conversion of α-tocopherol to α-tocopherol quinone [75]. The oxidative/nitrosative status of an individual is, therefore, central to that individual’s risk of developing atheroma on a number of levels. It follows that both smoking and obesity predispose to increased ROS and encourage atherogenesis, and recent evidence suggests that the prevalence of ROS is likely to be enhanced in

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atheroma not only through increased ROS generation but also reduced synthesis of the endogenous antioxidant glutathione and concomitant depression of the activity of glutathione peroxidase [80]. In the case of obesity, oxidative stress acts in concert with other well-recognized risk factors that are usually associated with the obese condition — namely, hypertension, type 2 diabetes mellitus, and metabolic syndrome, which in turn have been linked to some extent to oxidative stress. The net effect of increased oxidant load is raised levels of markers of oxidative stress [81] with an associated reduction in plasma total antioxidant status and superoxide dismutase (SOD) activity in blood [82]. Furthermore, there is now clear evidence that increased oxidative stress in accumulated fat is important in the development of metabolic syndrome on account of NAD(P)H oxidase activation in adipocytes [83]. The importance of ROS in mediating many of the secondary pathologies that stem from obesity was further conﬁrmed in this study by the beneﬁt achieved through antioxidant treatment with respect to dysregulation of the metabolic pathways relating to glucose and lipids, as well as the genes associated with adipocytokines. These are encouraging ﬁndings with respect to phytochemicals, which might prove even more effective than conventional therapy. Hyperlipidemia is a critical risk factor for vascular disease that one might intuitively believe to be raised in obese individuals, but a wealth of studies do not necessarily show the expected correlation between body mass index and total cholesterol, LDL cholesterol, or serum triglyceride, particularly in humans. Indeed, even though obesity is widely believed to be a risk factor for development of atherosclerosis [84,85] a body of evidence suggests that no correlation exists between obesity per se and plaque deposition in coronary arteries [86,87], although it clearly predisposes to other risk factors, most notably hypertension, insulin resistance, and diabetes [84,88]. Smoking, on the other hand, is a very well-recognized risk factor for vascular disease, an effect that is primarily mediated via its prooxidative [89,90] and proinﬂammatory effects [91].

IMPACT OF SMOKING AND OBESITY ON PLAQUE PROGRESSION AND RUPTURE LEADING TO THROMBOTIC EVENTS Atherosclerotic plaques evolve and grow as the ox-LDL accumulated in macrophage-derived foam cells causes further endothelial damage and is a chemoattractant for additional macrophage recruitment [92]; hence, a perpetual cycle of endothelial damage, monocyte recruitment, and accumulation of ox-LDL is established. Activated macrophages resident in the early lesion secrete numerous cytokines and growth factors, including platelet-derived growth factor (PDGF), basic ﬁbroblast growth factor (bFGF), interleukin 1 (IL-1), TNFα, and transforming growth factor β (TGF-β) [63]. All of these factors induce vascular smooth muscle cell (VSMC) hypertrophy and hyperplasia and promote secretion of extracellular matrix and connective tissue to form a mesh over the fatty streak. Eventually, calciﬁcation occurs and a ﬁbrous cap forms over the top of the plaque, encapsulating the highly thrombogenic lipid core and maintaining a barrier between the plaque contents and the circulation [68–72]. Although atherosclerotic lesions can be widespread by middle age, the vast majority remain subclinical with only a small minority of plaques becoming symptomatic. The physical presence of a plaque within an arterial wall may impinge on the vessel lumen, causing partial occlusion of the vessel which might be sufﬁcient to cause substantial blood ﬂow restriction and tissue ischemia, resulting in chronic stable angina pectoris. A more serious situation arises if the ﬁbrous cap is subject to mechanical breakdown or erosion such that it is considered to be unstable and liable to rupture, generating a thrombus and leading to the more serious acute cardiovascular syndromes such as unstable angina, myocardial infarction, and stroke [93]. The determinants of plaque vulnerability to rupture have yet to be fully identiﬁed, but a growing body of evidence is emerging that points to a critical role for both the thickness of the VSMC layer overlaying the core [94] and unresolved inﬂammation within the plaque [69,95,96]. The crucial role of unresolved inﬂammation in the progression of atherosclerosis and ultimately to destabilization of the plaque is increasingly being identiﬁed as a potential target for therapeutic intervention. It is entirely possible that cigarette smoking and obesity, through their proinﬂammatory

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effects, might exacerbate these important phases of plaque development, with potentially fatal consequences. Indeed, smoking is one of the most powerful risk factors for atherosclerotic disease, but the relationships between smoking and cardiovascular disease result from multiple mechanisms that interact to contribute to atherosclerosis, vascular injury, thrombosis, and vascular dysfunction [97]. Several products of tobacco combustion, including nicotine, free radicals, and aromatic compounds, have been shown to cause the release of catecholamines, endothelial injury, oxidation of LDL, increased plasma ﬁbrinogen, and alteration of platelet activity. All of these agents are proatherogenic in nature [98]. Prospective cohort studies have consistently shown smoking to be one of the strongest risk factors for development of peripheral vascular disease. Risk of progression of atherosclerotic peripheral vascular disease is also increased among patients who continue to smoke compared with those who quit [13,71]. The Atherosclerosis Risk in Communities study showed a substantial increase in atherosclerosis progression in patients who smoked compared with those who had never smoked and an intermediate progression in former smokers. The progression of atherosclerosis attributable to smoking was more substantial than that due to other cardiovascular risk factors. The risk of progression of atherosclerosis was highest in smokers who had other risk factors, such as hypertension and diabetes mellitus, smoking being one of the strongest cardiovascular risk factors for atherosclerotic diseases [14]. Several studies have revealed increased plasma levels of TNFα and of CRP in smokers as compared to nonsmokers [99,100], suggesting that part of the coronary risk associated with smoking may relate to increased inﬂammatory activity; however, the prevalence of cardiovascular disease varies substantially among smoking individuals [101]. This could indicate that genetic factors are important determinants of the biological pathways linking smoking with cardiovascular disease risk [102]. The effects of nicotine are much less important than the prothrombotic effects of other products of tobacco combustion, as there is no apparent dose–response relationship between nicotine and cardiovascular events [98]. Nicotine and carbon monoxide produce acute cardiovascular consequences, including altered myocardial performance, tachycardia, hypertension, and vasoconstriction. Smoking a cigarette, in view of its composition consisting of a host of oxidants, releases an array of signals that recruit and activate macrophages and other inﬂammatory cells. Persistent local or systemic oxidative stress due to sustained smoking leads to expression of cytokines and lipid peroxides which injure blood vessel walls by damaging endothelial cells, thus increasing permeability to lipids and other blood components. Among the metabolic and biochemical changes induced by smoking is a tendency for increased serum cholesterol, reduced high-density lipoprotein, elevated plasma free fatty acids, elevated vasopressin, and a thrombogenic imbalance of prostacyclin and thromboxane A2. In addition to rheologic and hematologic changes from increased erythrocytes, leukocytes, and ﬁbrinogen, smokers have alterations in platelet aggregation and survival that predispose to thrombosis [12]. In fact, it has recently been shown that the CC polymorphism in the promoter region of the CD14 gene (CD14-159C/T) is associated with common carotid artery intima-media thickness in smokers but not in nonsmokers [103]. Furthermore, smoking is known to reduce the activity of the endogenous ﬁbrinolytic pathway that usually degrades thrombi in an effort to restore blood ﬂow through an occluded vessel, while both smoking and obesity are prothrombotic through the activation of platelets. Once again, one could envisage the potential beneﬁts of phytochemicals not only in preventing the inﬂammatory events that might predispose to plaque rupture but also by reducing the propensity for thrombus formation.

PHYTOCHEMICAL TREATMENT OF OBESITY AND RELATED DISEASES Smoking induces oxidative stress and depletes antioxidants by elevating oxidant levels, resulting in depletion of the cellular antioxidants utilized to counter the effects of the oxidants. The downstream effect of smoke-dependent induction of oxidative stress leads to local generation of inﬂammatory

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cytokines such as TNFα, IL-1, and IL-8. The cytokines in turn activate and recruit more inﬂammatory cells and may lead to systemic effects at various sites in the body. While oxidative injury to the lungs can result in lung cancers, COPD, and ARDS, inﬂammatory responses in the blood vessel may lead to various cardiovascular anomalies. In obese subjects, the risk of oxidative injury is heightened by the fact that the fatty stores by themselves behave as seats of inﬂammatory reactions and, as discussed earlier, may trigger oxidative stress and activation of local macrophages thus leading to metabolic syndrome. This inﬂuence of obesity may augment consumption of the cellular antioxidant pools and further add to oxidative imbalance. Oxidatively modiﬁed molecules, especially lipids, act as triggers for expression of cell adhesion molecules in the vasculature. Circulating monocytes and platelets then adhere to the intimal surfaces and extravasate to the subintimal space, leading to atherogenesis; hence, antioxidant supplementation and therapies are logical, particularly via phytochemicals in addition to exercise, obesity, and cardiovascular management via pharmacological means. The regular consumption of fruits and vegetables is associated with a reduced risk of cancer, cardiovascular disease, stroke, and many functional declines associated with aging, and it has been estimated that one third of all cancer deaths in the United States could be avoided through dietary modiﬁcation to include an abundant intake of fruits and vegetables [104]. These foods contain phytochemicals that have anticancer, antioxidant, and antiinﬂammatory properties that confer many health beneﬁts; for example, red foods (e.g., tomatoes) often contain lycopene, which is localized in the prostate gland and may be involved in maintaining prostate health and which has also been linked with a decreased risk of cardiovascular disease. Green foods, including broccoli, Brussels sprouts, and kale, contain glucosinolates, which have also been associated with a decreased risk of cancer. Garlic and other white-green foods in the onion family contain allyl sulﬁdes, which may inhibit cancer cell growth. Other bioactive substances in green tea and soybeans provide health beneﬁts, as well. Plant-based diets have a lower calorie density and increased nutrient density, which are important factors in curbing the obesity epidemic. Several studies have suggested a strong link between dietary phytochemical intake and a reduced risk for cardiovascular disease. Dietary ﬂavonoids have been inversely correlated with mortality from coronary artery disease, plasma total cholesterol, and low-density lipoprotein. Oxidized LDL has been proposed as an atherogenic factor in heart disease as it promotes cholesterol ester accumulation and foam cell formation [105]. Dietary antioxidants from fruits and vegetables can be incorporated into LDL and become oxidized in preference to polyunsaturated fatty acids. Phytochemicals also reduce platelet aggregation, modulate cholesterol synthesis and absorption, and reduce blood pressure [106]. Systemic inﬂammation may also be a critical factor in cardiovascular disease; indeed, the inﬂammatory marker C-reactive protein might be a stronger predictor of cardiovascular disease than LDL cholesterol [107]. The antiinﬂammatory activity of phytochemicals, then, may play an important role in cardiovascular health. Phytochemicals found in fruits and vegetables can affect the above processes by several mechanisms. The chemical species involved in oxidative stress can cause DNA damage, in the form of base mutation, DNA cross-linking, and chromosomal breakage and rearrangement. This damage may be limited by the dietary antioxidants in fruits and vegetables through modulation of detoxifying enzymes, scavenging of oxidative agents, stimulation of the immune system, hormone metabolism, and regulation of gene expression in cell proliferation and apoptosis [108]. Whole plant extracts may induce these protective effects via more than one mechanism; for example, curcumin, a well-recognized phytochemical found in the spice turmeric, has been found to have several antimetastatic mechanisms in hepatocellular carcinoma cells [109]. Tomato products, including ketchup, tomato juice, and pizza sauce, are the richest sources of lycopene in the American diet and account for more than three quarters of the total lycopene intake of Americans [110]. Several studies have linked the consumption of tomatoes and tomato products with a decreased risk of cancer and cardiovascular disease. The health beneﬁts of lycopene have been attributed to its antioxidant properties, although other mechanisms of lycopene action are possible, including the modulation of intercellular communication, hormonal and immune system changes, and enhancement of gap junctional communication [111]. In breast cancer cells, lycopene can interfere

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with insulin-like growth factor 1 (IGF-1)-stimulated tumor cell proliferation [112]. The relationship between lycopene intake and prostate cancer risk has been reported and is supported by studies linking low plasma levels of lycopene with an increased risk [113]. Lycopene administration may reduce proliferation and increase apoptosis in human prostate tissue where lycopene is the predominant carotenoid [114].

CONCLUSIONS Smoking, oxidative stress, inﬂammation, and obesity are intricately associated phenomena. While many sociopsychological factors inﬂuence both smoking and feeding habits, the emerging physiological factors consequent to smoking and eating abuse lead to a variety of metabolic disorders, including diabetes mellitus, and can independently or in conjunction with metabolic disorders lead to cardiovascular diseases, including hypertension and atherosclerosis. Hormones synthesized by the adipocytes such as leptin, adiponectin, hormones of the intestinal tract such as cholecystokine, and brain-related peptides such as neuropeptide Y and ghrelin undergo a complex interplay of regulatory cascades that modulate hunger, insulin secretion, and a wide variety of other metabolic effects. Interestingly, adipocytes laden with fats can themselves generate free radicals, which in turn can initiate cytokine-dependent signals to activate and recruit macrophages and other inﬂammatory cells that may lead to the development of various metabolic disorders and more complex vascular diseases. Cigarette smoke, which itself consists of an array of oxidizing species, can elicit similar inﬂammatory responses and can either initiate obesity-dependent inﬂammatory processes or direct obese conditions to a particular disease; therefore, the obesity–oxidative stress–cigarette smoking triad appears to be a multifactorial complication, and several focal points may be available for therapeutic targeting. Decoding the exact mechanisms involved in the etiopathogenesis of complications of obesity and smoking will reveal newer strategies of therapy for the amelioration of such complications. Phytochemicals from various plant sources may speciﬁcally interfere with particular focal points of the etiopathogenesis of obesity and thus serve as better, cost-effective, and less toxic therapeutic alternatives for the treatment of obesity and related pathologies.

ACKNOWLEDGMENT Irfan Rahman is supported by the Environmental Health Sciences Center grant no. ES01247.

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Eating 5 Disordered as a Correlate in the Development of Obesity Gwendolyn W. Pla CONTENTS Introduction ......................................................................................................................................63 Description of the Disorders............................................................................................................64 Anorexia Nervosa .....................................................................................................................64 Bulimia Nervosa .......................................................................................................................64 Eating Disorders Not Otherwise Speciﬁed ..............................................................................64 Binge Eating Disorder .......................................................................................................64 Bulimic Behaviors Associated with Fasting .....................................................................65 Night Eating Syndrome ............................................................................................................65 Food Choices and Preferences.........................................................................................................65 Prevalence of Eating Disorders and Associated Obesity ................................................................66 Health Effects and Risks of Eating Disorders and Obesity............................................................66 Lois............................................................................................................................................67 Roseanne ...................................................................................................................................67 Ben ............................................................................................................................................68 Functional Foods and Phytochemicals ............................................................................................68 Medications in Eating Disorder Treatment .....................................................................................68 Conclusion........................................................................................................................................69 References ........................................................................................................................................69

INTRODUCTION Reports of disordered eating practices involving starvation related to asceticism date back to the 1600s, but descriptions found in early religious literature did not include treatment. Cases of starvation reported in the 1600s and 1700s included various treatment modalities, some of which were successful and some not. Anorexia nervosa was recognized as an emotional illness in the 1600s and received its current name in 1873. In the 19th century, weight concerns were known to be the motivating factor behind disordered eating practices [1]. A review by Russell [2] on bulimia nervosa, which received its name in 1979, shows a clear connection, historically, with anorexia. As he pointed out, bulimia is deﬁned as overeating; however, bulimia nervosa involves overeating with the addition of compensatory behaviors (e.g., vomiting or laxative abuse) and concerns about weight and body image. This chapter provides a review of disordered eating as it relates to obesity. It includes a brief description of eating disorders, as well as discussion regarding the prevalence of eating disorders; their associated eating patterns, health risks, and comorbidities; and the relationship of eating disorders to the development of obesity. Three relevant case reports are presented, and phytochemicals and psychotropic medications are discussed. 63

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DESCRIPTION OF THE DISORDERS The American Psychiatric Association (APA) has classiﬁed disordered eating practices as three diseases: anorexia nervosa, bulimia nervosa, and eating disorders not otherwise speciﬁed. The third category includes binge eating disorder and other practices that do not speciﬁcally ﬁt the criteria for anorexia nervosa or bulimia nervosa. Additionally, another disordered eating pattern that is not speciﬁcally included by the APA is night eating syndrome. All can compromise nutritional status and health. Just as for anorexia nervosa and bulimia nervosa, emotional comorbidities are associated with both binge eating disorder and night-eating syndrome.

ANOREXIA NERVOSA Anorexia nervosa involves severe undereating. An individual with this disorder refuses to maintain a body weight that is even minimally normal. He or she is intensely afraid of gaining weight or becoming fat and has a disturbed sense of the way his or her body is perceived (e.g., seeing fat where there is none, even when very emaciated). Females suffering from anorexia nervosa after the age of menarche become amenorrheic. The two types of anorexia nervosa are the restricting type and the binge eating/purging type, the latter of which involves self-induced vomiting or the abuse of laxatives, diuretics, or enemas [3].

BULIMIA NERVOSA Bulimia nervosa is characterized by binge eating followed by the use of inappropriate compensatory methods to avoid weight gain. Body shape and weight excessively inﬂuence how such patients view themselves. A binge has been deﬁned as eating, in a discrete period of time, an amount of food that is deﬁnitely larger than most people would eat under similar circumstances. Those so affected experience a lack of control, a feeling that they cannot stop or control the amount eaten. These practices are accompanied by compensatory behaviors to prevent weight gain such as selfinduced vomiting; the misuse of laxatives, diuretics, enemas, or other medications; and fasting or excessive exercise. To qualify for the diagnosis, the binge eating practices and compensatory mechanisms must occur at least twice a week for 3 months’ duration [3]. Despite their excessive concern about weight, bulimics are usually of normal weight.

EATING DISORDERS NOT OTHERWISE SPECIFIED The “eating disorders not otherwise speciﬁed” category includes eating disorders that do not meet the criteria for any speciﬁc eating disorder [3]. Examples include: (1) a disorder for which all criteria for anorexia nervosa are met except that, despite signiﬁcant weight loss, the individual’s current weight is in the normal range; (2) a disorder in females for which all the criteria for anorexia nervosa are met except that the individual has regular menses; and (3) a disorder in which all of the criteria for bulimia nervosa are met except that the binge eating and inappropriate compensatory mechanisms occur at a lesser frequency than for bulimia nervosa. Some additional disorders of eating that ﬁt this category include the use of inappropriate compensatory behavior by an individual of normal body weight after eating small amounts of food (e.g., self-induced vomiting after the consumption of two cookies); repeatedly chewing and spitting out, but not swallowing, large amounts of food; and binge eating disorder, which features recurrent episodes of binge eating in the absence of regular use of inappropriate compensatory behaviors characteristic of bulimia nervosa (e.g., purging, fasting, excessive exercise) [3]. Binge Eating Disorder Persons with binge eating disorder have recurrent episodes of binge eating. In a discrete period of time (e.g., within any 2-hour period), they eat an amount of food that is deﬁnitely larger than most people would eat in a similar period of time under similar circumstances. They also experience a

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sense of lack of control over eating during the episode (e.g., a feeling that they cannot stop eating or control what or how much they are eating). The binge eating episodes are associated with eating much more rapidly than normal or eating until feeling uncomfortably full. Those suffering from binge eating disorder may eat large amounts of food when they are not feeling physically hungry, or they may eat alone because of feeling embarrassed by how much they are eating. Other indicators are feeling disgusted with oneself, depressed, or very guilty after overeating. Binge eaters experience marked distress regarding the binge, and the binge eating occurs, on average, at least 2 days a week for 6 months [3]. Bulimic Behaviors Associated with Fasting It has been observed that extreme restriction may lead to binging and purging. Russell [2] noted in his historical review that two saints who lived between 1566 and 1727 exhibited bulimic behaviors associated with fasting. They ate very little for long periods of time but then were observed to binge on everything in sight. Purging was done to make reparations for their sins. In modern times, it has been observed that for some individuals anorexia nervosa, bulimia nervosa, and binge eating disorder exist on a continuum; that is, extreme restriction may lead to binging and purging and, for some individuals, obesity. Persons with binge eating disorder generally overeat in comparison to those with bulimia nervosa who generally restrict [4]. Restriction can also lead to food cravings and contribute to the continuum. In their discussion of the literature on cravings, Weingarten and Elston [5] noted that a craving is a desire to eat a certain food. They suggested that cravings result from not consuming a desired substance (in this context, food) followed by exposure to stimuli associated with that substance; thus, cravings may be the antecedents of binges. According to Weingarten and Elston [5], abstaining from an appropriate level of food intake triggers cravings for food.

NIGHT EATING SYNDROME Although not speciﬁcally identiﬁed by the APA as an eating disorder, night eating syndrome is another disordered eating practice that has been described by Stunkard [4]. It involves morning anorexia and evening hyperphagia. It is also characterized by awakening at night to consume highcalorie snacks. Depression is a comorbid feature. The pattern occurs for a period of at least 3 months, and subjects do not meet the criteria for any other eating disorder. Binge eating and night eating syndrome can both lead to a positive energy balance and excess weight. Emotional distress is a feature of both.

FOOD CHOICES AND PREFERENCES Anorectics lose weight by reducing their total food intake. Although they may begin by excluding foods that they believe are high in calories, the end result is a very restricted diet that is limited to just a few foods [3]. Reports on the food choices of eating-disordered subjects have revealed some differences among the various eating disorders. Some patients with bulimia nervosa were found to focus more on dessert and snack foods as compared to weight-matched controls, and those with binge eating disorder ate more fat and less protein. Also, subjects with binge eating disorder consumed more calories than obese subjects who were not binge eaters [6]. Excessive calorie consumption and underactivity are important factors in the development of obesity. Wurtman [7] suggested that, of the macronutrients, excessive consumption of carbohydrate-rich foods is a major factor in the development of obesity. In a later review, however, Wurtman and Wurtman [8] noted that patients often consume such foods as pastries and chips, which are high in both fat and carbohydrates, to try to make themselves feel better. In still other studies, dietary fat has been proposed to be the major factor in obesity, as obese women who consumed a lot of calories as fat

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were found to have higher levels of body fat [9]. It is signiﬁcant that many foods that are high in carbohydrates may also be high in fats, the converse of which is also true; for example, pastries, gravies, and chips have both fat and carbohydrates. Binge eaters have been shown to have a fondness for carbohydrates. Also, depression has been shown to occur at a greater rate in binge eaters than in obese persons who are not bingers [10]. Wurtman [11] suggested the existence of a relationship between depression and carbohydrate cravings, such that depression brings about carbohydrate cravings and carbohydrate intake relieves depression. This suggestion was based on the observation of depression in individuals consuming low amounts of carbohydrates and relief of the depression upon the intake of carbohydrates. Drewnowski et al. [9] pointed out, however, that food preference data can be misleading (e.g., people may have misconceptions about the macronutrient contributions of certain foods). Foods that people might consider to be carbohydrates because of their sugar content often have fat as the predominant energy source; examples of such foods are doughnuts, ice cream, and chips. Because of the food choices in dieting and binge eating, many important foods containing ﬁber and phytochemicals may not be present in the diet. For severe restrictors, such as subjects with anorexia nervosa who avoid carbohydrates and fats, other important constituents will be absent, as well.

PREVALENCE OF EATING DISORDERS AND ASSOCIATED OBESITY Data from the National Center for Health Statistics show that 65% of adults over the age of 20 are overweight or obese and 30% are obese. Among children, the rate has more than doubled in the past 25 years; 16% of children between the ages of 6 and 11 are overweight compared with 7% in 1980.12 The National Eating Disorders Association estimates that 5 to 10 million women and girls and 1 million men are affected with eating disorders, including anorexia nervosa, bulimia nervosa, and binge eating disorder [13], but prevalence estimates for binge eating disorder range from 2% in community studies to more than 25% in severely obese, treatment-seeking populations [14]. A signiﬁcant number, but not all, of obese subjects are binge eaters [6]. Dieting has been observed to be a risk factor for binge eating and for hyperphagia. Bulik et al. [15] reported the results of a study conducted to determined whether dieting was an antecedent of binging. They assessed 100 overweight women and determined that, of the women who reported binging behaviors, 80.5% reported dieting prior to binging; only 16.7% reported that binge eating preceded dieting or vomiting. Additionally, they concluded that, although dieting is not always a precursor to binging, it is a precursor to the development of bulimia nervosa. A positive relationship between binge eating and obesity has been reported by Lamerz et al. [16], Siqueira et al. [17], and Morgan et al. [18].

HEALTH EFFECTS AND RISKS OF EATING DISORDERS AND OBESITY Disordered eating can take a serious toll on health and the quality of life. The consequences of those disordered eating practices that lead to obesity include those same risks that are generally associated with excess weight and obesity. They are hypertension, dyslipidemia, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, and sleep disturbances, as well as endometrial, breast, and colon cancers. An exception, however, is that obese persons with binge eating disorders have more psychological stress and a more greatly impaired quality of life than those obese who are not binge eaters [19]. It is important to note that, because of the limited food intake and choices characteristic of anorexia nervosa, patients with this disorder are likely to be missing important nutrients, including fat, ﬁber, phytoestrogens, and carotenoids — those dietary

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components associated with gonadal hormone status [20]. Comorbid features of anorexia nervosa, bulimia nervosa, and eating disorders not otherwise speciﬁed include anxiety disorders, obsessive– compulsive disorders, body dysmorphic disorders, and depression. Devlin et al. [21] noted high rates of depression and anxiety among obese patients, particularly those with binge eating disorder. These ﬁndings were consistent with those of Yanovski et al. [22], who reported that major depression, panic disorder, borderline personality disorder, and avoidant personality disorder were signiﬁcantly higher in persons with binge eating disorder. Fahy et al. [23] discussed the relationship between obsessive–compulsive disorder and patients with anorexia nervosa. The following are composites of case reports that demonstrate the limited food choices, disordered eating practices, and emotional components that lead to obesity.

LOIS Lois recalls being a chubby little girl. Her mother put her on a lettuce and carrot diet when she was 8 years old but spent very little time with her, lavishing attention instead on her sisters and her brother. Lois recalls being too hungry to fall asleep at night and stealing cheese and crackers to satisfy this hunger. She didn’t want to eat with the family because of the constant criticism that she received from her mother. She is a 54-year-old, single, white female who has experienced ongoing difﬁculties controlling her weight. Lois weighs 260 lb and is 5'5''; she is hypertensive. When she was at 200 lb, her doctor gave her a 1200-kcal diet and told her that she needed to get busy losing weight now; however, instead of losing weight, Lois continued to gain weight. She tried to eat less than the diet her doctor provided but found herself more and more hungry. She talked about how much she missed “good” food. She now stays home every evening and eats several bags of cookies and corn chips while watching news and game shows on television, but she does not really pay much attention to them. Sometimes she orders in a double order of fried chicken wings from a local restaurant that delivers, but she rarely goes out for food. She eats until her stomach hurts and then feels disgusted with herself, but she is unable to stop once she starts eating. She does not eat breakfast because she gets up too late, and she never eats lunch at work because she does not want to eat around other people. Lois’ case provides a good example of how extreme dietary restriction and emotional factors can lead to binge eating disorder and obesity. The characteristics of binge eating disorder that Lois displays include eating until uncomfortably full, eating larger quantities than most people would eat in a ﬁnite period of time, feeling disgusted with oneself, and avoiding eating around other people.

ROSEANNE Two years ago Roseanne went on a diet that cut out all fat, fruit, and starchy vegetables; she ate only cucumbers, lettuce, and tomatoes. Her roommate’s boyfriend often sends boxes of chocolates, which her roommate offers freely. Roseanne loves chocolate but resists the offers to share. She lost about 100 pounds but had no energy and found herself having insatiable cravings for the chocolates. Roseanne is a 24-year-old African-American female who had been diagnosed with type 2 diabetes mellitus and complains of pain in her knees. Her weight is 290 lb, and her height is 5'4''. She has gained weight steadily over the last 5 years and acknowledges that she often binges on chocolate bars, eating them very quickly, especially when she feels sad or anxious; she feels unable to stop herself and is disgusted with herself when the binge ends. Her doctor referred her to a nutritionist, who suggested a 2000-kcal diet with liberal amounts of fruit and vegetables, told her to stop eating candy, explained the beneﬁts of exercise, and, because of the pain in her knees, suggested that she swim every day. She cries a lot, ﬁghts with her roommates, and is angry with both her doctor and the nutritionist. Roseanne’s case illustrates some of the components of binge eating disorder: a lack of control during the binge, feeling disgusted with oneself, and eating much more rapidly than normal. It also illustrates the role of cravings in binge eating disorder.

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BEN Before Ben began his current job 5 years ago, his weight was just under 200 lb. He played tennis several times a week, ate regular meals with lots of vegetables, had a girlfriend, and played saxophone in a small volunteer community band. Ben is a 35-year-old white male who now weighs 300 lb and is 6' tall. He works in a mid-level management position, puts in long hours, and usually does not eat until he gets home at around 9 p.m. He eats a light dinner and usually falls asleep at about 11 p.m. He wakes up several times during the night and eats a couple of hot dogs or a large bag of potato chips or corn chips, cookies, and peanuts. Sometimes he will drink a couple of beers or a shot or two of Kentucky bourbon. His day starts again at 7 a.m. He always feels very tired upon arising but never hungry. Ben meets the criteria for night eating syndrome, morning anorexia, evening hyperphagia, and depression.

FUNCTIONAL FOODS AND PHYTOCHEMICALS Although the beneﬁts of foods containing ﬁber and phytochemicals have been documented, many common popular weight-loss diets promote foods that are essentially devoid of or, at best, low in ﬁber and phytochemicals. Additionally, because of limited food choices, persons who have disordered eating patterns will not have the advantage of important nutrients and phytochemicals. Several functional foods, those that provide health beneﬁts in addition to providing basic nutrition, have been promoted for their various beneﬁts in combating disease. These include unchanged whole fruits, such as fruits and vegetables, as well as foods that have been fortiﬁed with nutrients or enhanced by the addition of phytochemicals. These may include, but are not limited to, fortiﬁed margarines, garlic, green tea, grape juice or red wine, whole oats, cranberry juice, and fermented dairy products. Although no well-designed clinical trials on functional foods have been conducted, some anecdotal evidence links such foods to health beneﬁts [24].

MEDICATIONS IN EATING DISORDER TREATMENT Only very limited data, if any, are available regarding the use of phytopharmaceuticals in the treatment of eating disorders. Psychotropic medications have sometimes been used in the treatment of eating disorders [25]. These have included antidepressants, mood stabilizers, anxiolytics, opiate antagonists, and fenﬂuramine for bulimia nervosa. Antipsychotics, antidepressants, anxiolytics, appetite-enhancing agents, and prokinetic agents have been used in the treatment of anorexia nervosa [25]. Selective serotonin reuptake inhibitors (SSRIs) and imipramine have been used for the treatment of binge eating disorder, and topiramate, an antiepileptic drug, has been reported to be effective in reducing the frequency and duration of binges and reducing obsessive–compulsive behaviors [26]. Shapira et al. [27] and Vaswami et al. [28] reported short-term beneﬁts of SSRIs in the treatment of anorexia nervosa. Wong et al. [29] conducted a literature review of herbal remedies that are used to treat psychiatric symptoms; they reported that for many of the herbal medications the quality and quantity of data were insufﬁcient to determine their safety and efﬁcacy. They did conclude, however, that good evidence suggests the efﬁcacy of St. John’s wort in treating depression. This is consistent with a report by Fugh-Berman [30], who conducted a meta-analysis of 23 studies and concluded that sufﬁcient data support the effectiveness of St. John’s wort in the treatment of mild to moderate depression. It is important to note, however, that the depression associated with anorexia is most effectively treated with refeeding and psychotherapy. The classic semi-starvation study of Keys et al. [32] found that depression lessened with refeeding; they reported that changes in the depression score during the period of nutritional rehabilitation were substantially in direct proportion to the level of supplementation.

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Lake [33] provided an extensive review of natural sources of psychotropic medications. A number of them are being investigated for their antidepressant activity and anxiolytic activity and include the vitamins folic acid, vitamin B-12, vitamin C, and pyridoxine, as well as the amino acids S-adenosyl methionine, L-tryptophan, L-tyrosine, and D,L-phenylalanine and the mineral magnesium. These ﬁndings underscore the value of a balanced and varied mixed diet for the improvement of health, both physical and mental.

CONCLUSION Disordered eating plays a role in the development of obesity. Progress on its prevention and treatment has been insufﬁcient, and the public is vulnerable to promises of quick weight loss. More research is needed with regard to effective and safe treatment modalities for those disordered eating practices that lead to obesity. This would include effective and safe phytopharmaceuticals to improve mental health.

REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]

[17] [18]

Silverman, J.A., Anorexia nervosa: historical perspective on treatment, in Handbook of Treatment for Eating Disorders, Garner, D.M. and Garﬁnkel, P.E., Eds., Guilford Press, New York, 1997, chap. 1. Russell, G.F.M., The history of bulimia nervosa, in Handbook of Treatment for Eating Disorders, Garner, D.M. and Garﬁnkel, P.E., Eds., Guilford Press, New York, 1997, chap. 2. APA, Eating disorders, in Diagnostic and Statistical Manual of Mental Disorders, 4th ed., American Psychiatric Publishing, Arlington, VA, 2000. Stunkard, A.J., Binge-eating disorder and the night-eating syndrome, in Handbook of Obesity Treatment, Wadden, T.A. and Stunkard, A.J., Eds., Guilford Press, New York, 2002, chap. 6. Weingarten, H.P. and Elston, D., The phenomenology of food cravings, Appetite, 15, 231, 1990. Cooke, E.A. et al., Patterns of food selection during binges in women with binge eating disorder, Int. J. Eat. Disord., 22, 187, 1997. Wurtman, J.J., Carbohydrate craving, mood changes, and obesity, J. Clin. Psychiatry, 49(Suppl.), 37, 1988. Wurtman, R.J. and Wurtman, J.J., Brain serotonin, carbohydrate-craving, obesity and depression, Obesity Res., 3(Suppl. 4), 477S, 1995. Drewnowski, A. et al., Food preferences in human obesity: carbohydrates versus fats, Appetite, 18, 207, 1992. Marcus, M.D. et al., Psychiatric disorders among obese binge eaters, Int. J. Eat. Disord., 9, 69, 1990. Wurtman, J.J., Carbohydrate cravings: a disorder of food intake and mood, Clin. Neuropharmacol., 11(Suppl. 1), S139, 1988. CDC, Overweight and Obesity, Centers for Disease Control and Prevention, Atlanta, GA, 2005, www.cdc.gov/nccdphp/dnpa/obesity. NEDA, Statistics, Eating Disorders and Their Precursors, National Eating Disorders Association, Seattle, WA, 2002, www.nationaleatingdisorders.org. Yanovski, S.Z., Binge eating disorder and obesity in 2003: could treating an eating disorder have a positive effect on the obesity epidemic?, Int. J. Eat. Disord., 34, S117, 2003. Bulik, C.M. et al., Initial manifestations of disordered eating behavior: dieting versus binging, Int. J. Eat. Disord., 22, 195, 1997. Lamerz, A. et al., Prevalence of obesity, binge eating, and night eating in a cross-sectional ﬁeld survey of 6-year-old children and their parents in a German urban population, J. Child Psychol. Psychiatry, 46, 385, 2005. Siqueira, K.S., Appolinario, J.C., and Sichieri, R., Overweight, obesity, and binge eating in a nonclinical sample of ﬁve Brazilian cities, Obesity Res., 12, 1921, 2004. Morgan, C.M. et al., Loss of control over eating, adiposity, and psychopathology in overweight children, Int. J. Eat. Disord., 31, 430, 2002.

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Obesity: Epidemiology, Pathophysiology, and Prevention Kolotkin, R.L. et al., Does binge eating disorder impact weight-related quality of life?, Obesity Res., 12, 999, 2004. Rock, C.L. et al., Nutritional characteristics, eating pathology, and hormonal status in young women, Am. J. Clin. Nutr., 64, 566, 1996. Devlin, M.J., Yanovski, S.Z., and Wilson, G.T., Obesity: what mental health professionals need to know, Am. J. Psychiatry, 157, 854, 2000. Yanovski, S.Z. et al., Association of binge eating disorder and psychiatric comorbidity in obese subjects, Am. J. Psychiatry, 150, 1472, 1993. Fahy, T.A., Osacar, A., and Marks L., History of eating disorders in female patients with obsessive– compulsive disorder, Int. J. Eat. Disord., 14, 439, 1993. ADA, Position of the American Dietetic Association: functional foods, J. Am. Diet. Assoc., 104, 814, 2004. Garﬁnkel, P.E. and Walsh, B.T., Drug therapies, in Handbook of Treatment for Eating Disorders, Garner, D.M. and Garﬁnkel, P.E., Eds., Guilford Press, New York, 1997, chap. 20. Arnone, D., Review of the use of topiramate for treatment of psychiatric disorders, Ann. Gen. Psychiatry, 4, 5, 2005. Shapira, N.A., Goldsmith, T., and McElroy, S.L., Treatment of binge eating disorder with topiramate, J. Clin. Psychiatry, 61, 368, 2002. Vaswani, M., Linda, F.K., and Ramesh, S., Role of selected serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review, Prog. Neuropsychopharmacol. Biol. Psychiatry, 27, 85, 2003. Wong, A.H., Smith, M., and Boon, H.S., Herbal remedies in psychiatric practice, Arch. Gen. Psychiatry, 55, 1033, 1998. Fugh-Berman, A., Clinical trials of herbs, Primary Care, 24, 889, 1997. Keys, A. et al., Biology of Human Starvation, University of Minnesota Press, Minneapolis, MN, 1950, chap. 36. Lake, J., Psychotropic medications from natural products: a review of promising research and recommendations, Altern. Ther. Health Med., 6, 36, 2000.

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of Neurotransmitters 6 Role in Obesity Regulation Sunny E. Ohia and Catherine A. Opere CONTENTS Introduction ......................................................................................................................................71 Neurotransmitters and Relevant Pharmacological Receptors .........................................................72 5-Hydroxytryptamine................................................................................................................72 Catecholamines .........................................................................................................................73 Histamine ..................................................................................................................................74 Neuropeptides and Relevant Pharmacological Receptors ...............................................................75 Neuropeptide Y .........................................................................................................................75 Galanin ......................................................................................................................................76 Corticotropin-Releasing Factor.................................................................................................76 Orexins ......................................................................................................................................77 Melanocortin .............................................................................................................................78 Other Chemicals and Relevant Pharmacological Receptors ...........................................................79 Endocannabinoids .....................................................................................................................79 Summary and Conclusions ..............................................................................................................80 Bibliography.....................................................................................................................................80

INTRODUCTION The main goal of this chapter is to provide a comprehensive review of neurotransmitters, neuropeptides, and other chemicals that have been reported to be involved in obesity regulation based on data obtained from animal and human studies. These substances affect obesity via several mechanisms: a decrease in food intake through satiety and non-satiety pathways or an effect on energy expenditure through hyperactivity and thermogenesis. An induction of weight loss is a resultant action of the ingestion of compounds that mimic or alter the action of neurotransmitters and neuropeptides, as described in this chapter. The neurotransmitters discussed in this chapter include 5-hydroxytryptamine (5-HT), or serotonin; the catecholamines norepinephrine (NE) and dopamine (DA); and histamine. For neuropeptides, the focus is on neuropeptide Y (NPY), galanin, corticotropin-releasing factor (CRF), orexin, and melanocortin. For both neurotransmitters and neuropeptides, an additional review of pharmacological receptors associated with their actions is provided. For brevity, only in highly relevant cases is a discussion of signal transduction pathways for neurotransmitters and neuropeptides included. We also discuss the role of other chemicals such as endocannabinoids and their respective receptors in the regulation of obesity. The reader is also provided with a bibliography of critical references for more information about the neurotransmitters and neuropeptides discussed in this chapter.

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NEUROTRANSMITTERS AND RELEVANT PHARMACOLOGICAL RECEPTORS 5-HYDROXYTRYPTAMINE In addition to its well-known actions on the gastrointestinal tract and cardiovascular system, 5-hydroxytryptamine (5-HT; serotonin) plays an important role as a neurotransmitter in the central nervous system (CNS). 5-HT is biosynthesized from the essential amino acid tryptophan by two enzymes: tryptophan hydroxylase and aromatic L-amino acid decarboxylase. Dietary tryptophan is converted into 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase. At the nerve terminal, 5HTP is rapidly converted into 5-HT by the enzyme aromatic L-amino acid decarboxylase. Newly synthesized 5-HT is stored in vesicles at serotonergic neurons and is released by exocytosis following a nerve action potential. In the nervous system, the effect of released 5-HT is terminated by a reuptake process into neurons by a speciﬁc transporter. The localization of 5-HT transporters on membranes of serotonergic axon terminals facilitates the reuptake process. It is pertinent to note that the 5-HT transporter plays an important role in the action of this neurotransmitter in the regulation of obesity. Drugs that inhibit the activity of this transporter (such as d-norfenﬂuramine and ﬂuoxetine) increase the concentration of 5-HT at synaptic sites and have been reported to have a suppressive action on food intake. Further evidence for the role of 5-HT in the regulation of feeding behavior is derived from both animal and human studies. For example, when 5-HT or its precursors, tryptophan and 5-HTP, are administered to experimental animals, a signiﬁcant decrease in food intake, eating rate, and meal size results. Baseline levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid, are lower in the hypothalamus of obese Zucker rats when compared to their lean counterparts. Similarly, in obese humans, plasma concentrations of tryptophan and brain 5-HT levels are low, indicating a role for this monoamine in the individual’s ability to control caloric intake. In general, compounds that increase the concentration of 5-HT (whether through inhibition of the transporter or via direct administration into the brain or periphery) have been shown to have a preferential suppressant action on carbohydrate and fat consumption with little or no effect on protein ingestion. In addition to the well-known selective serotonin reuptake inhibitors (SSRIs) such as ﬂuoxetine and fenﬂuramine, hydroxycitric acid has been reported to initiate its anti-obesity action through an action on the 5-HT metabolic pathway. Hydroxycitric acid increased brain concentrations of 5-HT in experimental animals and plasma 5-HT levels in humans. Although 5-HT appears to possess a selective action on carbohydrate and fat ingestion in animal studies, it is unclear whether these ﬁndings are relevant to humans. Be that as it may, an increase in 5-HT concentrations at synaptic and other sites produces a general inhibitory action on the pattern of food intake by modulating hunger and satiety. The pharmacological actions of 5-HT are mediated by speciﬁc receptors of seven different families (5-HT1 to 5-HT7). Of all the 5-HT receptors described, 5-HT1A, 5-HT1B, and 5-HT2C subtypes have been implicated in the regulation of feeding behavior. For example, activation of 5-HT1A receptors can lead to increased food intake, whereas stimulation of 5-HT1B and 5-HT2C receptors will cause a decrease in food consumption. 5-HT1A receptors are localized on nerve terminals, and both 5-HT1B and 5-HT2C receptors are found on postsynaptic sites. Evidence linking the action of 5-HT on food intake and feeding behavior with speciﬁc receptor subtypes was based on animal studies in which selective antagonists of 5-HT1B and 5-HT2C receptors were found to block the anorectic actions of serotonergic drugs such as fenﬂuramine and ﬂuoxetine. Further evidence is derived from studies using knockout mice that possess no functional 5-HT2C receptors. 5-HT2C receptor knockout mice demonstrate marked hyperphagia and late-onset obesity and exhibit metabolic hormone changes such as hyperleptinemia and hyperinsulinemia. Likewise, 5-HT1B receptor knockout mice gained more weight than the corresponding wild-type, indicating a higher degree of food intake. The observations made in the knockout mice provide strong evidence that

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these genetically altered obese animals possess a deﬁcient endogenous 5-HT satiety system. Animals deprived of food demonstrate intense food-seeking behavior and increased food intake when food is provided, a response that is linked to turnover of 5-HT and a differential expression of 5-HT2C receptor subtypes in the hypothalamus. In summary, studies on food intake and feeding behavior conﬁrm a signiﬁcant role for 5-HT (and its possible action on 5-HT1B and 5-HT2C receptors) in mediation of the hypophagic response induced by this monoamine. Attention is now being focused on producing receptor-selective 5-HT1B and 5-HT2C agonists that can serve as novel molecules for the treatment of obesity. Indeed, weight loss induced by fenﬂuramine is now ascribed to a direct stimulant action of its desmethyl metabolite, norfenﬂuramine, on 5-HT2C receptors. The effectiveness of 5-HT2C receptor agonists in regulating appetite and food intake in humans shows signiﬁcant promise for the serotonergic system in the development of new anti-obesity drugs. The ability of 5-HT to cause hypophagia may involve the interaction of this monoamine with other neurotransmitter and neuropeptide pathways; for example, neuropeptide Y (NPY)-induced hyperphagia can be blocked by fenﬂuramine. Treatment of animals with 5-HT has been reported to decrease hypothalamic NPY concentrations. Anorectic 5-HT drugs such as fenﬂuramine activate proopiomelanocortin neurons in the arcuate nucleus (ARC), thus indicating a role for downstream melanocortin pathways in the regulation of food intake and body weight. Orexin can stimulate 5-HT release in the hypothalamus, suggesting that serotonergic pathways are involved in the anorectic action of this neuropeptide. It is clear from the discussion above that, as a neurotransmitter, 5-HT plays a crucial role in satiety response and may serve as a template for future anti-obesity therapy. Compounds that increase its concentrations at synaptic sites or activate 5-HT1B or 5-HT2C receptors will continue to represent compelling therapeutic targets in the quest to develop highly selective pharmacological entities for the regulation of food intake and feeding behavior.

CATECHOLAMINES Of the three major catecholamines, dopamine and norepinephrine have been linked to the regulation of appetite and feeding behavior. Dopamine, an immediate precursor of norepinephrine and epinephrine, is a neurotransmitter in the CNS. It is synthesized from the amino acid tyrosine by two enzymes: tyrosine hydroxylase and aromatic L-amino acid decarboxylase. Tyrosine is converted to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase, which is subsequently metabolized to dopamine by aromatic L-amino acid decarboxylase. Dopamine is presumed to be one of the target neurotransmitters linking the genetic and environmental factors that contribute to obesity. It has a site-speciﬁc action on the regulation of food intake. The reinforcing action of dopamine on food intake is associated with the release of this neurotransmitter in the brain nucleus accumbens. The duration of meal consumption is ascribed to dopamine release in the hypothalamus. It appears that dopamine is required to initiate each meal and is also responsible for the number of meals and duration of feeding. Dopamine knockout mice do not express tyrosine hydroxylase activity; these animals do not lack the motor capabilities for feeding but cannot initiate this process. Evidence from biomedical literature supports the fact that dopamine is essential for feeding. Dopamine exerts its pharmacological actions via activity on ﬁve receptor subtypes classiﬁed into D1-like (D1 and D5) and D2-like (D2, D3, and D4) families. Both subtypes of dopamine receptors are found on hypothalamic neurons, thus supporting their role in the regulation of feeding behavior. Data from studies in animals show that chronic activation of D1 or D2 receptors results in a decrease in food consumption with concomitant body weight reduction. In humans, there is evidence that striatal D2 receptor activity is signiﬁcantly lower in obese individuals than in controls, a ﬁnding that was hypothesized to be due to the action of dopamine on motivation and reward circuits. In general, an effect of dopamine on D1 receptors is presumed to be regulation of satiety signals, thus leading to a decrease in meal size and duration of feeding. Activation of D2 receptors leads to a

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reduction in the rate of feeding. Drugs that activate or block dopamine receptors can affect appetite and feeding behavior; for example, the D1/D2 receptor agonist apomorphine has been shown to decrease both the rate and duration of feeding. On the other hand, behavioral studies in animals have revealed that antagonists of D2 receptors can increase meal size and the duration of feeding. In humans, patients treated with antipsychotics that block D2 receptors show an increase in body weight as a side effect. Clearly, both dopamine receptors play a very important role in the regulation of appetite and feeding behavior in both animals and humans. Norepinephrine is a neurotransmitter that is released from sympathetic nerves. It is a metabolic product of the action of dopamine β-hydroxylase on dopamine. Compounds that produce effects that resemble sympathetic nerve stimulation (i.e., sympathomimetics) such as amphetamine, phentermine, and sibutramine have been employed as anti-obesity drugs. The mechanism of action of these anti-obesity compounds is complex with a diverse activity spectrum, such as a reduction in food intake or increase in energy expenditure (through hyperactivity or thermogenesis). Amphetamine was the ﬁrst compound mimicking the action of sympathetic nerve stimulation that was employed for the treatment of obesity. Amphetamine reduces hunger, food intake, and the number of meals while increasing feeding latency and feeding rate. Due to its deleterious side effect on the cardiovascular system and high rate of abuse potential, this drug is no longer in use for the treatment of obesity. Sibutramine, a potent inhibitor of norepinephrine and serotonin reuptake, has anti-obesity actions through an inhibitory action on food intake. Norepinephrine produces its physiological and pharmacological actions via activation of three major receptor classes: α1-, α2-, and β-adrenoceptors. All three receptor classes have been implicated in the regulation of appetite and feeding behavior. In the brain, α1- and α2-adrenoceptors present in the paraventricular hypothalamus have been linked to the regulation of feeding behavior. In animal studies, stimulation of α1-adrenoceptors suppresses food intake, whereas activation of α2-adrenoceptors increases food intake. It appears that the observed anti-obesity action of sympathomimetics could be related to the degree to which they act on α1- and α2-adrenoceptors; for example, sibutramine is presumed to decrease appetite via an inhibitory action on α2-adrenoceptors. α-Adrenoceptors mediate glucose homeostasis through an effect on insulin and glucagon secretion, liver glucose production, and glucose uptake into muscle. Production of heat by the body (thermogenesis) can increase energy expenditure leading to weight loss. The adipose tissue serves both as a depot for fat storage and also as a dynamic endocrine organ involved in the control of energy balance. β3-Adrenoceptors present in adipose tissue are involved in catecholamine-stimulated lipolysis and thermogenesis. The discovery that mutation of a gene encoding β3-adrenoceptors is linked with the propensity to gain weight coupled with the observation that these receptors mediate thermogenesis in adipose tissue led to the search for anti-obesity drugs that act via this pathway. It remains to be determined whether β3-adrenoceptors present on adipose tissues could serve as a useful target for the treatment of obesity.

HISTAMINE Histamine is a neurotransmitter in the central nervous system that has also been linked to the regulation of feeding behavior. Apart from the CNS, histamine is found in abundance in mast cells, especially in skin, lungs, and the gastrointestinal tract. In the brain, histamine is synthesized in tuberomamillary nucleus hypothalamic neurons from the amino acid histidine. Histidine is decarboxylated to form histamine, a reaction that is catalyzed by the enzyme L-histidine decarboxylase. Unlike the catecholamines whose effect is terminated by reuptake mechanisms in synapses, histamine diffuses from synapses, where its action is terminated by degradative enzymes. Nerves containing histamine project throughout the brain to areas such as the thalamus and cerebral cortex. In animal studies, histamine has been shown to suppress food intake, and there is evidence that this neurotransmitter may regulate body weight and adiposity by an action on peripheral energy metabolism. Histamine-containing neurons have been linked to the rate of feeding and intake volume

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of meals. Histamine produces its pharmacological actions via effects on four different receptor subtypes: H1, H2, H3, and H4. Of these receptor subtypes, both H1 and H3 receptors have been associated with the regulation of appetite and feeding behavior. In animal studies, injection of H1 receptor agonists or peripheral administration of the histamine precursor histidine suppressed food intake in rats and mice. Furthermore, H1-receptor-deﬁcient mice demonstrated an increase in food intake when compared to their normal counterparts. Taken together, data from animal studies reveal a role for H1 receptors in the regulation of food intake and feeding behavior. Administration of the H3 receptor antagonist thioperamide into the brain has been reported to suppress food intake in rats. Presumably, by blocking inhibitory H3 receptors present on histamine-containing nerve terminals, thioperamide indirectly causes an increase in the release and availability of this amine, leading to enhanced stimulation of postsynaptic H1 receptors and the suppression of food intake. Based on this observation, several new compounds with antagonistic activity at H3 receptors have been developed by pharmaceutical companies for potential use as anti-obesity drugs. In spite of the evidence from preclinical studies that implicates histamine in the regulation of food intake, it remains to be determined whether compounds that interact with H1 and H3 receptors will be of therapeutic importance in the treatment of obesity in humans.

NEUROPEPTIDES AND RELEVANT PHARMACOLOGICAL RECEPTORS NEUROPEPTIDE Y Neuropeptide Y (NPY), a 36-amino-acid neurotransmitter that was discovered in 1982, is one of the most abundant and widely distributed neuropeptides in mammalian central nervous systems. It belongs to a family of pancreatic polypeptides with similar structural homology known as the NPY family. Other members of this family include peptide YY, pancreatic polypeptide, and polypeptide Y. NPY, which is also one of the most studied neuropeptides, is highly conserved across species from Drosophila to humans. Biosynthesis of NPY involves posttranslational enzymatic cleavage of the 98-amino-acid preproNPY to the 69-amino-acid prohormone proNPY, which is further cleaved to NPY by the prohormone convertases PC1/3 and PC2. It is often colocalized and coreleased with norepinephrine neurotransmitter in both the central and autonomic nervous system, where it is believed to modulate catecholamine release and activity. In addition to its regulatory role in the cardiovascular, reproductive, bone mass, and psychomotor systems, among others, NPY is a potent orexigenic neuropeptide that plays a central role in the regulation of appetite in the central nervous system. In the central nervous system, NPY is most abundant in the hypothalamic nuclei, such as the arcuate nucleus (ARC) and paraventricular nucleus (PVN), both key areas in the regulation of feeding. Indeed, several studies have shown that injection of NPY into the paraventricular nucleus stimulates hyperphagia, reduced energy expenditure, and the induction of obesity in the long run. Neuropeptide Y mediates its pharmacological actions by activating six Gi/Go-protein-coupled NPY receptor subtypes (Y1 to Y6), all of which have been cloned and have been shown to be expressed in both central nervous system and peripheral tissues. Three of these receptor subtypes (Y1, Y2, and Y5) have been implicated in the regulation of food intake; for example, evidence suggests that Y1 receptors are involved in selective stimulation of carbohydrate intake and meal size. Several studies utilizing receptor NPY agonists and receptor subtype antagonists have demonstrated that both Y1 and Y5 receptors independently and synergistically interact with each other to mediate NPY hyperphagic response. In contrast, the Y2 receptor subtype, which is located presynaptically (with postsynaptic expression in some brain regions) on neurons, suppresses carbohydrate intake. Other studies report that Y2 receptors have no effect in satiated animals but suppresses food intake in fasted animals. It appears that, under fasted conditions, Y2 receptor activity attenuates the release of PVN NPY and eliminates tonic inhibition of γ-aminobutyric acid

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(GABA) on proopiomelanocortin (POMC) neurons, thereby stimulating release of α-melanocytestimulating hormone (α-MSH) with the net effect of decreased food intake. It has been hypothesized that, in satiated animals, the Y2-sensitive NPY and GABA are rendered inactive, while the activity of α-MSH and POMC neurons predominates to reduce food intake. In general, Y2 receptors regulate the transport, synthesis, and release of NPY and other central mediators, in addition to playing a signiﬁcant role in the NPY-mediated effects of leptin. Although the central orexinogenic effect of NPY has been established in several studies, the use of transgenic mice has surprisingly revealed that neither overexpression nor deletion of NPY receptors interferes with normal weight and appetite. It appears that, although NPY is central to the regulation of food intake and energy balance, the body can adjust other orexigenic and anorexigenic signals to compensate for its receptor deletion or overexpression. The normal transgenic phenotype of both transgenic models thus reﬂects the rich functional redundancy of the system regulating food intake and energy balance. Based on studies utilizing transgenic models, it is not surprising that a Y5 antagonist was unsuccessful in clinical trials with human subjects. Although these observations suggest that NPY is not involved in morbid obesity, NPY analogs may still ﬁnd clinical application as appetite suppressants and anti-obesity drugs.

GALANIN Galanin is a 29-amino-acid (30 in humans) peptide that is widely expressed in mammalian central, peripheral nervous, and endocrine systems; it was originally identiﬁed in porcine intestines in 1983. It is colocalized with and regulates the release of several neurotransmitters and has been implicated in high-order physiological functions such as learning and memory, nociception, epileptic activity, spinal reﬂexes, sexual activity, mood changes, and food intake. The pharmacological effects of galanin are mediated through three G-protein-coupled receptors: GalR1, GalR2, and GalR3. It is unclear which of these receptors mediate the effects of galanin on the regulation of food intake. Injection of galanin into the brain stem stimulates food consumption. On the other hand, administration of galanin antagonists such as M40 decreases food intake. Evidence suggests that in the PVN of the hypothalamus, endogenous galanin selectively stimulates the intake of lipids and alcohol, and its production is stimulated by the same dietary components. Interestingly, consumption of a high-carbohydrate diet does not regulate endogenous galanin levels. Transgenic mice overexpressing galanin mRNA in the hypothalamus exhibit a higher preference for a lipid diet. It is therefore conceivable that a potent galanin antagonist may have potential clinical application as an anti-obesity drug.

CORTICOTROPIN-RELEASING FACTOR Corticotropin-releasing factor (CRF), also known as corticotropin-releasing hormone (CRH), is a 41-amino-acid neuropeptide that belongs to the CRH family of peptides. Other members of this family include urocortin I, II, and III. In addition to being one of the major physiologic secretagogs of adrenocorticotropic hormone (ACTH), CRF regulates the hypothalamic–pituitary axis; autonomic and behavioral responses to stress; cardiovascular, inﬂammatory, and gastrointestinal function; and food intake. CRF is synthesized by hypothalamic paraventricular neurons and is distributed throughout the brain and spinal cord. Biosynthesis of CRF involves cleavage of ﬂanking amino acid base pairs from a 191-amino-acid precursor. CRF activates two seven-transmembrane-domainspanning, G-protein-coupled receptors: CRF type 1 (CRF1) and CRF type 2 (CRF2). CRF1, which exhibits a higher afﬁnity for CRF, is expressed in cortical, hypothalamic, limbic, cerebellar, and pituitary regions of the brain and in the gastrointestinal tract. In contrast, CRF2 exhibits a lower afﬁnity for CRF and is distributed mainly in peripheral systems such as the gut and in more limited areas of brain compared to CRF1. Both receptors are positively coupled to adenylyl cyclase enzyme. In humans, CRF2(a) is localized in hypothalamic areas that control appetite such as the PVN, in the gastrointestinal tract, and on vagal afferent nerves, suggesting their role in the regulation of food intake.

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Chronic intracerebroventricular (i.c.v.) administration of exogenous CRF in rats elicits a potent anorexic effect via stimulation of synthesis and secretion of POMC-related peptides leading to suppression of food intake and a decrease in body weight. The discovery of endogenous-selective CRF2 receptor agonists (type 2 urocortins Ucn-II and Ucn-III) and the synthesis of more selective ligands continue to delineate the functional signiﬁcance of the CRF systems in brain and gut. Using some of the newly found ligands, it has been shown that agonists with higher afﬁnity for CRF2 exhibit a high potency of hypophagic response; for example, Ucn-I, which has a higher afﬁnity for CRF2, is more potent at suppressing food intake and less potent at modulating stress compared with CRF1, which has a moderate afﬁnity for this receptor subtype. In contrast, the selective CRF2 receptor antagonist antisauvagine-30 attenuates CRF-induced anorexia, unlike the CRF1 receptor antagonist counterpart. In support of this premise, deletion, reduction, or inhibition of the CRF2 receptor subtype attenuates the hypophagic effect caused by i.c.v. injection of Ucn-I and CRF. Other studies indicate that, in rats, CRF1 receptors mediate abbreviated, short-onset anorexia, while CRF2 elicits delayed-onset anorexia. Furthermore, activation of both CRF1 and CRF2 receptor subtypes using nonselective agonists provokes both prolonged and short-onset anorexia. Clearly, the exact mechanisms by which the CRF receptor system regulates appetite suppression remain to be fully elucidated. It is conceivable that CRF antagonists may ﬁnd therapeutic application in the treatment of overweight, obesity, and associated morbidities.

OREXINS Orexins (previously known as hypocretins) A and B are neuropeptides that were initially identiﬁed in rat hypothalamus in 1998. These novel neuropeptides have been shown to be involved in the regulation of food intake, in addition to sleep/wakefulness and energy homeostasis. Orexin A (33amino-acid residues) and orexin B (28-amino-acid residues) are proteolytically derived from 130–131 preproorexin. Orexins interact with two seven-transmembrane-domain-spanning, G-protein-coupled receptors: orexin receptor 1 (OX1R), which selectively binds orexin A, and orexin receptor 2 (OX2R), which has the same afﬁnity for both orexin A and B. Originally localized in the lateral and posterior hypothalamus, orexin neurons project diffusely into brain regions, including areas involved in the regulation of energy homeostasis such as the arcuate nuclei, paraventricular hypothalamus, and ventromedial hypothalamus. Interestingly, these hypothalamic regions also express orexin receptors, suggesting involvement of the orexin system in the regulation of food intake. In the lateral hypothalamus, orexin neurons are coexpressed with the hyperphagic endogenous opioid dynorphin. Both orexins and their receptors are now known to be expressed in the gastrointestinal system, as well. Administration of orexin A elicits an OX1R-receptor-sensitive hyperphagic response that is less potent than that of NPY but comparable to that of melanin-concentrating hormone (MCH). In rodents, acute administration of orexin A induces a transient orexinogenic effect that is preceded by anorexia with no net increase in food intake over a 24-hour period. It is therefore not surprising that chronic administration of orexin A does not induce obesity, unlike the orexigenic neuropeptides, NPY, and Agouti-related protein (AGRP). OX1R antagonists such as SB-334867 not only reverse orexin-Ainduced hyperphagia but may also induce satiety when administered alone. Interestingly, orexin-Ainduced feeding can also be blocked by nonselective opioid antagonist and partially reversed by NPY Y1 receptor antagonist, suggesting that the control of food intake involves an integration of various pathways. The hyperphagic effect of orexin A is supported by the observation that mice lacking preproorexin are hypophagic with normal body weight. Hypophagia is also observed in the selective deletion of orexin neurons using ataxin-3 in mice. Ataxin-3-treated mice develop late-onset obesity, an effect that can be ascribed to an orexin-induced increase in thermogenesis. In contrast, orexin B induces little or no hyperphagic response and promotes grooming and searching activities. Although these observations indicate that the orexin system does play the main regulatory role in food intake, OX1R antagonists have the potential to reduce food intake and reduce body weight.

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MELANOCORTIN The melanocortin (MC) system consists of a group of four peptides: α-, β-, and γ-melanocytestimulating hormones and ACTH, which are derived from posttranslational cleavage of the precursor molecule proopiomelanocortin. Other members of the system include two endogenous antagonists (Agouti and AGRP) and ﬁve melanocortin receptor subtypes (MC1R to MC5R). Although the behavioral effects of ACTH and α-MSH have been known since 1955, it was not until the 1980s that the regulatory effect of MC peptides on food intake was illustrated. So far, two receptor subtypes, MC4R and, to a lesser extent, MC3R (also known as the central receptors), have been implicated in the regulation of food intake. MC3R is highly expressed in hypothalamic nuclei that control feeding such as ventromedial hypothalamus, arcuate nucleus, lateral hypothalamus, and preoptic nucleus. MC4R is more widely expressed in multiple parts of the brain, including hypothalamic dorsal medial nucleus and PVN, which receive projections from ARC. Interestingly, MC3R and MC4R receptors are activated by all of the four MC peptides, with α-MSH exhibiting the highest selectivity for MC3R. In general, MC peptides suppress food intake and reverse a positive energy balance, while MCR antagonists increase food intake and body weight. For example, the endogenous antagonists Agouti and AGRP are competitive antagonists at MC4R that elicit a hyperphagic response. Similarly, synthetic selective MC4R inhibitors such as HS024, HS028, and SHU9119 induce hyperphagia in both normal and satiated mice. Targeted gene deletion of central MC receptors (MC4R and NC3R) and precursor molecules (POMC) can result in obese mice. Mice deﬁcient in MC4R are hyperphagic and exhibit an obese phenotype. Additionally, evidence suggests that the MC system interacts with other systems to regulate food intake; for example, in mice, centrally administered MCR agonists attenuate fasting or NPY-induced hyperphagia. On the other hand, NPY1 receptor inhibitors attenuate hyperphagia induced by selective MC4R antagonists. MC4R antagonists also attenuate the effects of leptin on food intake and body weight, suggesting the involvement of the MC system in the effects of leptin. In support of this hypothesis, leptin has been reported to stimulate hypothalamic POMC mRNA. Furthermore, administration of peripheral and central leptin to obese MC4R knockout mice does not alter food intake, thus implicating MC4R in the regulation of food intake by leptin. The effects of individual MC peptides on food intake are summarized below: •

•

α-MSH — α-MSH is a 13-amino-acid MC receptor agonist that appears to be the primary endogenous agonist for central MC receptors mediating suppression of food intake. It is expressed in both central (highest levels in the hypothalamus) and peripheral tissues. Central administration of α-MSH has been shown to induce suppression of food intake in experimental animals such as the rat. Injection of α-MSH into the ventricles of fasted rats has been shown to attenuate food intake. It also reverses NPY-mediated or darkphase-mediated feeding following administration into the paraventricular nucleus. In addition to its central effects, α-MSH exhibits peripheral effects on weight gain; for example, it elicits weight loss in POMC-deﬁcient and diet-induced obese mice. Taken together, these data suggest that α-MSH plays a vital role in MC-mediated inhibition of food intake. β-MSH — β-MSH is a 22-amino-acid peptide derived from the C-terminus fragment of POMC that exhibits a higher afﬁnity for MC4R than α-MSH or γ-MSH in humans and rats. Findings regarding its effect on the regulation of food intake are conﬂicting. Whereas it has been reported to be equivalent to α-MSH in attenuating food intake in rats fasted for 24 hours, other studies indicate it failed to reduce the food intake of rats fasted for 48 hours. Evidence from other studies suggests a dose-dependent attenuation of food intake in freely feeding rats after i.c.v. administration of β-MSH. Although some data suggest that β-MSH is involved in the regulation of food intake, the exact nature of its involvement remains to be fully elucidated.

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ACTH — ACTH is a 39-amino-acid peptide formed by the action of PC1 on POMC in anterior pituitary corticotrophs; it plays a signiﬁcant role in the regulation of appetite. Cleavage of ACTH by PC2 yields α-MSH. Other fragments of ACTH include ACTH(1–16), ACTH(4–16) and ACTH(7–16). Interestingly, ACTH is the only endogenous MC that activates all ﬁve MCRs. The anorectic effects of ACTH are mediated by ACTH(1–24), whose activity is protected by ACTH(25–39). Central administration of ACTH(1–24) attenuates feeding in both fasted and freely feeding rat. Furthermore, ACTH(1–24) was found to inhibit the hyperphagic effect of intraperitoneally administered kappa opiate agonists. Neither adrenalectomy nor subcutaneous administration (dose up to 200 µg/kg in rats) of ACTH(1–24) was found to suppress food intake, suggesting that the anorectic effects of ACTH are not linked to adrenal steroids nor are they mediated by interaction with peripheral feeding regulatory pathways but via sites in the central nervous system.

In summary, evidence from studies using experimental animals clearly demonstrates a role for several neuropeptides in the regulation of appetite and feeding behavior. The wide array of neuropeptides involved offers great potential for the identiﬁcation of several classes of these agents that could ultimately be employed in the treatment of obesity in humans.

OTHER CHEMICALS AND RELEVANT PHARMACOLOGICAL RECEPTORS ENDOCANNABINOIDS It is well known that the cannabis plant (Cannabis sativa) and its extract have an appetite-stimulating action due to the presence of the psychoactive compound ∆9-tetrahydrocannabinol (THC). The discovery of endogenous ligands for plant-derived cannabinoids (endocannabinoids) has led to the description of a physiological basis for the efﬁcacy of these compounds in experimental animals and humans. Endocannabinoids are derived from arachidonic acid, and they include substances such as anandamide and 2-arachidonoylglycerol (2-AG). In low doses, centrally or systemically administered THC has been shown to stimulate feeding in a variety of animal models. In high doses, THC can decrease feeding due to its potent sedative actions. In humans, THC has also been reported to increase food intake, a factor that has been found to be beneﬁcial in the treatment of conditions involving appetite loss such as AIDS and cancer. It is important to note that the hyperphagic effects of THC can be mimicked by endocannabinoids, anandamide, and 2-AG. Endocannabinoids have been linked with a physiological process involved in the regulation of feeding behavior. Increased concentrations of anandamide and 2-AG have been found in the nucleus accumbens during fasting. A decline in the 2-AG level was found during the feeding state, suggesting that the endocannabinoids play an important role in the motivation to obtain food. Both exogenous cannabinoids and endocannabinoids increase food intake and promote weight gain by stimulating two subtypes of receptors: CB1 and CB2. CB1 receptors are found in the central nervous system and some peripheral tissues, whereas CB2 receptors are localized in peripheral immune cells. CB1 receptors are linked to the regulation of appetite and feeding behavior. Evidence suggests that the pharmacological blockade of CB1 receptors with drugs such as rimonabant (SR141716) produces a reduction of food intake and body weight. Indeed, CB1 gene-deﬁcient mice are found to be lean and resistant to diet-induced obesity. In summary, it appears that endocannabinoids, acting on brain CB1 receptors, can stimulate appetite and feeding behavior in both experimental animals and humans. The discovery of the link between endocannabinoids and their potential to regulate feeding behavior provides immense opportunities for the treatment of diseases or conditions that require either an increase or decrease in appetite.

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SUMMARY AND CONCLUSIONS A wide variety of neurotransmitters and neuropeptides are involved in the regulation of appetite and feeding behavior in both experimental animals and humans. Receptors for classical neurotransmitters (5-hydroxytryptamine, norepinephrine, and histamine) are well known and appear to be ready targets for the development of compounds with therapeutic potential as anti-obesity drugs. The neuropeptides NPY, galanin, corticotropin-releasing factor, orexin, and melanocortin are a diverse group with the potential to interact with classical neurotransmitters in the pathways involved in appetite and food regulation. The discovery of endocannabinoids and their receptors has revealed additional targets for the manipulation of pathways that control food intake in experimental animals and humans. In conclusion, concerted efforts should be focused on the effects of the neurotransmitters and neuropeptides that are important in the regulation of food intake and energy metabolism in humans. It may well be that formulations that contain more than one neurotransmitter or neuropeptide could produce the optimum action in terms of controlling food intake and energy metabolism.

BIBLIOGRAPHY Bays, H.E., Current and investigational antiobesity agents and obesity therapeutic treatment targets, Obesity Res., 12 (8), 1197–1211, 2004. Cerulli, J., Lomaestro, B.M., and Malone, M., Update on the pharmacotherapy of obesity, Ann. Pharmacother., 32, 88-102, 1998. Feletou, M. and Levens, N.R., Neuropeptide Y2 receptors as drug targets for the central regulation of body weight, Curr. Opin. Invest. Drugs, 6(10), 1002–1011, 2005. Halford, J.C.G., Pharmacology of appetite suppression: implication for the treatment of obesity, Curr. Drug Targets, 2, 353–370, 2001. Halford, J.C.G., Harrold, J.A., Lawton, C.L., and Blundell, J.E., Serotonin (5-HT) drugs: effects on appetite expression and use for the treatment of obesity, Curr. Drug Targets, 6, 201–213, 2005. Haynes, A.C., Jackson, B., Overend, P. et al., Effects of single and chronic intracerebroventricular administration of the orexins on feeding in the rat, Peptides, 20, 1099–1105, 1999. Irani, B.G. and Haskell-Luevano, C., Feeding effects of melanocortin ligands: a historical perspective, Peptides, 26, 1788–1799, 2005. King, P.J., The hypothalamus and obesity, Curr. Drug Targets, 6, 225–240, 2005. Kirkham, T.C., Endocannabinoids in the regulation of appetite and body weight, Behav. Pharmacol., 16, 297–313, 2005. Mastorakos, G. and Zapanti, E., The hypothalamic–pituitary–adrenal axis in the neuroendocrine regulation of food intake and obesity: the role of corticotropin releasing hormone, Nutr. Neurosci., 7(5/6), 271–280, 2004. Souza, C.J. and Burkey, B.F., Beta3-adrenoceptor agonists as anti-diabetic and anti-obesity drugs in humans, Curr. Pharmaceut. Des., 7, 1433–1449, 2001. Wang, G.J., Volkow, N.D., and Fowler, J.S., The role of dopamine in motivation for food in humans: implications for obesity, Expert Opin., 6(5), 601–609, 2002. Xu, Y.-L., Jackson, V.R., and Civelli, O., Orphan G protein-coupled receptors and obesity, Eur. J. Pharmacol., 500, 243–253, 2004. Xu, Z.Q.D., Zheng, K., and Hokfelt, T., Electrophysiological studies of galanin effects in brain: progress during the last six years, Neuropeptides, 39, 269–275, 2005.

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7 Neurobiology of Obesity Nina Eikelis CONTENTS Introduction ......................................................................................................................................81 Obesity Epidemic.............................................................................................................................82 Regulation of Body Weight .............................................................................................................82 Leptin ...............................................................................................................................................83 The ob Gene..............................................................................................................................83 The Leptin Protein ....................................................................................................................83 Leptin Receptors (Ob-R) ..........................................................................................................84 Transport of Leptin into the CNS....................................................................................................85 Leptin and Eating Disorders ............................................................................................................86 Mechanisms of Leptin Action in the Brain.....................................................................................86 Leptin Resistance in Obesity ...........................................................................................................87 Leptin Signaling Pathways ..............................................................................................................88 Role of Neuropeptide Y in the Control of Food Intake...........................................................88 Central Melanocortin System in the Regulation of Food Intake.............................................89 Ghrelin Effects in the Hypothalamus .......................................................................................90 Conclusions ......................................................................................................................................90 References ........................................................................................................................................91

INTRODUCTION Food is a necessity of life, like sleep. It is also one of the pleasures of life. We may eat when we are not hungry just because it tastes, looks, or smells good! In fact, a lot of people will eat much more than their bodies actually need for fuel. Not surprisingly, the obesity epidemic is sweeping the world. Obese people go to extreme measures in hopes of gaining control over their body weight, but why is it so difﬁcult to control our body weight? In recent years, remarkable progress has been made in our understanding of the molecular basis of obesity. The mammalian energy balance is controlled by complex networks between brain structures, such as the hypothalamus, brainstem, and higher brain centers, and in the periphery between the stomach, gut, liver, thyroid, and adipose tissue. Advances in molecular techniques have resulted in major advances being made in the understanding of hypothalamic circuits involved in body weight regulation. More than ten years ago scientists discovered a gene (ob gene), a mutation of which causes severe obesity in a strain of laboratory mice. This gene encodes a hormone, leptin, which is mainly secreted by fat cells and acts within the hypothalamus to reduce appetite and increase energy expenditure. When mice are injected with leptin, they lose weight dramatically. Overweight people have elevated leptin levels due to increased adipose tissue mass; however, they seem to be leptin resistant when it comes to its anorexigenic effects — despite high levels of leptin levels, they continue to overeat. Several mechanisms have been suggested to explain leptin resistance in humans, such as impaired leptin transport in the brain, where it informs the central nervous system about the state of body fat, defects in leptin receptor, or altered leptin downstream signaling. 81

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OBESITY EPIDEMIC The Western world is experiencing an epidemic. Although people should be aware of this epidemic, as the evidence is literally under our noses, the rise in obesity prevalence continues to sweep the world unabated. Globally, more than 1 billion adults are overweight, and at least 300 million of these are obese. Often coexisting in developing countries with undernutrition, obesity is a multidimensional condition affecting virtually all ages and socioeconomic groups. Alarmingly, this trend is even greater in young children, suggesting that this problem will escalate in the foreseeable future. Why is this happening? A decade or two ago it was common to blame the individual for being overweight. While there is no doubt that the rising epidemic to a great extent reﬂects changes in lifestyle due to a simultaneous decrease in activity and increase in caloric intake, today a different approach is being taken to address the problem of weight control that considers the strong and complex factors involved in the tendency to increase body weight. Twin and adoption studies, as well as experimental models of obesity, now indicate that obesity results from both genetic and environmental factors. The health, economic, and psychosocial consequences of obesity are substantial. The health consequences of obesity range from a number of nonfatal complaints that impact on the quality of life, such as skin problems (particularly infections in ﬂexural creases), respiratory difﬁculties, and infertility, to complaints that reﬂect an increased risk of premature death, including diabetes, gallbladder disease, and cardiovascular problems (hypertension, stroke, and heart disease). Hypertension and diabetes, for example, are between two and six times more prevalent among heavier people. From a social perspective, being overweight may have deleterious effects on a person’s selfesteem, social and economic characteristics, and physical health. In our culture, being thin means more than just good health; it symbolizes self-control, hard work, ambition, and success in life. Positive attributes are assigned to thin people, whereas those with less than perfect bodies are often thought to be lazy and self-indulgent.

REGULATION OF BODY WEIGHT The regulation of body weight may be considered a homeostatic process, directed at conserving an energy balance, seeking food in times of need and storing energy in times of plenty; however, the homeostatic system in humans is strongly biased toward weight gain and storage of fat, with only a few mechanisms that encourage weight loss. This biased homeostatic system is probably due to little evolutionary pressure to decrease food intake once energy stores are full [1]. Regulation of body weight in humans involves genetic, environmental, and psychosocial factors that affect the physiological regulators of food intake and energy expenditure [2]. Most animals, including humans, can maintain constant body weight over prolonged periods of time. This means that energy intake (derived from ingested foods) must equal energy expenditure over a long term to maintain a stable body weight. Although the equation seems pretty straightforward, regulation of body weight is actually a far more complex interplay of energy intake and expenditure, satiety factors, and other controls of appetite. Food intake elicits sensory inputs — nutrient and gastrointestinal signals mediated by distension of the stomach or local hormones, which together modulate appetite. The mechanisms involve various neurotransmitters, such as norepinephrine, dopamine, serotonin, orexins, melanocortins, and neuropeptide Y (NPY), to name just a few [3]. All of these signals produce neural and humoral outputs that cause appropriate adjustments in nutrient intake and metabolism [4]. Many of the hormones that are involved in the regulation of body weight via appetite and satiety are released from the gastrointestinal tract after a meal. Some of these are cholecystokinin, glucagon, and gastrin-releasing peptide, which act by reducing food intake after a meal. Nutrients such as glucose and fatty acids provide another signal that regulates food intake. Long-term regulators of food intake include insulin, ghrelin, corticosteroids, and leptin.

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In addition to appetite, thermogenesis is another mechanism involved in body weight regulation. Several prospective studies have shown that a relatively low energy expenditure predicts body weight gain [5–7]. Results from most overfeeding studies indicate that short-term, diet-induced weight gain is associated with an increase in energy expenditure [8,9]. Similarly, underfeeding is accompanied by a decrease in energy expenditure beyond the predicted values [10–12]. Such overcompensatory metabolic changes are presumably acting to oppose any further weight gain. It is currently assumed that the major factors involved in obesity include the genetic background of an individual and the individual’s dietary and physical activity habits. The role of inheritance in human obesity has been extensively studied over the last decade, with adoption and twin studies showing that obesity has a genetic component. More recently, the studies have shown that both body fat mass and partitioning between central and peripheral fat depots are inﬂuenced by genetics [13]. It is likely, therefore, that genes involved in weight gain increase the susceptibility of an individual to develop obesity when exposed to an environment that favors positive energy balance. The discovery and cloning of speciﬁc genes involved in fat accumulation have led to a renewed interest in genetic factors responsible for the development of human obesity. The relatively recent isolation of the ob gene, which encodes leptin, has attracted particular attention. Other genetic mutations that lead to the excessive accumulation of fat in animal models have also been identiﬁed, and some of them involve the leptin receptor, melanocortin-4 receptor, and proopiomelanocortin (POMC). Body weight is regulated by the central nervous system, which can sense the body’s metabolic status from a wide range of humoral and neural signals. The integration of the signals takes place largely, but not solely, in the hypothalamus. The hypothalamus is the structure that is generally considered to be the most sensitive to manipulations that modulate appetite and eating behaviors. Hypothalamic amines, hormones, and neurotransmitters participate in a complex network of systems that inﬂuence eating behavior and the metabolism of speciﬁc nutrients. Stimulation of some systems results in an increase in food consumption, while stimulation of other systems results in a reduction in food intake and storage; therefore, it is likely that disturbances in one or many of these systems may underlie body weight changes.

LEPTIN THE Ob GENE The ob gene was ﬁrst discovered in adipose tissue of the obese mouse through positional cloning [14]. The full coding sequence contains 167 amino acids and represents a 21-amino-acid signal peptide and 146-amino-acid circulating bioactive hormone [14]. In both human and mouse, the leptin gene is composed of three exons and two introns. Interestingly, the leptin peptide has structural similarities to members of the cytokine family [15]. In mammals, leptin is predominantly produced in adipose tissue and secreted into the bloodstream; however, non-adipocyte leptin production has been also documented in the stomach [16], placenta [17], and brain [18,19]. Nonadipose sources of leptin production may perhaps suggest a far more complex role for leptin than originally thought.

THE LEPTIN PROTEIN The ob gene codes for a protein secreted by fat cells. This protein is hypothesized to regulate fat storage by signaling the brain to suppress appetite when the body’s fat stores are full. When mutated in mice, the ob gene is no longer able to express leptin and therefore can no longer deliver its appetite-suppressing message. The mice consequently develop a syndrome that resembles extreme obesity and type 2 diabetes in humans. Human leptin is 84% homologous to mouse and 83%

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Leptin Leptin binding to its receptor

Ob-Rb

Jak

Jak

Jak

Jak

Tyr

Tyr

P

P STAT

phosphorylation

STAT

P

STAT STAT

STAT

plasma membrane

P

STAT

P

STAT

nuclear membrane P

transcription

FIGURE 7.1 Schematic representation of leptin signaling cascade. Leptin–Ob-Rb complex formation leads to the induction of tyrosine phosphorylation through its association with JAK2, which leads to the activation of STAT proteins.

homologous to rat leptin. Leptin consists of four antiparallel α-helices (A, B, C, and D), connected by two long crossover links (AB and CD) and one short loop (BC), arranged in a left-handed twisted helical bundle. The four-helix bundle is folded as packing of antiparallel helix pairs A and D against B and C; a disulﬁde bond between the C-terminus of the protein and the beginning of the CD loop is important for stability and biological activity [20].

LEPTIN RECEPTORS (OB-R) Leptin is predominantly produced by adipocytes, but leptin receptors are located in many tissues. The leptin receptor is encoded by the diabetes (db) gene. Tartaglia et al. [21] were the ﬁrst to isolate and describe the leptin receptor (Ob-R) in a mouse. To date, at least six leptin receptor isoforms have been described [22]. Alternative gene splicing explains the number of leptin receptors. All isoforms share the same extracellular domain; however, only one of them, the long form, has all of the intracellular motifs required for signal transduction via the JAK/STAT pathway (Figure 7.1). Based on sequence homology, the Ob-R belongs to the class I cytokine receptor family, which includes receptors for interleukin 6, leukocyte inhibitory factor, and granulocyte-colony-stimulating factor [23]. Leptin–Ob-Rb complex formation leads to the induction of tyrosine phosphorylation through its association with JAK2 (Figure 7.1). The activated JAK2 phosphorylates a distal tyrosine (Tyr-1138) on the receptor, similar to STAT proteins. Although leptin can activate STAT1, STAT3, STAT5, and STAT6, it only activates STAT3 in the rodent hypothalamus. Mutations in the functional leptin receptor result in an obese phenotype identical to that of ob mice. In fatty Zucker rats, a point mutation in the extracellular domain inhibits signal transduction. On the other hand, db/db mice predominantly express the short form of leptin receptor, which leaves these mice with a nonsignaling leptin receptor system. Ob-Rb is highly expressed in the hypothalamus. Experimental studies have identiﬁed the hypothalamic arcuate nucleus (ARC),

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dorsomedial nucleus of the hypothalamus (DMH), paraventricular nucleus (PVN), ventromedial nucleus of the hypothalamus (VMH), and lateral hypothalamic nucleus as the principal sites of leptin receptor expression in the central nervous system [24,25]. Each of these nuclei is important in regulating body weight. A soluble form of leptin receptor consisting of an extracellular domain only also exists. It binds leptin with an afﬁnity similar to that of membrane receptors. Results from animal experiments have demonstrated that the soluble form of leptin receptor may modulate leptin levels in plasma by delaying its clearance and it may determine the amount of free vs. bound leptin [26]. In obese subjects, a considerable greater proportion of leptin circulates in the free form compared to lean individuals, and the amount of free leptin increases with increasing body mass index (BMI), suggesting that the soluble form of this receptor is saturated in the state of obesity [27]. In addition, short-term fasting results in a decrease of total leptin levels, which is mostly attributable to the decrease in free leptin. Mutations in the db gene are extremely rare in humans. The ﬁrst case of leptin receptor mutation was ﬁrst described by Clement [22]. In these patients, a single G–A substitution in the splice donor site of exon 16 resulted in a nonfunctional leptin receptor lacking both transmembrane and intracellular domain. As a result of that mutation, the truncated leptin receptor is unable to activate the STAT signal transduction pathway. Similar to the ob gene mutation in humans, human db mutation results in hyperphagia and early-onset obesity, with BMIs reaching as high as 70 kg/m2.

TRANSPORT OF LEPTIN INTO THE CNS Leptin is primarily secreted by adipocytes, circulates in blood (in part while linked to binding proteins), and exerts its effects in speciﬁc regions of the brain. The delivery of leptin into the brain represents a crucial step toward the regulation of body weight and energy balance. How leptin gains access to speciﬁc regions in the brain is still a controversial issue. Different studies have demonstrated the presence of leptin receptors in the brain capillaries as well as the binding of leptin to human and mouse brain capillaries [28,29]. Potentially, the presence of leptin receptors in the brain capillaries would allow leptin access through the capillary wall to speciﬁc regions (such as hypothalamic nuclei) to exert its effects. In rodents, leptin enters the brain via saturable transport mechanisms across the blood–brain barrier. Results from the previous studies demonstrated that brain microvessels express the short form of the leptin receptor (Ob-Ra) at a high rate. It has been suggested that the same short form of leptin receptor, which is highly expressed in the choroid plexus (the site of cerebrospinal ﬂuid [CSF] production), mediates blood-to-CSF leptin transport. In fact, the experiments conducted by Hileman and coworkers [30] on Madin–Darby canine kidney showed that the short form of leptin receptor is capable of mediating transcellular transport of leptin. These data further suggest that the short form of the leptin receptor expressed at the blood–brain barrier is capable of transporting leptin from the circulation into the brain. It is also of interest to note that the receptor is preferentially expressed on the apical membrane, which faces the bloodstream; therefore, the Ob-Ra is well positioned to mediate the transport of leptin from the circulation into the brain. Once in the brain, leptin can reach the neurons containing the long form signaling leptin receptor (Ob-Rb) to activate the signal transduction pathway [30]. These data are supportive of the concept that Ob-Ra mediates the passage of leptin across the cerebral microvessels that constitute the blood–brain barrier. Furthermore, deﬁcits in Ob-Ra function at this site could result in leptin resistance. On the other hand, leptin is present in the CSF of Koletsky rats, which lack leptin receptors altogether, thereby suggesting that leptin receptors are perhaps not essential for leptin receptor transport into CSF. In addition, recent evidence from our laboratory also suggests that leptin is actually synthesized by the human brain itself, as evident from the net leptin efﬂux into the internal jugular vein [19,31,32], as well as leptin mRNA expression in human cadaver hypothalami [33,34].

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Human obesity is characterized by a state of leptin resistance, which is likely caused by a combination of resistance at the receptor and post-receptor levels, as well as reduced transport of circulating leptin across the blood–brain barrier. A few lines of evidence have suggested impaired leptin transport across the blood–brain barrier; for example, it has been demonstrated that obese humans have a reduced CSF-to-serum ratio for leptin. Experimental evidence also supports the idea of impaired leptin transport across the brain in obesity by showing that some obese animal models that no longer respond to peripherally administered leptin can still respond to leptin given centrally.

LEPTIN AND EATING DISORDERS Because eating disorders such as anorexia nervosa and bulimia nervosa are characterized by abnormal eating behaviors, dysregulation of endogenous endocrine axes, alterations of reproductive and immune functions, and increased physical activity, extensive research has been carried out in the last decade to ascertain a role of leptin in the pathophysiology of eating disorders. It has been reported that plasma leptin levels are dramatically reduced in underweight anorectic patients as compared to healthy age-matched people [35]; however, although markedly reduced, circulating leptin is signiﬁcantly and positively correlated with the person’s BMI, indicating that even at extremely low body weight and fat circulating leptin still functions as a signal of energy stores. Longitudinal studies have shown that, in anorexia nervosa patients undergoing refeeding during recovery, circulating leptin levels increase progressively and reach values disproportionately higher than compared to stable-weight healthy people [35]. It has even been suggested that hyperleptinemia in these patients during refeeding treatment may be one of the factors making it difﬁcult for patients to reach and maintain their target weights. In fact, it has been demonstrated that, in patients undergoing refeeding treatment, too rapid of a weight gain followed by hyperleptinemia is associated with poor prognosis [36]. In normal-weight patients with bulimia nervosa, plasma leptin levels have been reported to be increased, decreased, or normal [37–39]. The reason for such a discrepancy among the results may be due to the heterogeneous composition of the patient groups. It seems that a group of bulimic patients hyposecreted leptin despite their body weights being similar to otherwise healthy people [37]; therefore, even if body weight is a major determinant of circulating leptin levels, other factors are likely to be involved in suppressing leptin production in these patients. It has been proposed that the chronicity and severity of the illness could be determinants of the leptin hyposecretion [37]. Although leptin does not seem to be directly involved in the pathogenesis of eating disorders, derangements in its physiology may contribute to some clinical alterations occurring in the course of these disorders.

MECHANISMS OF LEPTIN ACTION IN THE BRAIN The brain has been hypothesized to be the primary site of leptin action, as peripherally administered leptin has been shown to rapidly induce the hypothalamic signal transduction pathway. In situ hybridization studies have shown that the Ob-Rb is predominantly expressed in hypothalamic nuclei such as the arcuate nucleus (ARC), the dorsomedial nucleus of the hypothalamus (DMH), the paraventricular nucleus (PVN), the ventromedial nucleus of the hypothalamus (VMH), and lateral hypothalamus (LH). Early experimental work demonstrated that destruction of the PVN and VMH produced hyperphagia and obesity, while lesions to the LH caused anorexia. Leptin-sensitive neurons in the hypothalamus are known to express neuropeptides and neurotransmitters involved in the central regulation of appetite. The long-form leptin receptor has been shown to be coexpressed with neuropeptide Y (NPY), Agouti-related peptide (AGRP), proopiomelanocortin (POMC), and cocaine- and amphetamine-regulated transcript (CART) in the arcuate nucleus; therefore, leptin-

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sensitive neurons in the arcuate nucleus may inﬂuence other peptides involved in the regulation of appetite. In addition, leptin is known to modulate the effects of the orexigenic peptides in the brain by inhibiting their synthesis, such as in the case of NPY [40,41].

LEPTIN RESISTANCE IN OBESITY The observation that high leptin levels in overweight and obese individuals fail to induce weight loss has given rise to the notion of “leptin resistance.” Although the mechanisms underlying leptin resistance are still a matter of considerable research, a number of biological processes hypothesized to be involved include leptin binding to bloodborne proteins (one of which is the soluble leptin receptor), active and passive transport of leptin into the brain, leptin receptor expression levels, and alterations of leptin receptor second-messenger responsiveness [22]. The failure of leptin to reach its target in the brain, in particular the hypothalamus, has received much attention. Experimental studies provided some evidence of leptin-impaired transport across the blood–brain barrier in animal models of diet-induced obesity [42]. Moreover, in some animal models, the delivery of leptin into the central nervous system seems to be a crucial step toward the regulation of food intake and energy balance. Different studies have shown the presence of speciﬁc leptin receptors in the brain capillaries as well as the binding of leptin to brain capillaries [28,43]. Thus, the presence of the leptin receptors on endothelial cells would suggest that leptin can gain access to the speciﬁc hypothalamic nuclei to initiate the signaling cascade. Leptin has also been shown to be transported by a saturable transport system, the activity of which is impaired in obesity [44]. When ﬁrst discovered, leptin was thought to be secreted exclusively by adipocytes into the bloodstream [14]. Later evidence, however, suggests that adipose tissue may not be the only site of leptin production due to the demonstration of leptin gene expression in other tissues, such as stomach [16], placenta [45], and skeletal muscles [46]. The results of previous studies from our laboratory demonstrated a net efﬂux of leptin from the brain into the internal jugular veins [19,32]. This observation suggests that perhaps the brain itself produces leptin, which is subsequently released into the circulation and contributes to the total leptin plasma pool [32]. In fact, leptin mRNA expression has been shown in the rat pituitary and the brain [18]. Another possible mechanism in leptin resistance could involve defects in the leptin receptor. A few isoforms of the leptin receptor are spliced abnormally and therefore do not result in the appropriate signal transduction. The mutation of the db gene generates a truncated version of the leptin receptor that lacks most of the intracellular domain. In fa/fa Zucker rats, a missense mutation occurs in the leptin receptor. This mutation causes obesity, despite the fact that the expression of the leptin gene is signiﬁcantly augmented. These examples demonstrate that the defects in the leptin receptor may result in leptin resistance. An extensive search has been conducted in the human hypothalamic leptin receptors for possible variations that would explain the leptin resistance in human obesity. The full-length functional receptor, Ob-Rb, was found to be expressed in the human hypothalamus. In addition, no abnormal splicing of the human leptin receptor was observed, and no difference was found in leptin receptor mRNA expression between lean and obese individuals. Some sequence variations have been detected in the human leptin receptor, with most variations being the single-base substitutions that did not result in a change in the amino acid. A single-base substitution was detected in the leptin receptor gene that results in the change of the amino acid from glutamine to arginine; however, this substitution was detected in both lean and obese individuals, thus making it unlikely that this polymorphism is the basis for leptin resistance in humans. A few mutations in the human leptin receptor gene result in the truncated receptor being unable to activate the signal transduction pathway. These mutations result in early-onset obesity, highlighting the importance of leptin in body weight regulation in humans. Mutations in the leptin receptor gene are very rare in humans, however.

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ladder

BMI

30

19

28

25

28

38

439 bp

FIGURE 7.2 Leptin receptor (Ob-Rb) expression in the human hypothalamus of six donors of different body mass index (BMI). No association was found between adiposity and Ob-Rb expression.

We have examined full-length leptin receptor expression (Ob-Rb) in the human hypothalamus in males and females across a broad range of BMIs (Figure 7.2); however, we have not found any relation between the level of its expression and adiposity, suggesting that other factors must operate that regulate Ob-Rb levels. So, it would seem that leptin resistance cannot simply be explained on the basis of mutations in the leptin receptor. Because most cases of human obesity are not associated with inappropriate leptin levels or mutated leptin receptor, a defect could lie in the signaling cascade. Suppressor of cytokine signaling 3 (SOCS-3) has been demonstrated to play a role in leptin resistance [47]. SOCS proteins are negative regulators of the JAK/STAT signaling pathways. It has been shown experimentally that injection of leptin stimulates the production of SOCS-3. The signaling cascade induced by leptin binding to its receptor is blocked due to SOCS-3 binding to leptin. Although several biological mechanisms that may participate in leptin resistance have been identiﬁed, the sequence of events that initiate this state, as well as treatment possibilities, still remain to be determined.

LEPTIN SIGNALING PATHWAYS It is clear that leptin and its receptors are only one of many maybe important determinants in the control of body weight and the pathogenesis of obesity (Table 7.1). It has been proposed that two classes of neurons account for the actions of leptin in the central nervous system: NPY- and POMCcontaining neurons (Figure 7.3).

ROLE

OF

NEUROPEPTIDE Y

IN THE

CONTROL

OF

FOOD INTAKE

Neuropeptide Y (NPY), a 36-amino-acid protein, is synthesized as a long precursor molecule with the active portion at the amino end of the polypeptide. It is expressed in many areas of the brain and acts as a transmitter in the nervous system. It selectively binds to Y1 and Y5 receptors in the hypothalamus and is a potent stimulator of feeding. Most attention given to the role of NPY in feeding behavior has focused on its central action in the hypothalamus, where a single injection of NPY stimulates overeating, and its repeated administration results in obesity. NPY seems to be a partner of leptin in the regulation of body fat through its participation in the energy balance and neuroendocrine signaling. Leptin appears to inhibit feeding partly by suppressing the synthesis of NPY. Not surprisingly, leptin deﬁciency results in elevation of the central NPY levels. To examine the role that NPY plays in feeding behavior, scientists have examined NPY gene knockout mutants. Because knockout NPY mutant mice birth rates follow mathematical probability calculations and these mice have normal lives and fertility, it can be concluded that the presence of NPY is not vital to maintain a seemingly normal feeding and body weight regulation. Although NPY is clearly involved in the control of feeding behavior, leptin effects on body weight are only partly mediated by its effects on NPY expression. No doubt other overlapping systems are involved in the control of food intake and energy homeostasis.

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TABLE 7.1 Neuropeptide Systems Involved in the Control of Food Intake Orexigenic (Increase Energy Intake)

Anorexigenic (Decrease Energy Intake)

Agouti-related peptide (AGRP) Neuropeptide Y (NPY) Melanin-concentrating hormone Ghrelin Orexin Opioid

Leptin α-Melanocyte-stimulating hormone (α-MSH) Cholecystokinin (CCK) Corticotropin-releasing factor (CRF) Glucagon Neurotensin

CENTRAL MELANOCORTIN SYSTEM

IN THE

REGULATION

OF

FOOD INTAKE

One of the central systems activated by leptin is the melanocortin system. The melanocortin system refers to a family of peptide hormones and hormone receptors that controls a number of functions in our bodies such as energy metabolism, sexual functions, and skin pigmentation. Bioactive peptides, generated from the prohormone proopiomelanocortin (POMC), are key regulators of appetite control and energy homeostasis. It is therefore important to understand many aspects of POMC gene regulation, particularly in the brain, as pharmacological manipulations of POMC expression and processing could be a potential strategy to combat obesity. Proteolytic processing of POMC results in a number of different hormones and neuropeptides that are mainly divided into two classes: melanocortins and endorphins. Melanocortin peptides include adrenocorticotropin and α-, β-, γ-melanocyte-stimulating hormones (MSHs), which exert their effects via G-protein-coupled melanocortin receptors (MC1 through to MC5). Agouti-related peptide (AGRP) is a naturally occurring antagonist of melanocortin action. It is a neuropeptide expressed in the arcuate nucleus of the hypothalamus that increases appetite and decreases metabolism. It is one of the most potent and longest lasting appetite stimulators. AGRP levels are elevated in obese males [48]. AGRP is an endogenous antagonist at the MC3 and MC4 receptors, whereas POMC products, such as α-MSH, act as agonists [49]. Leptin has been shown to activate AGRP-containing neurons and POMC/CART-containing neurons in the hypothalamus via activation of the long-form leptin receptor coexpressed in these neurons. Central infusion of leptin stimulates expression of the POMC gene while reducing expression of the AGRP gene in the arcuate nucleus of the hypothalamus. Not surprisingly, animals deﬁcient in either leptin or leptin-signaling pathways have increased levels of AGRP but reduced POMC levels. Potential signaling pathways in the regulation of food intake

Fasting

Overeating

Stomach ghrelin release

Leptin levels

Stomach ghrelin release

Leptin levels

Hypothalamic NPY/AGRP

-MSH

Hypothalamic NPY/AGRP

-MSH

Energy expenditure

Food intake

Energy expenditure

Food intake

FIGURE 7.3 Schematic representation of the potential signaling pathways in the regulation of food intake.

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The melanocortin system plays a key role in the central control of appetite and energy expenditure, which is highlighted by the studies showing that mice deﬁcient in MC4 receptors, as well as mice with increased levels of AGRP, are obese. In humans, mutations in the α-MSH gene also lead to obesity. Abnormalities in the melanocortin system produce obesity through changes in appetite and food intake; moreover, melanocortin agonists have been shown to suppress appetite. Animals and humans with defects in the central melanocortin system display a characteristic melanocortin obesity phenotype typiﬁed by increased adiposity, hyperphagia, metabolic defects, and increased linear growth.

GHRELIN EFFECTS

IN THE

HYPOTHALAMUS

The hormone ghrelin is expressed mainly in the stomach. It was initially discovered as the endogenous ligand of the growth hormone secretagogue receptor type 1a [50]. Now it is also known to participate in the regulation of energy homeostasis. It is the only known systemic signal to date to promote a positive energy balance by stimulating food intake and decreasing fat oxidation [51]. During fasting, ghrelin levels are increased; however, they fall after meals. As such, this hormone plays a critical role in signaling the brain when we are hungry or full and has become an important focus of obesity research. In both rodents and humans, ghrelin acts to increase hunger through its actions on the hypothalamic feeding centers. It has been shown that ghrelin-dependent food intake is at least partially mediated by its action in the arcuate nucleus [52]. The neurons of the arcuate nucleus are also known to express NPY and AGRP. In fact, it has been demonstrated that ghrelin increases the expression of these two orexigenic peptides [52], which perhaps suggests indirect action of ghrelin on food intake via the NPY/AGRP signaling pathway. Evidence has been found that ghrelin administration in humans leads to reported sensations of hunger. Ghrelin administration in the experimental setting leads to increased AGRP and NPY mRNA levels in the arcuate nucleus of the hypothalamus [52]. This perhaps indicates that AGRP/NPY neurons are the primary target of the orexigenic effects of ghrelin in the hypothalamus. In a recent elegant study, Theander-Carrillo et al. [53] reported that, apart from ghrelin’s stimulation of appetite, it also has an effect on adipocyte metabolism. In white adipocytes, ghrelin caused glucose and triglyceride uptake, increased lypogenesis, and inhibited lipid oxidation; in brown adipose tissue, ghrelin inhibited the expression of uncoupling proteins, which usually contribute to energy expenditure [53]. Ghrelin can also regulate feeding through the inhibition of leptin. Leptin receptors are found in the hypothalamus, including the arcuate nucleus, and hypothalamic NPY-positive neurons are the target of leptin action. Leptin suppresses arcuate NPY mRNA expression, and ghrelin can reverse leptin-induced downregulation of NPY expression, thereby inhibiting leptin effects. It would seem, then, that leptin and ghrelin share the hypothalamic NPY/AGRP signaling pathway.

CONCLUSIONS Nothing seems simpler or more natural than eating; yet, every article on feeding behavior emphasizes how complex it is. Feeding behavior has intrigued scientists for centuries, but it was not until the late 1990s that the most amazing discoveries were made. The discovery of the fat-derived peptide leptin set in motion an intense research effort to better understand the genetic, hormonal, and neurochemical basis of obesity. No other hormone has drawn more attention than leptin in studies on the control of body weight and appetite. Several neuropeptides and transmitters have been identiﬁed and shown to be mediators of the central actions of leptin, with POMC and NPY having opposing effects. It is unlikely that leptin has evolved to prevent obesity, because high circulating leptin does not prevent the development of obesity.

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as a Vasoactive 8 Leptin Adipokine: Link Between Metabolism and Vasculature Anne Bouloumié, Cyrile Anne Curat, Alexandra Miranville, Karine Lolmède, and Coralie Sengenès CONTENTS Introduction ......................................................................................................................................93 Central Effects of Leptin .................................................................................................................94 Energy Homeostasis..................................................................................................................94 Blood Pressure ..........................................................................................................................95 Peripheral Effects of Leptin.............................................................................................................96 Fatty Acid Metabolism .............................................................................................................96 Vascular Wall Homeostasis.......................................................................................................96 Vascular Tone.....................................................................................................................97 Vascular Wall Remodeling ................................................................................................97 Conclusion........................................................................................................................................99 References ......................................................................................................................................100

INTRODUCTION The discovery of leptin has opened up new perspectives and introduced new concepts regarding our understanding of the regulation of the body weight. With recognition of its important endocrine activity, adipose tissue has acquired a central role in the regulation of energy homeostasis but also in the immune function and reproductive capacity. Obesity is frequently clustered with a number of cardiovascular risk factors such as insulin resistance, diabetes mellitus, hyperlipidemia, and arterial hypertension, commonly referred to as the metabolic syndrome. Although each component of the metabolic syndrome may contribute to the increased risk of cardiovascular disease observed in obesity, the adipose tissue may also directly inﬂuence the pathogenesis of hypertension and atherosclerosis by the secretion of adipocytokines and more particularly leptin. Leptin is an adipocyte-derived hormone [1–3] that exhibits structural similarities with the cytokine family. Other tissues also express leptin, although at lower levels, including placenta, ovaries, skeletal muscle, stomach, pituitary, and liver [4]. Leptin gene expression in adipocyte is regulated in the context of hormonal and nutritional status (Table 8.1) [5].

93

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TABLE 8.1 Regulation of Leptin Expression Upregulation

Downregulation

Refeeding Insulin/glucose Oestrogens Glucocorticoids TNFα/IL-1 Acute inﬂammation

Fasting/dieting β-Adrenoceptor agonists Androgens PPARγ agonists (thiazolidinediones) Cigarette smoking

CENTRAL EFFECTS OF LEPTIN The interest in leptin focused initially on appetite and body weight regulation (Figure 8.1).

ENERGY HOMEOSTASIS Leptin acts as an afferent satiety signal inﬂuencing the central regulation of food intake and energy expenditure via central leptin receptors. Fasting and dieting induce a fall in leptin, thus signaling the brain to initiate adaptive responses, such as suppression of reproductive and thyroid function and stimulation of the hypothalamic–pituitary–adrenal axis. Two genetic obese animal models, the ob/ob and db/db mouse, have been extensively investigated, the former being defective in leptin synthesis and the latter in leptin receptor function. Several isoforms (a through f) of the leptin receptor (Ob-R) exist as a result of alternative mRNA splicing [6]. Db/db mice lack the llong isoform of the Ob-R (Ob-Rb) that has a cytoplasmic domain required for activation of signal transducers and activators of transcription (STATs) but still express the four other isoforms of the leptin receptor (the lshort isoforms: Ob-Ra, Ob-Rc, Ob-Rd, and Ob-Re). The short isoforms exhibits abbreviated intracellular amino acid sequences and have little intracellular signaling capacity [6]. Their physiological role is less clear. The short isoforms Ob-Ra and Ob-Rc seem to be important for blood–brain barrier function [7], whereas the circulating Ob-Re isoform might play a role in preventing the hormone from degradation and clearance. The long form leptin receptor belongs to the cytokine receptor superfamily coupled to the Janus kinase (JAK)/STAT pathway. This pathway is essential for the regulation of energy homeostasis by leptin but not for the leptin-dependent control of reproductive function and glucose homeostasis [8]. Activation of the phosphoinositol 3-kinasedependent pathways [9] as well as inhibition of AMP-activated protein kinase (AMPK)-dependent pathways [10] are also involved in the control of appetite and weight loss by leptin. Hypothalamus Decreases food intake Increases energy expenditure

LEPTIN

Pancreas Skeletal muscle, liver, adipose tissue Modulates insulin secretion Increases FA oxidation Increases lipolysis Decreases lipogenesis

FIGURE 8.1 Central and peripheral effects of leptin on energy homeostasis.

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95

Hypothalamus Increases sympathetic nerve activity

Blood vessel LEPTIN Balance Endothelin-1/nitric oxyde

Kidney Sodium and water retention

FIGURE 8.2 Central and peripheral effects of leptin on blood pressure

Although some cases of leptin deﬁciency in humans have been reported, most obese subjects and animals with diet-induced obesity are characterized by elevated systemic leptin concentrations. Those observations have led to the concept of a hypothalamic leptin-resistant state that is associated with obesity due to the action of leptin on body weight and appetite [11]. Suppressor of cytokine signaling (SOCS) proteins have emerged recently as a potential mechanism of leptin resistance. In the hypothalamus, SOCS-3 is thought to participate in the physiologically negative feedback of leptin signaling by its inhibition of JAK activity once activated by STAT-3 [12]. SOCS-3 haploinsufﬁciency or brain SOCS-3 deﬁciency increases leptin sensitivity and protects mice against the development of high-fat, diet-induced obesity [13,14]. Thus, SOCS-3 appears to be an important mechanism of leptin resistance, suggesting that targeting SOCS-3 may be an interesting therapeutic approach for the treatment of obesity and associated diseases. Protein tyrosine phosphatase 1B (PTP1B) is another negative regulator of leptin signaling that might contribute to leptin resistance. Mice lacking PTP1B exhibit enhanced leptin sensitivity and are protected from diet-induced obesity [15,16]. Inhibition of this pathway is also considered as a potential target for anti-obesity drugs.

BLOOD PRESSURE In addition to its effect on appetite and energy homeostasis, leptin also affects blood pressure (Figure 8.2). A positive correlation has been found between mean blood pressure and leptin serum levels in lean subjects with essential hypertension [17]. Leptin acts in the hypothalamus to increase blood pressure through activation of the sympathetic nervous system [18]. Administration of leptin to ob/ob mice increases arterial pressure, despite a reduction in food intake and body weight, as well as urinary catecholamine. Because blood pressure normalized after acute alpha adrenergic or ganglionic blockade, it appears that leptin exerts a sympathetically mediated pressor response [19]. Long-term sympathoactivation could raise arterial pressure by causing peripheral vasoconstriction and by increasing renal tubular sodium reabsorption (Figure 8.2). Leptin was shown to increase sympathetic activity to the kidney and extremities [20]; in humans, obesity is associated with increased sympathetic activity to the kidney [21]. Leptin may thus represent a link between excess adiposity and increased cardiovascular sympathetic activity in human obesity leading to hypertension [22]. The observation that in Agouti mice (a genetically induced obesity rodent model characterized by a resistance to the anorexic and weight-reducing effect of leptin) the renal sympathoactivation of leptin is preserved [23] has led to the concept of a selective hypothalamic leptin resistance. The mechanisms underlying the selective hypothalamic leptin resistance are not well deﬁned. Several hypotheses have been suggested. In diet-induced obese mice, the inability of leptin to activate leptin signaling pathways such as STAT3 proteins has been shown to be restricted to the arcuate nucleus, where a speciﬁc upregulation of SOCS-3 was found [24]. Because leptin-induced increases in renal sympathetic activity and blood pressure are mediated by the ventromedial and dorsomedial hypothalamus [25], it has been suggested that the leptin resistance associated with

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obesity is restricted to a speciﬁc hypothalamic area such as the arcuate nucleus. The selectivity in leptin resistance may also relate to the divergent signaling pathways downstream from the leptin receptor, depending on the physiological processes [26].

PERIPHERAL EFFECTS OF LEPTIN The signaling form of the leptin receptor, initially described as being expressed only in the hypothalamus, is also found in peripheral tissues.

FATTY ACID METABOLISM The Ob-Rb is expressed on the major tissues involved in the regulation of glucose and fatty acid metabolism, pancreas, adipose tissue, muscle, and liver (Figure 8.1). The presence of Ob-Rb in pancreatic islets [27] indicates that leptin can directly regulate the secretion of insulin in rodents, although inconsistent ﬁndings have been reported [28,29]. In other metabolically active tissues, a clear effect of leptin is the promotion of energy dissipation through the stimulation of fatty acid (FA) oxidation and prevention of ectopic lipid deposition [30]. In adipocytes, leptin directly decreases lipogenesis [31], increases the enzymes involved in FA oxidation, and stimulates a novel form of lipolysis in which glycerol is released without a proportional release of free fatty acids [32]. In liver and muscle, leptin also inhibits lipogenesis and stimulates FA oxidation [33]. The mechanisms underlying these actions of leptin may be the leptin binding to its receptor with succeeding activation of the JAK/STAT pathway; the direct stimulation of the AMPK [34], which will phosphorylate and thereby inhibit acetyl-CoA carboxylase activity and lipogenesis; and inhibition of expression of the sterol regulatory element-binding protein 1c (SREBP-1c) [35]. The lack of adipose tissue and thus leptin, as observed in lipodystrophy or incorrect leptin action, is associated with ectopic fat deposition in liver, pancreas, and muscle [33]. Administration of leptin to lipodystrophic patients [36] or to rodent models of leptin deﬁciency [37] reverses many lipotoxic effects, in part due to the direct effects of leptin on lipid metabolism; however, the impact of hyperleptinemia in the peripheral regulation of metabolic ﬂuxes under the background of insulin resistance remains to be determined in obese people.

VASCULAR WALL HOMEOSTASIS The blood vessel wall is composed of three different layers: intima, media, and adventitia. The intima is a monolayer of endothelial cells that separates circulating blood from the underlying media. The media consists of concentric layers of smooth muscle cells and elastic lamella. The outer layer of the vessel, the tunica adventitia, is formed of collagen and elastic ﬁbers, ﬁbroblasts, and vasa vasorum. With the discovery of nitric oxide (NO) as an endothelium-derived relaxing factor in the 1980s, the endothelial layer has acquired the status of a paracrine tissue, the integrity of which is necessary for vascular homeostasis. Through its production of contractile and relaxant factors, the endothelium regulates the medial function but also a wide range of proatherogenic and inﬂammatory processes such as platelet activation and aggregation, proliferation and migration of smooth muscle cells, and inﬁltration of inﬂammatory cells within the vessel wall [38]. Endothelial dysfunction mainly characterized by an impaired NO production or bioavailability is observed in obesity [39] and is considered as one of the primary event in the genesis of cardiovascular diseases. Although mechanisms linking obesity with endothelial dysfunction have not yet been fully clariﬁed, several observations suggest that hyperleptinemia might contribute to endothelial dysfunction. Indeed, in obese women leptin was positively correlated with plasma levels of soluble thrombomodulin (sTM) and vascular cell adhesion molecule 1 (VCAM-1), two markers of endothelial activation [40]. This relationship was independent of body mass index (BMI), waist-to-hip ratio (WHR), C-reactive protein (CRP), and insulin sensitivity. Many blood vessels are surrounded by

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adipose tissue in variable amounts. Several works [41,42] support the hypothesis of a paracrine role of white adipose tissue in the regulation of vascular function. An increasing number of reports suggests that the periadventitial adipose tissue has a pathophysiological role in the vascular dysfunction associated with obesity [43–45]. We and others have described the expression of Ob-Rb in human endothelial cells [46,47]. Later, Ob-Rb was also found in smooth muscle cells [48] as well as in platelets [49] and inﬂammatory cells [50]. Vascular Tone Vascular tone is regulated through the actions of locally produced factors. NO is a critical modulator of blood ﬂow and is released by the endothelium in response to shear stress, thereby playing an important role in ﬂow-mediated vasodilation. Endothelial release of NO opposes the vasoconstrictor effects of norepinephrine, endothelin-1, and angiotensin II. Endothelin-1 is one of the most potent vasoconstrictor factors produced in the arterial wall. Vascular tone in health reﬂects the balance of these opposing factors. Several observations suggest that hyperleptinemia may contribute to the alteration of endothelial-dependent dilation in the obese. For example, plasma leptin correlates inversely with the extent of NO-dependent coronary vasodilation in healthy obese males [51], and obese-related concentrations of leptin infused to anesthetized dogs induce impairment of acetylcholine-induced dilations of the coronary arteries, suggesting that hyperleptinemia produces signiﬁcant coronary endothelial dysfunction [52]. In contrast, however, no relationship between plasma leptin and ﬂow-mediated dilatation of the brachial artery was found in healthy adolescents [53] or in normolipidemic healthy obese women [54]. Those observations suggest that the hyperleptinemiadependent effect on vascular tone is dependent on the vascular bed location. Nitric Oxide Production Direct vasodilatory actions of leptin have been inconsistently reported. It appears that any direct effects of leptin on the endothelial-dependent production of NO may be restricted to some vascular beds and that they are generally insufﬁcient to oppose sympathetically mediated vasoconstriction [55,56]. Fruhbeck [57] reported that acute administration of leptin increases endothelial NO release and decreases blood pressure in anesthetized Wistar rats. Such an effect is only observed in sympathectomized rats, suggesting that leptin-dependent activation of the sympathetic nervous system offsets the vasodilatory effect of leptin [58]. The mechanism by which leptin induces NO production in some vascular beds is in part related to activation of the Akt–endothelial nitric oxide synthase phosphorylation pathway [59]. Endothelin-1 Production Leptin at high concentrations upregulates endothelin-1 production in vitro in human umbilical vein endothelial cells (HUVECs) [60]. Because endothelin-1 exerts a potent direct vasoconstrictive effect but also may itself reduce bioavailable NO, increased vascular production of endothelin-1 has been suggested as a potential mechanism for endothelial dysfunction associated with obesity [39,61]. Consistent with such a hypothesis, blockade of endothelin-A (ETA) receptors induces signiﬁcant vasodilation in overweight and obese patients but not in lean hypertensive subjects [62]. Vascular Wall Remodeling After the West of Scotland Coronary Prevention Study (WOSCOPS) demonstrated that hyperleptinemia is an independent risk factor for coronary heart disease [63], recent studies have conﬁrmed a role for increased leptin concentration in cardiovascular disease [64–66]. Reilly et al. [67] reported an association between plasma leptin levels and the degree of coronary artery calciﬁcation in type 2 diabetic patients after controlling for traditional indices such as obesity and C-reactive protein. Leptin levels are increased in non-diabetic patients with restenosis after stenting, whereas no

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differences were demonstrated in patients without restenosis and in control subjects [68]. Finally, leptin impairs vascular compliance [53]. An increase in vascular stiffness has long-term adverse effects on the cardiovascular system by increasing impedance to blood ﬂow and thereby increasing cardiovascular work and contributing to the development of left ventricular hypertrophy [69]. In animal models, neointimal formation after endovascular arterial injury is markedly attenuated in db/db mice [70], whereas it is promoted by leptin in normal strains [71]. The pathobiology of restenosis in stented arteries is linked to neointimal hyperplasia. Atherosclerotic lesions are the result of an excessive proliferative and inﬂammatory response that involves several cellular events, including smooth muscle cell migration and proliferation, inﬂammatory cell inﬁltration, neovascularization, production of extracellular matrix, and accumulation of lipids [72]. Leptin signaling has been implicated in the promotion of atherosclerosis [73]. Indeed, in vivo, the expression of leptin receptors are increased in atherosclerotic lesions [74,75], and leptin signaling promotes atherosclerosis in mice models [76,77]. In vitro proatherogenic effects of leptin include endothelial cell activation, migration, and proliferation; smooth muscle cell proliferation, migration, hypertrophy, and calciﬁcation; activation of monocytes; and modulation of the immune response as well as platelet aggregation. Leptin and Endothelial Cells Neovascularization within the plaque is known to be essential in the atheromatous plaque formation [78,79]. Atherosclerotic aortic plaques have demonstrated a marked increase in Ob-Rb immunoreactivity, predominantly in foam cells, vascular smooth muscle cells, and the vascular endothelial lining of intimal neovessels [80]. Bouloumié et al. [46] and others [47] showed that leptin increases in vitro the proliferation and migration of endothelial cells and promotes the formation of new blood vessels in vivo on various angiogenic models. Such a proangiogenic effect of leptin has been suggested to contribute to the growth of the fat mass itself, as the development of the adipose tissue is dependent on its own vasculature [81], as well as to the progression of atheromatous plaques [80] and neointimal hyperplasia after endothelial damage. Endothelial cells play an important role in the initiation and maintenance of inﬂammatory processes and acute tissue injuries. Indeed, activation of the endothelial cell surface leads to the expression of several adhesion molecules as well as chemokines that promote the adhesion and transmigration of circulatory inﬂammatory cells into the vascular wall (Figure 8.3). The adhesion of bloodborne monocytes and migration through the endothelial surface is a prerequisite for the monocyte–macrophage conversion. Curat et al. [82] recently demonstrated that in vitro leptin at high concentration promotes the adhesion as well as the transmigration of human blood monocytes through the endothelial cell layer. Moreover, Bouloumié et al. [83] and others have shown that leptin leads to the increased endothelial expression of monocyte chemotactic protein 1 (MCP1). Furthermore, this effect is dependent on the leptin-induced production of reactive oxygen species [83,84]. It is thus tempting to speculate that the intracellular accumulation of oxidant radicals stimulated by high leptin concentrations and the consecutive expression of MCP1 in endothelial cells might play a key role in the inﬁltration of inﬂammatory cells within the vessel wall. In addition, chronic endothelial oxidative stress under hyperleptinemia, as in human obesity, might be involved in the genesis of endothelial dysfunction linked to atherosclerosis through a direct interaction with NO to form a more harmful oxygen radical compound, the peroxynitrite, thus leading to a decreased NO bioavailability (Figure 8.3). Leptin and Smooth Muscle Cells High leptin concentrations stimulate the proliferation and migration of smooth muscle cells [85] as well as smooth muscle cell hypertrophy through the p38 MAP kinase pathway [86]. Moreover, leptin at obese-relevant concentrations promotes the accumulation of reactive oxygen species in human smooth muscle cells [87]. Finally, Parhami et al. [75] demonstrated that leptin enhances the calciﬁcation of vascular cells.

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Blood monocyte Rolling Adhesion adhesion Chemokines molecules Transmigration Endothelial cell

Oxidative stress

LEPTIN NO

Macrophage oxLDL Foam cell

FIGURE 8.3 Hyperleptinemia and endothelial dysfunction.

Leptin and Inflammation Inﬂammatory reactions in the vascular wall play an important role in the development of atherosclerosis and in plaque destabilization and rupture; consequently, systemic markers of inﬂammation (in particular, CRP) are independent risk factors of cardiovascular events [88]. CRP exerts many proatherogenic effects, including impairment of endothelial NO production, activation of vascular smooth muscle cells, and stimulation of monocyte adhesion to endothelial surfaces [89]. Leptin exerts strong proinﬂammatory and immunostimulatory effects [90]. Leptin, per se, acts on monocytes and macrophages by inducing their release of proinﬂammatory cytokines, oxygen radicals, and eicosanoids [91–93]. Leptin also affects natural killer (NK)-cell development and activation both in vitro and in vivo [94]; moreover, leptin has been demonstrated to also modulate adaptive immune response [95]. In addition, inﬂammatory stimuli have previously been shown to induce elevated systemic leptin concentrations [96], suggesting that leptin induction is part of the ubiquitous acute-phase reaction. In agreement with this notion, plasma leptin has been demonstrated to correlate with acute-phase reactants, such as CRP, in both normal weight and obese subjects [97–99]. Taken together, these data suggest that leptin might contribute to the proinﬂammatory state associated with obesity. Leptin and Platelets Human obesity is associated with an elevated risk for arterial and venous thrombosis [100], and hyperleptinemia has been suggested to play a role in the development of atherothrombotic disease in obesity [101,102]. Platelets express the leptin receptor, and leptin potentiates platelet aggregation through a leptin-receptor-dependent mechanism [49,103]. Leptin-deﬁcient ob/ob mice have delayed and unstable thrombus formation after arterial injury, and leptin normalizes this phenotype [104], whereas inhibition of endogenous leptin protects mice from arterial and venous thrombosis [105].

CONCLUSION Leptin is now well recognized as an adipose-tissue-originating signal that informs the hypothalamus about the amount of energy stored, resulting in modulation of metabolic ﬂuxes, energy intake, and energy expenditure, as well as reproductive capacity and immune functions. Leptin-dependent regulation of vascular tone according to the vessel bed location certainly plays an important role in the efﬁciency of oxygen and nutrient delivery to tissues and the subsequent effectiveness of metabolic activities. Such effects on vascular reactivity are similar to those of insulin [106]. Despite

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this acute action of leptin, the majority of studies performed to date indicate that chronic hyperleptinemia is atherogenic. Although it is not clear whether or not hyperleptinemia is associated with the development of a peripheral leptin resistance, high concentrations of leptin are known to increase oxidative stress in endothelial cells. The long-term consequences of oxidative stress may include reductions in NO bioavailability and increases in the expression of adhesion molecules and chemokines that mediate vascular inﬂammation and atherogenesis. Furthermore, the associated metabolic changes that occur in the insulin-resistant state (e.g., increased levels of plasma fatty acids) associated with obesity are also known to impair endothelial function. Thus, hyperleptinemia together with insulin resistance might exert powerful detrimental effects on the vascular wall, leading to the genesis of vascular pathologies associated with obesity [107,108].

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of Ghrelin, 9 Overview Appetite, and Energy Balance Rafael Fernández-Fernández and Manuel Tena-Sempere CONTENTS Introduction ....................................................................................................................................105 Discovery of Ghrelin......................................................................................................................106 Structure of Ghrelin and Its Functional Receptor, GHS-R...........................................................106 Distribution and Biological Functions of Ghrelin: An Overview.................................................107 Ghrelin and the Control of Appetite: Major Effects and Mechanisms of Action ........................108 Regulation of Ghrelin Levels and Interaction with Leptin System ..............................................109 Ghrelin as a Neuroendocrine Integrator Linking Energy Status and Other Key Functions ........111 Major Conclusions and Future Perspectives .................................................................................111 Acknowledgments ..........................................................................................................................112 References ......................................................................................................................................112

INTRODUCTION Homeostatic control of energy balance is a key biological function essential for the survival of individuals and species. Maintenance of the energy status of an organism critically relies on the dynamic balance between energy expenditure and food intake. In this equation, expression of appetite (deﬁned as the motivational drive toward an energy source) appears as a pivotal, highly regulated phenomenon, based on the complex physiological interaction of afferent signals (which promote or inhibit appetite) and effector mechanisms (which restrain or get into motion the drive toward food intake). Among the former, multiple peripheral factors, arising mostly from the adipose tissue, pancreas, and gastrointestinal tract, have been identiﬁed in the last decades as powerful regulators of central circuits at the hypothalamus, as well as in the brainstem and limbic system. At those sites, such factors actively modulate neuropeptide release and, thereby, participate in the control of food intake and energy expenditure [1,2]. In this context, leptin is probably the most illustrative paradigm of a peripheral regulator of energy balance. Leptin was originally identiﬁed in 1994 as a secreted hormone, primarily produced in the white adipose tissue and displaying a very potent satiating activity. Interestingly, circulating leptin levels were demonstrated to directly correlate with the amount of adiposity; therefore, leptin appeared to serve an essential function in signaling the amount of body energy stores to the hypothalamic centers controlling food intake, thus contributing to body weight homeostasis [3,4]. Indeed, a wealth of experimental and epidemiological evidence gathered in the last decade has fully conﬁrmed the crucial role of leptin in the control of metabolism and energy balance. Moreover, identiﬁcation of leptin in the mid-1990s, coinciding with the exponential increase in the prevalence of obesity and other weight disorders, boosted an extraordinary activity in terms of basic and clinical research aimed at identifying the molecular and physiological basis for the dynamic regulation of body weight. This research activity has not only helped to characterize the physiology of leptin

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but has also signiﬁcantly contributed to expanding our knowledge on the molecules and networks involved in the dynamic control of food intake. One of these molecules turned out to be the gutderived hormone ghrelin.

DISCOVERY OF GHRELIN The gastric hormone ghrelin was originally identiﬁed by Kangawa et al. in late 1999 (at the National Cardiovascular Center Research Institute in Osaka, Japan) during their search for an endogenous ligand of the growth hormone secretagogue receptor (GHS-R) [5,6]. Cloning of ghrelin was the endpoint of a long search for the endogenous counterpart of a large family of peptidyl and nonpeptidyl synthetic compounds, globally termed growth hormone secretagogues (GHSs), with the ability to elicit the release of growth hormone in vivo and in vitro in a wide spectrum of species, including humans [7,8]. Synthesis of the ﬁrst GHSs dates back to the late 1970s, when Bowers and coworkers [9] reported that some synthetic peptide analogs of metenkephalin, although devoid of any opioid activity, speciﬁcally induced GH secretion. Although early GHSs showed very weak activity, further development of many peptide- and non-peptide-related molecules led to the generation of much more potent GH secretagogues; thus, GHRP-6 was the ﬁrst hexapeptide shown to actively release GH in vivo [10], and it is still considered the gold standard for peptidergic GHSs. Among non-peptidyl members of the family, MK-0677 is probably the most representative GHS, showing a potent GH-releasing effect even after oral administration [11]. A major breakthrough in the course of identiﬁcation of ghrelin was the cloning in 1996 of the GHS receptor (GHS-R), distinct from that of the major elicitor of GH release, the GH-releasing hormone receptor (GHRH-R) [12]. This provided conclusive evidence for the existence of a natural counterpart of GHSs: the endogenous ligand of GHS-R. Moreover, discovery of GHS-R allowed the implementation of routines for identiﬁcation of its ligand using an orphan receptor strategy. Given the prominent expression of GHS-R reported at the pituitary and hypothalamus (among other central areas), its potential ligand was expected to exist also in the brain [13]. The weak activation of GHS-R reporter systems by brain extracts, however, suggested that such a ligand might be present only at low levels at this site. Instead, a very prominent expression of this molecule was ﬁnally demonstrated by Kojima and coworkers [5] in rat stomach extracts. This molecule turned out to be a 28-amino-acid peptide, highly conserved between rat and human species, harboring an essential n-octanoyl modiﬁcation at Ser3. This molecule was named “ghrelin” from the Proto-Indo-European root ghre, which means growth, and the sufﬁx relin, for its reported GH-releasing activity [5].

STRUCTURE OF GHRELIN AND ITS FUNCTIONAL RECEPTOR, GHS-R The functional ghrelin peptide results from the cleavage of a precursor form, the preproghrelin, which is composed of 117 amino acids. In the human and rat, the mature ghrelin peptide consists of 28 amino acids, with divergence in 2 residues only [5]. Even in non-mammalian species, such as chicken, the sequence homology is rather high (54% identity with human ghrelin) [14]. In the rat, a second form of the peptide, termed des-Gln(14)-ghrelin, has been described. Its biological activity and sequence are identical to ghrelin, except for the lack of one glutamine in position 14 [15]; however, this variant is present only in low amounts in the stomach, indicating that 28-aminoacid ghrelin is the main active form of the molecule [16]. Interestingly, although no obvious structural homology between ghrelin and peptidyl GHSs was found, the gastric peptide motilin was shown to share 36% structural homology with ghrelin [17]. In fact, after the discovery of ghrelin, Tomasetto et al. [18] reported the identiﬁcation of a gastric peptide called motilin-related peptide (MTLRP) [18], whose amino acid sequence was identical to preproghrelin, except for the lack of Ser26 [18]. In terms of its structure–function relationship, the N-terminal seven-amino-acid

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stretch of ghrelin is very well conserved across vertebrate species [19], suggesting that this region is relevant for its biological functions. Another highly conserved (and rather unique) feature of ghrelin molecule is the addition of an n-octanoyl group at Ser3, which appears essential for most of its biological activities [5]. Such a posttranslational modiﬁcation (acylation) is the ﬁrst reported in a secreted protein [20]; yet, acyl modiﬁcations had been previously observed in G proteins and membrane-bound receptors. The enzymatic system responsible for acylation of ghrelin is yet to be identiﬁed, while the biological roles, if any, of unacylated ghrelin (whose concentration in plasma largely exceeds that of mature ghrelin) have remained largely neglected. Nonetheless, compelling evidence has been recently presented demonstrating that des-acyl ghrelin is not merely an inert form of the molecule [21,22]. The biological actions of ghrelin are mostly conducted through interaction with its speciﬁc cell surface receptor, namely the GHS-R. The cognate ghrelin receptor belongs to the large family of G-protein-coupled, seven-transmembrane-domain-spanning receptors [12,23]. This receptor is highly expressed at central neuroendocrine tissues such as the pituitary and hypothalamus [13]. Two GHS-R subtypes, generated by alternative splicing of a single gene, have been described: the full-length type-1a receptor and the truncated type-1b receptor [12,23]. The GHS-R1a is the functionally active, signal-transducing form of the receptor. In contrast, the GHS-R1b lacks the transmembrane domains 6 and 7, and it is apparently devoid of high-afﬁnity ligand-binding and signal-transduction capacity [26]. Thus, its functional role, if any, remains unclear. In addition, evidence for GHS-R1a-independent biological actions of ghrelin, as well as of synthetic GHSs, has been presented recently [21,23]. These seem to include (at least some of) the potential weight gain-promoting effects of ghrelin [24]; however, the search for ghrelin receptors other than GHS-R has not yet provided conclusive evidence.

DISTRIBUTION AND BIOLOGICAL FUNCTIONS OF GHRELIN: AN OVERVIEW Despite its identiﬁcation in the context of GH control, in recent years it has become evident that the biological actions of ghrelin are much wider than those originally anticipated. Indeed, a striking feature of ghrelin is its widespread pattern of distribution [21,22]. Thus, while the peptide was initially isolated from the stomach (which is undoubtedly the major source of circulating ghrelin), ghrelin expression has been also demonstrated in an array of tissues and cell types, including small intestine, pancreas, lymphocytes, placenta, kidney, lung, pituitary, brain, and the gonads [21,22, 25,26]. Overall, such a ubiquitous pattern of expression strongly suggests that, in addition to systemic actions of the gut-derived peptide, locally produced ghrelin might be provided with paracrine/autocrine regulatory effects in different tissues, the physiological relevance of which awaits to be completely deﬁned. In terms of endocrine function, the ﬁrst biological effect assigned to ghrelin was the ability to elicit GH secretion, as predicted by its capacity to activate GHS-R1a in cell reporter systems. This GH secretagogue action is conducted both at the pituitary and the hypothalamus, where ghrelin has been proven to regulate GH-releasing hormone and somatostatin systems [27]. Yet, the importance of gut-derived ghrelin in the control of GH secretion remains controversial. In addition, a wealth of data has now demonstrated that ghrelin may serve additional central neuroendocrine functions, such as modulation of lactotropic, corticotropic, and gonadotropic axes [25,26]. Indeed, ghrelin has been proposed to be a putative neuroendocrine integrator linking the function of several endocrine systems essential for survival. These likely include the neuroendocrine networks responsible for the control of body weight and energy balance, as reviewed in detail later in this chapter. Finally, in addition to the endocrine actions of ghrelin summarized above, solid evidence has been presented recently showing that ghrelin is also involved in the regulation of quite diverse peripheral non-endocrine functions. These include regulation of gastric motility and acid secretion,

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various effects upon the cardiovascular system, and modulation of glucose metabolism (and pancreatic insulin secretion), as well as control of adipogenesis and cell proliferation. Detailed descriptions of these functional properties of ghrelin exceed the goals of this chapter and have been recently provided elsewhere [20–22].

GHRELIN AND THE CONTROL OF APPETITE: MAJOR EFFECTS AND MECHANISMS OF ACTION Undoubtedly, the facet of ghrelin physiology that has attracted the most attention is its ability to promote food intake. Considered in retrospect, the fact that ghrelin has been shown to enhance body weight should not be considered totally unexpected, given previous reports of the ability of GHSs to stimulate food intake. Nonetheless, these effects of GHSs had remained largely neglected [21]. Thus, the demonstration in 2000 that administration of ghrelin efﬁciently induced body weight gain [28] opened up a new dimension of ghrelin biology focused on characterization of the effects and mechanisms of action of this gut-derived hormone in the control of appetite and energy balance. Undisputed evidence indicates that the administration of ghrelin to rodents stimulates food intake [28], an effect that is far more potent after intracerebral delivery of the peptide, which suggests a primary central site of action. The relevance of central vs. peripheral ghrelin in the control of food intake remains controversial, mainly due to conﬂicting data on the expression of only minute amounts of ghrelin at the hypothalamus. Nonetheless, the importance of ghrelin/GHS-R signaling in the homeostatic control of body weight is supported by the observed decrease in food intake after antisense disruption of GHS-R at the hypothalamus [29] and the effects of centrally and peripherally injected ghrelin on body weight [21]. Although the potency of systemically derived ghrelin in terms of food intake induction is somewhat modest, the latter is a rather unusual feature, as virtually all of the orexigens known to date are only effective when acting centrally. This has led to the conclusion that ghrelin is the most important, if not the only one, appetite stimulant in the bloodstream [30], and that it may serve an important role as a meal-initiating signal as well as in the long-term regulation of body weight in combination with leptin. The central circuitries whereby ghrelin conducts its modulatory actions upon food intake have been exhaustively explored in the last years. Assuming a bipartite model of food intake control at the hypothalamus, with neuropeptide Y (NPY) and Agouti-related peptide (AGRP) neurons as major orexigenic effectors and proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) neurons as major anorexigenic effectors, ghrelin has been demonstrated to modulate expression of some (if not all) of the elements of this network. Thus, ghrelin appears to enhance AGRP and NPY after acute and chronic administration — actions that might contribute to the observed short- and long-term effects of ghrelin on body weight gain [21]. In addition, ghrelin has been shown to target POMC and CART neurons at the hypothalamus. Moreover, orexins and other neuropeptides with roles in the central control of appetite are apparently modulated by ghrelin. This complex mode of action of ghrelin upon the hypothalamic centers controlling energy balance and food intake is illustrated in Figure 9.1. Some of the reported effects of ghrelin on food intake might not derive from direct central actions of the gut-derived peptide but instead might be mediated by peripheral activation of afferent activity of the vagal nerve [31]. Indeed, blockade of gastric vagal inputs has been shown to blunt ghrelin effects in terms of food intake and hypothalamic NPY expression [32], and vagal resection associated with gastroplastic surgery has been implicated in the lowering of ghrelin levels following some of these surgical procedures [33], although the latter is still a matter of debate. Additional contributors to the observed effects of ghrelin upon body weight likely include its direct actions upon the adipose tissue, where it primarily promotes adipogenesis and antagonizes lipolysis, as well as its ability to reduce cellular fat utilization and decrease locomotor activity. These, together with is potent orexigenic action, drive the energy equation toward a state of positive energy balance [21].

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Hypothalamus

+

Neurons -

NPY/ AGRP

-

-

+

Energy expenditure

Food intake

POMC/ CART

-

+ Leptin

GHRELIN

Insulin

PYY3-36

WAT Stomach Pancreas Ghrelin:

Intestinal Tract

• Produced by the stomach • Only known circulating orexigen • Levels inverse to BMI • Stimulates appetite • Reduces fat utilization • Reciprocal interplaywith leptin

FIGURE 9.1 Illustration of the major biological actions of ghrelin in the control of appetite. Produced by the stomach under the regulation of metabolic cues (putative regulators: prepradial state, caloric meal intake, body mass index, leptin, insulin), ghrelin primarily operates at central levels by modulating the function of leptin-responsive circuits, such as NPY/AGRP neurons. Other hypothalamic targets of ghrelin (such as PMOC/CART neurons) have also been suggested. In addition, some of the orexigenic actions of ghrelin might be conducted via modulation of vagal afferents (not shown). Importantly, the function of ghrelin in the control of appetite and energy balance is counterbalanced by the concerted action of a set of peripheral signals, of adipose (leptin and other adipocytokines), pancreatic (insulin), and gastrointestinal (PYY3-36 and other guthormone) origin. Among these, the most prominent functional opponent for ghrelin actions appears to be leptin, which dynamically interplays with ghrelin in the long-term control of energy homeostasis.

REGULATION OF GHRELIN LEVELS AND INTERACTION WITH LEPTIN SYSTEM Although pharmacological evidence for the appetite-promoting effects of ghrelin is unquestioned, its physiological relevance in the dynamic regulation of body weight and energy homeostasis was initially the subject of an intense debate. Several observations seemed to cast doubts on the

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importance of ghrelin in this function, including: (1) the low to negligible expression of ghrelin at the hypothalamus, (2) the limited passage of circulating ghrelin through the blood–brain barrier, and (3) the modest orexigenic effects of ghrelin after its systemic administration [21]. In addition, initial studies on mouse models of the genetic inactivation of ghrelin and its functional receptor revealed rather mild metabolic phenotypes, without a clear-cut effect of the absence of ghrelin signaling upon body weight [34,35]. Nonetheless, recent experimental observations appeared to dissipate those concerns, as expression of ghrelin has been demonstrated in discrete neuronal populations at the hypothalamus [36], ghrelin or GHSs have been proven to act at hypothalamic regions (such as certain areas of the arcuate nucleus) where the permeability of the blood–brain barrier is signiﬁcantly enhanced [21], and, albeit less potent, consistent orexigenic responses to peripheral ghrelin delivery have been obtained in different experimental models, in contrast to other well-known orexigens devoid of systemic activity [21]. Moreover, detailed metabolic analyses of GHS-R knockout animals have recently shown that mice lacking ghrelin signaling are resistant to developing diet-induced obesity [37]. One of the hallmarks of gut-derived ghrelin is that its circulating levels appear to be regulated by a number of metabolic factors. Strikingly, ghrelin concentrations have been reported to increase preprandially, thus suggesting a role in meal initiation [38]. Moreover, circulating ghrelin levels decrease after meal intake, the magnitude of such a drop being proportional to the ingested caloric load [39]. In addition, ghrelin concentrations seem to be inversely correlated with the body mass index (BMI), and ghrelin levels have been reported to increase in fasting conditions or persistent undernutrition in a wide array of species [21]. Taken together, these observations support the contention that ghrelin may play complementary roles in the short-term regulation of pre-meal hunger and the duration of episodes of ingestion, as well as in the long-term control of energy homeostasis, acting as a signal for energy insufﬁciency [40]. In keeping with the proposed metabolic control of ghrelin, as the ultimate afferent signaling an energy deﬁcit, changes in glucose homeostasis, insulin, and leptin have been demonstrated, among others, as putative regulators of ghrelin secretion [21]. From a homeostatic perspective, the functions and regulation of ghrelin cannot be independently considered but rather integrated in the context of a complex network of peripheral modulators of energy balance and food intake. Within this system, ghrelin possesses quite unique features, as it is the only known circulating orexigen, and may serve both short- and long-term regulatory functions [21,22]. The major functional opponent of ghrelin appears to be leptin [40]. Indeed, leptin and ghrelin show remarkable opposite characteristics in terms of their effects on food intake and energy balance, as well as in their correlation with the nutritional state and body mass index. Thus, although an excess of body weight and adiposity is associated with elevated leptin levels, situations of negative energy balances and low BMIs are generally linked to persistently elevated ghrelin levels. This inverse relationship has led to the proposal that leptin (as the signal for energy abundance) and ghrelin (as the signal for energy insufﬁciency) are the two major peripheral players in the maintenance of appropriate food intake and energy stores [40]. The neuroendocrine substrate for such a reciprocal interaction appears to involve the convergent actions of these hormones onto similar central pathways [40], as ghrelin has been shown to regulate leptin-responsive neurons in speciﬁc hypothalamic areas [21,40]. Additional levels of interplay between leptin and ghrelin are found at the periphery, where leptin has been suggested to modulate ghrelin expression [21]. Overall, although it is probably a simpliﬁcation of a complex regulatory system, this “yin/yang” model of the regulation of appetite and energy homeostasis by orexigenic (ghrelin) and anorexigenic (leptin) signals is tremendously illustrative of the basic mechanisms governing energy homeostasis, the deregulation of which may lead or contribute to alterations in body weight such as obesity, anorexia, or cachexia [40]. Obviously, other peripheral factors, such as insulin and other gastrointestinal hormones (e.g., PYY3-36) and adipocytokines, likely contribute, together with ghrelin and leptin, to the dynamic control of appetite, metabolism, and energy balance, as shown in Figure 9.1.

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GHRELIN AS A NEUROENDOCRINE INTEGRATOR LINKING ENERGY STATUS AND OTHER KEY FUNCTIONS The pleiotropic nature of ghrelin and the diversity of its biological functions clearly demonstrate that ghrelin is much more than a simple regulator of appetite. Instead, ghrelin appears to play a fundamental role in several key endocrine and non-endocrine systems, suggesting that ghrelin is an important member of the survival kit of nature [40]. Interestingly, the concurrent actions of ghrelin upon different neuroendocrine axes make it a suitable candidate for the integrated control of energy balance and other essential endocrine functions, such as growth and reproduction. The former has been assumed on the basis of the ability of ghrelin to elicit GH secretion; yet, its physiological relevance remains to be fully deﬁned. Indeed, from a teleological point of view, the proposed role of ghrelin as a signal for energy insufﬁciency is difﬁcult to reconcile with a supposed action of this molecule as a major elicitor of GH secretion and growth. In contrast, although the potential link between ghrelin and reproduction has received limited attention to date, some fragmentary data strongly suggest that ghrelin may operate as putative modulator (mostly inhibitor) of the reproductive axis in different mammalian species, including primates, sheep, and rats [25,26,41]. As evidences for the reproductive aspect of ghrelin, its expression has been demonstrated in human and rodent placenta, and ghrelin has been reported to inhibit early embryo development in vitro and pregnancy outcome in vivo [25,26]. In addition, ghrelin has been shown to suppress luteinizing hormone (LH) secretion in vivo and to decrease LH responsiveness to gonadotropin-releasing hormone (GnRH) in vitro. Moreover, repeated administration of ghrelin induced a partial delay in the timing of puberty in male rats [42,43]. Finally, transcripts of ghrelin and its cognate receptor have also been identiﬁed in rat and human gonads, and ghrelin has been reported to inhibit stimulated testicular testosterone secretion [25,26]. Given its proposed role as a peripheral signal for energy insufﬁciency [40], the above data suggest that ghrelin exerts a negative inﬂuence on the gonadotropic axis, contributing to the complex neuroendocrine network linking energy status and fertility. From a general perspective, ghrelin appears to operate as a neuroendocrine integrator involved in the coordinated control of several functions essential for the survival of organisms or species, such as food intake and energy homeostasis, growth, and reproduction.

MAJOR CONCLUSIONS AND FUTURE PERSPECTIVES Despite the astonishing amount of studies published on ghrelin during the last 5 years (more than 1450 scientiﬁc papers registered in PubMed database), controversies and open questions still exist regarding ghrelin physiology that await to be elucidated, as exhaustively reviewed elsewhere [30]. In the context of appetite control, a key issue to be deﬁned is the contribution of central vs. peripheral ghrelin in the control of food intake and the relevance of centrally produced ghrelin, if any, in the neuronal networks involved in such function. Other important aspects to be fully characterized are the mechanisms (neuronal targets and central effectors) by which ghrelin conducts its orexigenic actions and whether some of the body-weight-gain-promoting effects of ghrelin might be mediated via GHS-R1a-independent mechanisms, as recently suggested by pharmacological studies [24]. From a metabolic perspective, the reciprocal interplay between leptin and ghrelin and, more importantly, between ghrelin and insulin remains to be fully clariﬁed, as conﬂicting data on the ability of ghrelin to modulate insulin secretion have been presented [30]. Finally, a contentious issue is whether unacylated ghrelin has speciﬁc or common physiologic functions. In this sense, original reports ﬁrmly demonstrated that octanoylation of ghrelin at Ser3 is mandatory for GHS-R1a binding and stimulation of GH secretion [5,6]. Although this ﬁnding remains undisputed, the wealth of data presented over the last several years strongly suggests that unacylated ghrelin is not merely an inert form of the molecule. In contrast, several non-endocrine actions of octanoylated ghrelin can be mimicked by its desacyl counterpart [21,22], including

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cardiovascular, adipogenic, and (anti)proliferative effects. More important for the purposes of this chapter, evidence for the central and peripheral neuroendocrine and metabolic effects of ghrelin independent of GHS-R1a has also been recently reported [24,43,44]. These studies included demonstration of the ability of desacyl ghrelin to modulate hypothalamic expression of neuropeptides relevant for food intake control, such as CART, and to induce signiﬁcant decreases in body weight and food intake in mice. These observations suggest that, in rodents, unacylated ghrelin might operate as a counterbalancing signal for ghrelin in some of its metabolic responses, in line with recent reports in humans [45]. In summary, ghrelin has recently emerged as a key metabolic regulator playing an essential role in the control of food intake and energy balance. Among other unique features, ghrelin appears as the only known circulating orexigenic factor, whose serum proﬁle (with preprandial elevation and postprandial decrease) is highly suggestive of a major function of ghrelin as a pre-meal hunger signal. In addition, circulating ghrelin levels seem to be negatively correlated with body mass index, leading to the hypothesis that ghrelin operates as a peripheral signal for energy insufﬁciency. Indeed, on the basis of their biological properties and their reciprocal ﬂuctuation, it has been proposed that leptin and ghrelin are the most prominent antagonic afferents of a dynamic (yin/yang) regulatory system that allows precise tuning of the long-term control of body weight and energy balance. Importantly, the biological roles of ghrelin clearly exceed those related with its metabolic aspect, as ghrelin has been shown to be involved in a wide diversity of functions, from cell proliferation to reproduction. Complete elucidation of ghrelin biology promises to be an active ﬁeld in endocrine research in the coming years.

ACKNOWLEDGMENTS The authors are indebted to C. Dieguez, E. Aguilar, L. Pinilla, and other members of the research team at the Physiology Section of the University of Cordoba for their continuous collaboration and support in their studies on neuroendocrine aspects of ghrelin physiology, as well as for their helpful discussions during preparation of this manuscript. The work from the authors’ laboratory described herein was funded by grants BFI 2000-0419-CO3-03 and BFI 2002-00176 from DGESIC (Ministerio de Ciencia y Tecnología, Spain), funds from Instituto de Salud Carlos III (Red de Centros RCMN C03/08 and Project PI042082), and EU research contract EDEN QLK4-CT-2002-00603.

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Genetics of 10 Molecular Obesity Syndrome: Role of DNA Methylation Rama S. Dwivedi, Atul Sahai, and Bernard L. Mirkin CONTENTS Introduction ....................................................................................................................................115 Molecular Genetics of Obesity ......................................................................................................116 Clinical Syndromes of Obesity......................................................................................................117 Prader–Willi Syndrome: A Clinical Description...........................................................................117 Role of DNA Methylation .............................................................................................................117 Conclusions ....................................................................................................................................118 Acknowledgments ..........................................................................................................................118 References ......................................................................................................................................119

INTRODUCTION The prevalence of obesity in developed and industrialized countries has reached alarming levels. Worldwide, almost 1 billion adults are overweight, with a body mass index (BMI) of 25.0 kg/m2, and more than 300 million individuals are obese, with a BMI of 30.0 kg/m2, at 20 years of age and older. The incidence of obesity in adults has increased by approximately 50% over the past 7 years in the United States [1]. Based on data from the 1999–2002 National Health and Nutrition Examination Survey, the percentage of overweight children between the ages 6 of 11 increased from 4.2 to 15.8% compared to the 1963–1965 survey. In 2001, nearly 58 million Americans were overweight; among them, 40 million were obese. Each year, approximately 300,000 die due to obesity-related disorders [2]. The data collected by the Centers for Disease Control and Prevention/National Center for Health Statistics between 1999 and 2002 showed that the percentage of overweight adolescents (ages 12 to 19) had increased from 4.6% to 16.1%. A great economic and ﬁnancial stress has been placed on society, as obesity-related disorders such as type 2 diabetes, osteoporosis, hypertension, heart and liver disease, postmenopausal breast cancer, colon cancer, and endometrial cancer have increased dramatically. Annual medical costs to treat these diseases are expected to exceed $100 billion in the United States, thus making obesity a major public health concern [4]. One of the national public health goals for the year 2010 is to reduce the incidence of obesity among adults to less than 15%. The focus of this review is on describing the putative role of DNA methylation in regulating and altering the function of obesity-related genes and disorders.

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MOLECULAR GENETICS OF OBESITY The update of the human obesity gene map in 2005 revealed that about 425 genes or biomarkers were directly or indirectly linked with the onset of human obesity [4,5]. Some genes, such as those that regulate the expression of uncoupling proteins, leptin, leptin receptors, adrenergic receptors, peroxisome proliferator-activated receptors, and fatty-acid-binding protein, modulate the control of energy metabolism and may be affected by dietary composition and physical activity. Speciﬁc genes such as proopiomelanocortin are involved in controlling food intake, while others such as peroxisome proliferator-activated receptors regulate adipogenesis, thus affecting body weight and fat deposition in individuals who are carriers of defective gene mutations or polymorphisms. Variations in adrenergic receptors and leptin receptors have been shown to be positively correlated with increased weight gain [4,5]. The genetic basis of obesity was signiﬁcantly advanced by the discovery of the leptin gene in the obese mouse model in 1994 [6]. Since then, autosomal recessive mutations in the genes for leptin [7,8], leptin and melanocortin-4 receptors [9,10], prohormone convertase 1 [11], and proopiomelanocortin [12] have been linked to the onset of obesity in humans. Deletion of a single guanine nucleotide in the leptin gene in children was associated with increased weight gain, which was reversed by administration of recombinant leptin, causing a signiﬁcant loss of weight and adipose tissue mass [7]. A truncated leptin receptor lacking both the transmembrane and intracellular domain was present in the children of a family with a mutation in the human leptin receptor gene and was associated with obesity and pituitary dysfunction. Thus, a genetic defect in leptin or leptin receptors may be one of the factors contributing to the impaired regulation of body weight in obese children [13]. As yet, no deﬁnitive correlation has been established. Many candidate genes are found to be altered in Mendelian or rare obesity syndromes, such as leptin, proopiomelanocortin, melanocortin-4 receptor, and Bardet–Biedel syndrome loci [14]. An established association between monogenic forms of obesity and mutations in the melanocortin-4 receptor, accounting for about 4% of early-onset obesity, has been reported [15]; however, mutations in the melanocortin-4 receptor do not seem to play a prominent role in the late-onset, more common type of obesity. Mutations in the leptin gene lead to severe early-onset obesity. Although treatment with leptin successfully reverses the progression of early-onset obesity, it has not proven to be effective in treating this syndrome [16]. Ultimately, identiﬁcation of the rare mutations in candidate genes may facilitate identifying the pathways that can lead to severe obesity. Genetic defects in the prohormone convertase 1, which is involved in the posttranslational processing and sorting of prohormones and neuropeptides, have been implicated in the neuroendocrine control of energy balance in obese children [11]. Genetic mutations associated with additional manifestations of the obesity syndrome, such as adrenal insufﬁciency, red hair (proopiomelanocortin), impaired fertility (prohormone convertase 1, leptin, and leptin receptor), and impaired immunity (leptin), have been suggested as causative factors [12]. A defect in proopiomelanocortin protein due to impaired synthesis of melanocortin peptides; adrenocorticotropin; melanocyte-stimulating hormone (MSH); or the α-, β-, and γ-opioid receptor ligand β-endorphin results in early-onset obesity due to increased food intake or reduced energy utilization. The melanocortin-4 gene, which can be detected in 2 to 4% of all extremely obese children [17,18], has been linked to the onset of obesity. Another important monogenic form of obesity is due to mutations in the peroxisome proliferator-activated receptor γ2 (PPARγ2) gene [19]. More than 30 rare mutations have been identiﬁed worldwide that occur very infrequently in association with obesity. Children with melanocortin-4 gene mutations have been found to eat more meals than controls without mutations [9,16,20]. Experimental studies using melanocortin-4 gene knockout mice have demonstrated a signiﬁcant increase in food uptake when compared with controls, leading to the development of obesity [21]. These ﬁndings support earlier observations made by Farooqi et al. [16] with regard to additional meals being taken by obese children.

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Recently, it has been suggested that polymorphisms in the sterol regulatory element-binding transfactor gene predispose diabetic patients to obesity [22]. Analysis of the human melaninconcentrating hormone receptor-1 gene has identiﬁed 11 infrequent variations and 2 single nucleotide polymorphisms (SNPs) in its coding sequence and 18 SNPs (8 novel) in the ﬂanking sequence of this gene in subjects with juvenile-onset obesity syndrome [23]. The mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK), have also been proposed to play an important role in the differentiation of preadipocyte cell lines to adipocytes with a consequent effect on obesity [24]. Recent studies with obese and type 2 diabetic (db/db) mice suggest that osteopontin may also be a factor in the etiology of obesity syndrome [25,26]. These ﬁndings indicate that upregulation of osteopontin signaling in obese mice potentiates the development of hepatic ﬁbrosis and nonalcoholic steatohepatitis [24,25]. Although heredity and environmental factors play a critical role in the development of obesity and related disorders, at this stage their respective roles and signiﬁcance remain unresolved.

CLINICAL SYNDROMES OF OBESITY The clinical syndromes associated with obesity include Prader–Willi syndrome (PWS) with endocrine disorders, acanthosis nigricans characterized by thickening and pigmentation of skin folds, Blount’s disease associated with orthopedic anomalies, sleep disorders, neurological (pseudotumor cerebri) and cardiovascular problems, and polycystic ovary syndrome.

PRADER–WILLI SYNDROME: A CLINICAL DESCRIPTION The Prader–Willi syndrome is a common syndrome associated with human obesity. It was ﬁrst described in 1956, although speciﬁc diagnostic criteria were not established until 1993 [27]. The main clinical characteristics of this syndrome are hypotonia during the neonatal period and failure to thrive due to feeble sucking reﬂex and low energy intake. In males, bilateral cryptorchidism associated with profound hypotonia may draw attention to the diagnosis. Hypoplasia of the external genitalia (labia minora and clitoris) also occurs in females but may be difﬁcult to recognize. Limited hip and knee extension may be detected during routine newborn examination for congenital dislocation of the hip. Hands are frequently delicate, with a puffy appearance. Orthopedic problems such as scoliosis are common, as a consequence of both the syndrome itself and the presence of gross obesity [27]. Gastrointestinal symptoms such as hyperphagia (a continuous hunger apparently without a normal sensation of satiety), vomiting, and rectal bleeding may occur. The insatiable hunger has been attributed to anomalies in development of hypothalamic paraventricular nucleus [27]. Hyperphagia is commonly associated with aggressive and self-abusive behavior, the theft of food, poor social relationships, and mental retardation. Obesity has been identiﬁed as one of the major factors contributing to the morbidity and mortality associated with the Prader–Willi syndrome. Development of non-insulin-dependent diabetes mellitus and impaired cardiac and pulmonary function leading to severe disability and early death have also been described.

ROLE OF DNA METHYLATION Robinson et al. [29] reported that the Prader–Willi syndrome may be associated with deletion of the q11–q13 fragment of paternal chromosome 15 or the presence of uniparental disomy (i.e., two complete chromosomes 15 of maternal origin). A third type of genetic or epigenetic alteration involving impairment of the imprinting center due to changes in methylation patterns has also been proposed. DNA methylation is the covalent modiﬁcation of DNA that is associated with the regulation of gene expression during development, genomic imprinting, X-chromosome inactivation, and silencing of functional genes [30,31]. The Prader–Willi syndrome is a neurodevelopmental

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disorder that arises from the lack of expression of paternally inherited genes known to be imprinted and located in the chromosome 15q11–q13 region. It is considered the most common syndrome causing life-threatening obesity, with an estimated incidence of 1 in 10,000 to 20,000 individuals. Approximately 99% of patients have an abnormality in the parent-speciﬁc methylation imprint within the Prader–Willi imprinting center at chromosome 15q11.2–q12. Among these subjects, a de novo paternally derived chromosome 15q11–q13 deletion is the cause of the Prader–Willi syndrome in about 70% of patients, and maternal disomy-15 accounts for about 25% of cases. The remaining 5% of cases result from genomic imprinting defects (microdeletions or epimutations) of the imprinting center in the 15q11–q13 region or from chromosome 15 translocations [32]. A deﬁciency of methyl (CpG) binding protein 2 (MeCP2) in the Prader–Willi syndrome causes an epimutation at the maternal small nuclear ribonucleoprotein polypeptide N promoter allele. This results in an open chromatin structure that is associated with increased histone H3 acetylation and H3(K4) methylation and decreased H3(K9) methylation [33]. Methylation-speciﬁc polymerase chain reaction (PCR) and real-time PCR analyses demonstrated that approximately 50% of the blood cells had an imprinting defect and 50% of the cells were normal in a young woman with the Prader–Willi syndrome due to a mosaic imprinting defect [34]. Imprinting of the 2-Mb Prader–Willi and Angelman syndrome domain in human chromosome 15q11–q13 and its mouse ortholog in mouse chromosome 7C is believed to be regulated by a regional imprinting control center; however, the mechanism by which this occurs remains unclear. The entire 2-Mb domain contains numerous paternally expressed genes and at least two maternally expressed genes. A breakthrough in our understanding of the regulation of the imprinting control mechanism was achieved by studying the Prader–Willi and Angelman syndromes in families with imprinting mutations caused by microdeletions of two sequences: a 4.3-kb sequence (PWS–SRO) that includes the small nuclear ribonucleoprotein polypeptide N promoter/exon 1 and an 880-bp sequence (AS–SRO) located 35 kb upstream from the transcription start site. Deletion of the AS–SRO sequence was implicated in the Angelman syndrome and deletion of the PWS–SRO sequence in the Prader–Willi syndrome. These sequences, although separated by a 35-kb intervening sequence, are able to communicate and constitute an imprinting center that regulates imprinting of the entire 2-Mb domain. In view of the altered methylation patterns in the Prader–Willi syndrome imprinting center, it is currently being diagnosed by identiﬁcation of abnormal DNA methylation patterns in the small nuclear ribonucleoprotein polypeptide N gene [35].

CONCLUSIONS New molecular and genetic tools are becoming available that should expedite the identiﬁcation of candidate obesity genes. Because the complete sequence of the human genome as well as the full genome sequence of other species are now available, they may be used to study the imprinting center and its critical sites for methylation-mediated mutations in candidate obesity genes. Information about methylation-based functional and transcriptional activation and inactivation of candidate genes involved in early-onset obesity may be useful in the development of anti-obesity drugs. The genetic variants and patterns of common variation elucidated by use of whole-genome linkage disequilibrium studies to map common genes in disease states will also facilitate the selection of speciﬁc genes for future studies in obesity and related disorders [36].

ACKNOWLEDGMENTS This investigation was partially supported by grants from the Anderson Foundation, North Suburban Medical Research Junior Board, Medical Research Institute Council, Wile Foundation. We thank Dr. Adarsh Rani Bairsetty for her excellent support in manuscript preparation and Ms. Roberta Gerard for editorial assistance.

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Mokdad, A.H., Serdula, M.K., Dietz, W.H., Bowman, B.A., Marks, J.S., and Koplan, J.P., The spread of the obesity epidemic in the United States, 1991–1998, JAMA, 282, 1519–1522, 1999. Allison, D.B., Fontaine, K.R., Manson, J.E., Stevens, J., and VanItallie, T.B., Annual deaths attributable to obesity in the United States, JAMA, 282, 1530–1538, 1999. Correia, M.L. and Haynes, W.G., Emerging drugs for obesity: linking novel biological mechanisms to pharmaceutical pipelines, Expert Opin. Emerg. Drugs, 10, 643–660, 2005. Perusse, L., Rankinen, T., Zuberi, A., Chagnon, Y.C., Weisnagel, S.J. et al., The human obesity gene map: the 2004 update, Obes. Res., 13, 381–490, 2005. Snyder, E.E., Walts, B., Perusse, L., Chagnon, Y.C., Weisnagel, S.J. et al., The human obesity gene map: the 2003 update, Obes. Res., 12, 369–439, 2004. Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., and Friedman, J.M., Positional cloning of the mouse obese gene and its human homologue, Nature, 372, 425–432, 1994. Strobel, A., Issad, T., Camoin, L., Ozata, M., and Strosberg, A.D., A leptin missense mutation associated with hypogonadism and morbid obesity, Nat. Genet., 18, 213–215, 1998. Issad, T., Strobel, A., Camoin, L., Ozata, M., and Strosberg, A.D., Leptin and puberty in humans: hypothesis of the critical adipose mass revisited, Diabetes Metab., 24, 376–378, 1998. Govaerts, C., Srinivasan, S., Shapiro, A., Zhang, S., Picard, F. et al., Obesity-associated mutations in the melanocortin 4 receptor provide novel insights into its function, Peptides, 26, 1909–1919, 2005. Clement, K., Vaisse, C., Lahlou, N., Cabrol, S., Pelloux, V. et al., A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction, Nature, 392, 398–401, 1998. Jackson, R.S., Creemers, J.W., Ohagi, S., Rafﬁn-Sanson, M.L., Sanders, L. et al., Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene, Nat. Genet., 16, 303–306, 1997. Krude, H., Biebermann, H., Luck, W., Horn, R., Brabant, G., and Gruters, A., Severe early-onset obesity, adrenal insufﬁciency and red hair pigmentation caused by POMC mutations in humans, Nat. Genet., 19, 155–157, 1998. Paracchini, V., Pedotti, P., and Taioli, E., Genetics of leptin and obesity: a HuGE review, Am. J. Epidemiol., 162, 101–114, 2005. Jacobson, P., Ukkola, O., Rankinen, T., Snyder, E.E., Leon, A.S. et al., Melanocortin 4 receptor sequence variations are seldom a cause of human obesity: the Swedish Obese Subjects, the HERITAGE Family Study, and a Memphis cohort, J. Clin. Endocrinol. Metab., 87, 4442–4446, 2002. Hirschhorn, J.N. and Altshuler, D., Once and again: issues surrounding replication in genetic association studies, J. Clin. Endocrinol. Metab., 87, 4438–4441, 2002. Farooqi, I.S., Matarese, G., Lord, G.M., Keogh, J.M., Lawrence, E. et al., Beneﬁcial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deﬁciency, J. Clin. Invest., 110, 1093–1103, 2002. Sina, M., Hinney, A., Ziegler, A., Neupert, T., Mayer, H. et al., Phenotypes in three pedigrees with autosomal dominant obesity caused by haploinsufﬁciency mutations in the melanocortin-4 receptor gene, Am. J. Hum. Genet., 65, 1501–1507, 1999. Hinney, A., Schmidt, A., Nottebom, K., Heibult, O., Becker, I. et al., Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans, J. Clin. Endocrinol. Metab., 84, 1483–1486, 1999. Ristow, M., Muller-Wieland, D., Pfeiffer, A., Krone, W., and Kahn, C.R., Obesity associated with a mutation in a genetic regulator of adipocyte differentiation, N. Engl. J. Med., 339, 953–959, 1998. Vaisse, C., Clement, K., Durand, E., Hercberg, S., Guy-Grand, B., and Froguel, P., Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity, J. Clin. Invest., 106, 253–262, 2000. Huszar, D., Lynch, C.A., Fairchild-Huntress, V., Dunmore, J.H., Fang, Q. et al., Targeted disruption of the melanocortin-4 receptor results in obesity in mice, Cell, 88, 131–141, 1997. Eberle, D., Clement, K., Meyre, D., Sahbatou, M., Vaxillaire, M. et al., SREBF-1 gene polymorphisms are associated with obesity and type 2 diabetes in French obese and diabetic cohorts, Diabetes, 53, 2153–2157, 2004. Wermter, A.K., Reichwald, K., Buch, T., Geller, F., Platzer, C. et al., Mutation analysis of the MCHR1 gene in human obesity, Eur. J. Endocrinol., 152, 851–862, 2005.

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Obesity: Epidemiology, Pathophysiology, and Prevention Bost, F., Aouadi, M., Caron, L., and Binetruy, B., The role of MAPKs in adipocyte differentiation and obesity, Biochimie, 87, 51–56, 2005. Sahai, A., Malladi, P., Pan, X., Paul, R., Melin-Aldana, H. et al., Obese and diabetic db/db mice develop marked liver ﬁbrosis in a model of nonalcoholic steatohepatitis: role of short-form leptin receptors and osteopontin, Am. J. Physiol. Gastrointest. Liver Physiol., 287, G1035–G1043, 2004. Sahai, A., Malladi, P., Melin-Aldana, H., Green, R.M., and Whitington, P.F., Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model, Am. J. Physiol. Gastrointest. Liver Physiol., 287, G264–G273, 2004. Holm, V.A., Cassidy, S.B., Butler, M.G., Hanchett, J.M., Greenswag, L.R. et al., Prader–Willi syndrome: consensus diagnostic criteria, Pediatrics, 91, 398–402, 1993. Swaab, D.F., Purba, J.S., and Hofman, M.A., Alterations in the hypothalamic paraventricular nucleus and its oxytocin neurons (putative satiety cells) in Prader–Willi syndrome: a study of ﬁve cases, J. Clin. Endocrinol. Metab., 80, 573–579, 1995. Robinson, W.P., Spiegel, R., and Schinzel, A.A., Deletion breakpoints associated with the Prader–Willi and Angelman syndromes (15q11–q13) are not sites of high homologous recombination, Hum. Genet., 91, 181–184, 1993. Feinberg, A.P. and Vogelstein, B., Hypomethylation distinguishes genes of some human cancers from their normal counterparts, Nature, 301, 89–92, 1983. Feinberg, A.P., Cui, H., and Ohlsson, R., DNA methylation and genomic imprinting: insights from cancer into epigenetic mechanisms, Semin. Cancer Biol., 12, 389–398, 2002. Shao, J., Qiao, L., Janssen, R.C., Pagliassotti, M., and Friedman, J.E., Chronic hyperglycemia enhances PEPCK gene expression and hepatocellular glucose production via elevated liver activating protein/ liver inhibitory protein ratio, Diabetes, 54, 976–984, 2005. Makedonski, K., Abuhatzira, L., Kaufman, Y., Razin, A., and Shemer, R., MeCP2 deﬁciency in Rett syndrome causes epigenetic aberrations at the PWS/AS imprinting center that affects UBE3A expression, Hum. Mol. Genet., 14, 1049–1058, 2005. Wey, E., Bartholdi, D., Riegel, M., Nazlican, H., Horsthemke, B. et al., Mosaic imprinting defect in a patient with an almost typical expression of the Prader–Willi syndrome, Eur. J. Hum. Genet., 13, 273–277, 2005. Chen, C.J., Hsu, M.L., Yuh, Y.S., Cheng, S.N., Kuo, P.L., and Lee, C.M., Early diagnosis of Prader–Willi syndrome in a newborn, Acta Paediatr. Taiwan, 45, 108–110, 2004. Kruglyak, L., Prospects for whole-genome linkage disequilibrium mapping of common disease genes, Nat. Genet., 22, 139–144, 1999.

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Part III Obesity and Degenerative Diseases

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Stress Status 11 Oxidative in Humans with Metabolic Syndrome Chung-Yen Chen and Jeffrey B. Blumberg CONTENTS Introduction ....................................................................................................................................123 Increases in Oxidation Products in Patients with Components of Metabolic Syndrome ............125 Biomarkers of Lipid Peroxidation..........................................................................................125 Obesity and Lipid Peroxidation ......................................................................................125 Hyperglycemia and Lipid Peroxidation ..........................................................................125 Hypertension and Lipid Peroxidation .............................................................................125 Susceptibility of Low-Density Lipoprotein to Oxidation ......................................................126 Production of Protein Oxidation.............................................................................................126 Changes of Antioxidant Defense Mechanisms in Patients with Components of Metabolic Syndrome ...................................................................127 Small Molecule Antioxidants .................................................................................................127 Obesity and Dietary Antioxidants ...................................................................................127 Insulin Resistance and Dietary Antioxidants ..................................................................127 Metabolic Syndrome and Dietary Antioxidants..............................................................127 Antioxidant Enzymes..............................................................................................................128 Paraoxonase.............................................................................................................................128 Changes in Biomarkers of Oxidative Stress in Patients with Components of Metabolic Syndrome ...................................................................128 Physical Activity, Metabolic Syndrome, and Oxidative Stress Status...................................129 Hypocaloric Diets, Metabolic Syndrome, and Oxidative Stress Status ................................129 Pharmacotherapy of Metabolic Syndrome and Oxidative Stress ..........................................130 Antihyperglycemia Therapy ............................................................................................130 Antihypertension Therapy ...............................................................................................130 Dyslipidemia Therapy .....................................................................................................130 Antioxidant Supplementation ..........................................................................................131 Conclusion......................................................................................................................................132 References ......................................................................................................................................133

INTRODUCTION The concept of metabolic syndrome (MS) was ﬁrst introduced by Reaven as “syndrome X” [1]. Subsequently, the World Health Organization (WHO) [2] and the National Cholesterol Education Program Adult Treatment Panel (ATP III) [3,4] deﬁned criteria of MS with a speciﬁc focus on dyslipidemia, hyperglycemia, hypertension, and obesity as key signs — that is, a constellation of 123

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Regulation of antioxidant enzyme activity

Increase of oxidation products

ascorbate tocopherols carotenoids uric acid lipoic acid ubiquinol glutathione total antioxidant capacity

superoxide dismutase glutathione peroxidase catalase

Lipid

Loss of small-molecule antioxidants

Protein

DNA

malondialdehyde

protein carbonyls

oxidatively modified bases

F2-isoprostanes

oxidized amino acids

strand breaks

lipid peroxides

dityrosine, Cl-tyrosine, NO2-tyrosine, O-tyrosine

conjugated dienes expired hydrocarbons

FIGURE 11.1 Oxidative stress sorted by functionality of antioxidants and products of oxidation.

risk factors leading to cardiovascular disease (CVD) [4]. Using ATP III criteria, the National Health and Nutrition Examination Survey (NHANES) II Mortality Study [5] indicated a nearly linear correlation between the number of these MS components and mortality from CVD [5] and estimated a prevalence of MS at 23.7%, or ~47,000,000 adults in the United States [6]. Although the precise etiology of MS is unresolved and undoubtedly complex, abdominal obesity, insulin resistance, and physical inactivity are signiﬁcant contributing risk factors and, thus, suggest a number of practical solutions for both prevention and treatment of the condition [7]. Reactive oxygen, nitrogen, and halide species (or free radicals), such as hydrogen peroxide, peroxynitrite, and hypochlorous acid, respectively, have been implicated in the etiology of CVD and diabetes [8]. Consistent with free radicals initiating or promoting the pathophysiology of these diseases, dietary antioxidants have been implicated in a reduction of their risk, although it is important to recognize that these compounds may function via mechanisms unrelated to their antioxidant properties [9,10]. These relationships have given rise to hypotheses that oxidative stress may be linked to early events in the development of CVD (as well as diabetes) via both independent mechanisms and dynamic interactions between the dyslipidemia, hyperglycemia, hypertension, and obesity of MS. Examining antioxidant defenses and biomarkers of oxidative stress in vivo in human studies offers a robust approach to testing these hypotheses. These studies generally utilize determinations of: (1) the modulation of antioxidant enzyme activity, (2) the concentration of antioxidants or measures of total antioxidant capacity, or (3) products of oxidatively modiﬁed lipids, protein, or DNA (Figure 11.1). However, these data must be interpreted with caution as they may not necessarily reﬂect a clinically signiﬁcant or pathogenic event but instead indicate a temporary response of the antioxidant defense network. Assays for determining oxidation products of lipids, proteins, and DNA have been previously reviewed [11–16] and are beyond the scope of this chapter. We consider here evidence from human studies suggesting a role of antioxidant defenses and oxidative stress in the etiology and progression of MS and subsequent risk for CVD.

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INCREASES IN OXIDATION PRODUCTS IN PATIENTS WITH COMPONENTS OF METABOLIC SYNDROME Oxidative stress is the disturbance in the oxidant/antioxidant balance in favor of the former and can be a consequence of diminished protection by antioxidant defenses or increased generation of free radicals, with both resulting in production of oxidation products (e.g., lipid peroxides) [16].

BIOMARKERS

OF

LIPID PEROXIDATION

Obesity and Lipid Peroxidation Obesity, a key component of MS [17–19], appears to be associated with increased generation of free radicals and lipid peroxidation reactions [20]. For example, in an observational study of 140 nondiabetic men and women (mean age, 59 years), body mass index (BMI; in kg/m2) and waist circumference (WC; in cm) were directly associated with plasma thiobarbituric acid reactive substances (TBARS) and urinary 8-epi-prostaglandin-F2α (8-iso), products of lipid peroxidation [21]. Analyses of 2828 subjects (mean age, 61) from the Framingham cohort revealed a linear correlation between obesity and lipid peroxidation, as each 5 kg/m2 of BMI was associated with a 9.9% increase in urinary 8-iso after adjustment for creatinine [22]. Similarly, 8-iso has also been associated in studies of age-matched men with adiposity, insulin resistance, and endothelial adhesion molecules [23,24]. Although 8-iso is the best validated measure of lipid peroxidation, it is worth noting that no difference was found when malondialdehyde (MDA), another indicator of lipid peroxidation, was determined in a study with 9 obese normotensive men (BMI, 32.6; mean age, 31) and age-matched controls [25]. Further, the type of obesity may dictate the magnitude of lipid peroxidation, as Davi et al. [26] found that urinary 8-iso was higher in 24 android obese, nonsmoking women (BMI, 39; waist-to-hip ratio [WHR], 0.96; mean age, 45) than in 25 gynoid obese women (BMI, 33; WHR, 0.80; mean age, 40) but higher in all obese women when compared to 24 nonobese women (BMI, 22.5; mean age, 38). Hyperglycemia and Lipid Peroxidation Hyperglycemia can increase the generation of free radicals via autoxidation events, polyol pathways, and Amadori reactions [27,28]; for example, an acute oral administration of 100 g glucose to 8 healthy men (BMI, 22.4; mean age, 23) increased plasma MDA [29]. Consistent with this result, Facchini et al. [30] found that plasma lipid peroxides were signiﬁcantly higher in 12 insulin-resistant healthy people (BMI, 25.9; mean age, 49) than in 12 insulin-sensitive individuals (BMI, 24.6; mean age, 47). Quantifying the relationship between obesity and lipid peroxidation, Keaney et al. [22] calculated that each 25-mg/dL increase in fasting glucose was associated with a 4.3% increase in urinary 8-iso (adjusted for creatinine). Hypertension and Lipid Peroxidation Koska et al. [31] found increased MDA and lipofuscin concentrations in plasma of 11 men with essential hypertension (blood pressure [BP, in mmHg], 151/97; BMI, 28.6; mean age, 44.3) when compared to 10 normotensive men (BP, 119/79; BMI, 25.3; mean age, 44.4) at 0.85 vs. 1.3 ng/mL and 11.8 vs. 16.2 units, respectively. Importantly, the magnitude of lipid peroxidation appears greater in people with two or more risk factors of MS than in those with one or less. Konukoglu et al. [32] found that obesity and hypertension were associated with a greater oxidative stress status than with either obesity or hypertension alone, as plasma TBARS ascended in order in 25 nonobese normotensives (BP, 95.5/75.4; BMI, 21.5; mean age, 54.5), 25 non-obese hypertensives (BP, 165.5/105.3; BMI, 23.5; mean age, 56.5), 35 obese normotensives (BP, 109.5/75.5; BMI, 32.5; mean age, 60.5), and 45 obese hypertensives (BP, 168.8/115.6; BMI, 33.8; mean age, 58.5) at 5.55,

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6.85, 7.20, and 8.45 µmol/L, respectively. When Stojiljkovic et al. [33] examined the relationship between lipid peroxidation and hypertension, obesity, and insulin resistance, they found increased urinary 8-iso excretion in 10 obese hypertensives with insulin resistance (BMI, 31; BP, 131/88; mean age, 40) compared to 12 healthy normotensives without insulin resistance (BMI, 22; BP, 106/72; mean age, 38) at 5.0 vs. 3.3 ng/mg creatine, respectively. Using ATP III guidelines, Hansel et al. [34] found that plasma 8-iso was 3.7-fold greater in 10 MS patients (BMI, 31.1; WC, 102.3; BP, 148/85; mean age, 53.5) than in 11 healthy individuals (BMI, 23.4; WC, 81; BP, 127/80; mean age, 52.3) in a case control study. In contrast, also using ATP III criteria, Sjogren et al. [35] observed no difference in urinary 8-iso between 22 men with MS (BMI, 30.1; WC, 108; BP, 148/87) and healthy men (BMI, 24.2; WC, 92; BP, 120/75) or men with one or two MS risk factors (BMI, 26.1; WC, 97; BP, 141/83) in a cross-sectional cohort of 289 men (ages 62 to 64). The absence of a correlation here between lipid peroxidation and MS could be attributed to a lack of power with so few MS patients in this population.

SUSCEPTIBILITY

OF

LOW-DENSITY LIPOPROTEIN

TO

OXIDATION

Oxidation of lipoproteins, especially low-density lipoprotein (LDL), has been implicated in the pathogenesis of atherosclerosis and CVD [36]. Thus, it is of interest to note that Myara et al. [37] found that the resistance of LDL to oxidation in vitro was negatively correlated with BMI (r = –0.35) in 75 obese patients (BMI, 30–50). However, as in vitro LDL oxidation assays may indicate only the oxidizability of LDL with a modest relationship to in vivo pathophysiology, some studies have evaluated circulating oxidized LDL (ox-LDL) in vivo, although the origin of ox-LDL in the circulation is unclear. Consistent with Myara et al. [37], Couillard et al. [24] found a positive correlation (r = 0.52) between ox-LDL and WC in 56 sedentary men with abdominal obesity (WC, 102; BMI, 30.4; mean age, 40). Extending this relationship to glycemic status, Kopprasch et al. [38] found that ox-LDL was higher in 113 subjects with impaired glucose tolerance (BMI, 28.0; mean age, 60) than in 376 with normal glucose tolerance (BMI, 26.4; mean age, 57). Similarly, Mizuno et al. [39] found higher ox-LDL in 12 healthy, nonsmoking, insulin-resistant men (BMI, 24.5; mean age, 29.1) than in 24 insulin-sensitive men (BMI, 22.1; mean age, 28.7) at 146 vs. 101 IU/L, respectively. In contrast, Schwenke et al. [40] found no correlation between glucose intolerance and in vitro LDL susceptibility to oxidation in 352 men and postmenopausal women from the Insulin Resistance Atherosclerosis Study. Examining directly 1147 MS patients (BMI, 29; WC, 102; BP, 139/72; mean age, 74) with their multiple risk factors for CVD according to ATP III criteria, Holvoet et al. [41] found elevated ox-LDL in comparison to 1886 healthy subjects (BMI, 27; WC, 98; BP, 134/71; mean age, 74), independent of sex and ethnicity. Employing World Health Organization (WHO) criteria, a similar correlation between increasing number of MS criteria and ox-LDL was reported in a cross-sectional study in Sweden among 391 nondiabetic men [42,43]; however, as with their inability to detect a difference using urinary 8-iso, Sjogren et al. [35] found no difference in ox-LDL concentrations between MS and healthy men.

PRODUCTION

OF

PROTEIN OXIDATION

Nitrotyrosine (NT) can serve as a biomarker of peroxynitrite radical attack on proteins, although no studies have been conducted assessing MS with NT [44–46]. Although Marfella et al. [47] found that acute hyperglycemia induced by glucose infusion increased plasma NT from 0.2 to 0.5 µmol/L in 20 healthy subjects (BMI, 24; mean age, 34), Bo et al. [48] found no different in plasma NT between 96 healthy subjects (BMI, 22.9; WC, 85.9; BP, 126.9/80.5; mean age, 53.8) and 204 people with central obesity (BMI, 29.4; WC, 101.9; BP, 138.6/86.4; mean age, 55.3) in a cohort study. Plasma NT was found to be elevated in 40 type 2 diabetic patients (BMI, 26.2; mean age, 56.2) relative to 35 healthy subjects with a similar BMI (BMI, 25.9; mean age, 55.4) [45].

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CHANGES OF ANTIOXIDANT DEFENSE MECHANISMS IN PATIENTS WITH COMPONENTS OF METABOLIC SYNDROME SMALL MOLECULE ANTIOXIDANTS Non-enzymatic, small-molecule dietary antioxidants include vitamins C and E, carotenoids, polyphenols, and other compounds. In addition to their presence in some foods, endogenous synthesis of α-lipoic acid, glutathione (GSH), uric acid, ubiquinols, and other compounds contributes to the body’s antioxidant defense network. If the etiology or progression of MS were associated with oxidative stress, then an increased utilization and requirement or lower concentrations in a vicious cycle with oxidative stress would be anticipated for these antioxidants. Obesity and Dietary Antioxidants The increases in lipid peroxidation associated with obesity suggest an increased utilization of antioxidant vitamins. Indeed, Myara et al. [37] found an inverse association between BMI and plasma vitamin E (r = –0.53) in a study of 75 nondiabetic, normotensive obese patients (mean age, 39.1). In contrast, no such association was found by Visentin et al. [25] with plasma vitamins A, C, and E; β-carotene; or lycopene in 9 obese, normotensive men (BMI, 32.6; mean age, 31) and 9 non-obese men (BMI, 23.3; mean age, 29). Menke et al. [49] reported that the plasma coenzyme Q10 and redox ratio (oxidized to total coenzyme Q10) was not different between 67 obese children and 50 age-matched, normal weight children. However, these studies are of small size and also absent assessments of diet and oxidative stress, so it is not possible to determine whether the results are due to changes in antioxidant intake or utilization in vivo, free radical generation, or compensatory mechanisms in endogenous antioxidant synthesis. Insulin Resistance and Dietary Antioxidants Inverse associations between insulin resistance and plasma vitamin E (r = –0.21) and β-carotene (r = –0.2) were observed among 103 Korean children by Konukoglu et al. [51]. Facchini et al. [30] also observed lower plasma α- and β-carotene, lutein, and α-tocopherol in 12 healthy insulinresistant individuals (BMI, 25.9; mean age, 49) than in 12 insulin-sensitive individuals (BMI, 24.6; mean age, 47). Konukoglu et al. [51], however, found that erythrocyte GSH was not different between 18 middle-aged subjects with normal glucose tolerance and 15 with impaired glucose tolerance. To date, the evaluation of insulin resistance with assays purporting to measure total antioxidant capacity have not revealed any relationship between these parameters, even when other biomarkers of oxidative stress were affected [38] or when hyperglycemia or hyperinsulinemia were induced [52]. Metabolic Syndrome and Dietary Antioxidants Ford et al. [53] observed in 8808 adults from the NHANES III cohort that those with MS had lower plasma retinyl esters, vitamins C and E, and carotenoids after adjustments for age, sex, race, education, smoking, physical activity, fruit and vegetable intake, and supplement use. Concerned by the growing prevalence of MS among children [54], Molnar et al. [55] examined 15 children with MS (BMI, 34.2; mean age, 13.4), 17 with obesity (BMI, 30.4; mean age, 14.4), and 16 healthy children (BMI, 20.7; mean age, 16.2) and also found signiﬁcant reductions in plasma α-tocopherol, β-carotene, and total antioxidant capacity. In contrast, using ATP III criteria, Miles et al. [56] found that total plasma ubiquinol was higher in 134 MS subjects (BMI, 33.2; mean age, 49.9) than in 178 healthy subjects (BMI, 26.5; mean age, 43). It may be possible, then, that MS is associated with lower dietary antioxidant status due to increased utilization but higher endogenous antioxidant status due to induction of compensatory mechanisms and thus no readily apparent change in total antioxidant capacity.

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ANTIOXIDANT ENZYMES Antioxidant enzymes could be subject to compensatory regulation in MS associated with oxidative stress. Ozata et al. [57] found that the activity of erythrocyte superoxide dismutase (SOD) and GSH peroxidase (GSHPx) was lower in 76 obese men (BMI, 36.6; mean age, 49.1) than in 24 healthy men (BMI, 21.2; mean age, 48.5). However, Visentin et al. [25] found no difference in the activity of erythrocyte SOD, GSHPx, or catalase in 9 normotensive, obese men (BMI, 32.6; mean age, 31) vs. 9 healthy men (BMI, 23.3; mean age, 29). Although neither of these studies suggests an upregulation of antioxidant enzymes with obesity, it should be noted that their populations were small and of different ages, factors that can affect this outcome [58]. Further, questions regarding compensatory mechanisms might best include a longitudinal rather than a cross-sectional examination. Investigating the response of antioxidant enzymes to acute hyperglycemia, Koska et al. [29] induced an increase in erythrocyte GSHPx and SOD activity by administering 100 g glucose to 8 healthy males (BMI, 22.4; mean age, 23); however, the chronic hyperglycemia of 103 Korean children with insulin resistance was associated with an attenuated activity of erythrocyte catalase [50]. Interestingly, Pedro-Botet et al. [59] found that hypertension was also associated with lower activity of SOD and GSHPx when they compared 30 normolipidemic, untreated mild hypertensive patients with 164 age-matched, healthy subjects at 806 vs. 931 U/g Hb and 5491 vs. 6669 U/L, respectively; however, the inﬂuence of the combined constellation of MS signs on antioxidant enzymes has yet to be determined.

PARAOXONASE Paraoxonase-1 (PON-1) is an ester hydrolase bound to high-density lipoprotein (HDL) that catalyzes the hydrolysis of a number of organic esters and protects LDL from oxidation. PON-1 activity is considerably lower in patients with diabetes, hypercholesterolemia, and myocardial infarction [60,61]. With regard to symptoms of MS, Ferretti et al. [62] found that 12 obese women (BMI, 45.3; mean age, 38.2) had fourfold less PON-1 activity than 31 healthy controls (BMI, 20.1; mean age, 31.5) at 112.2 vs. 470.5 U/mg. Further, an inverse correlation (r = –0.76) was observed between PON-1 activity and LDL lipid peroxides. Employing WHO criteria, Garin et al. [63] observed that 139 MS patients (BMI, 30; BP, 139/82; mean age, 62.1) had 22% lower serum PON-1 activity than 634 non-MS patients (BMI, 26.6; BP, 130/79; mean age, 59.6), a decrement sufﬁcient to attenuate the antioxidant protection of LDL by HDL [64]. Using ATP III criteria, Senti et al. [65] found that the magnitude of attenuation of PON-1 activity was dependent on the number of MS symptoms and related metabolic disturbances in a cohort of 713 men and 651 women (ages 25 to 74). In contrast and also using ATP II criteria, Hansel et al. [34] found no difference in serum PON-1 activity between 10 MS patients (mean age, 53.5) and 11 healthy, normolipidemic controls (mean age, 52.3), although they did observe that HDL from MS patients had less antioxidant activity to protect LDL against oxidation in vitro. Results such as these are encouraging investigations exploring the therapeutic potential of PON-1 induction in patients with MS.

CHANGES IN BIOMARKERS OF OXIDATIVE STRESS IN PATIENTS WITH COMPONENTS OF METABOLIC SYNDROME The management goal for patients with MS is reducing the risk of atherosclerosis and CVD [66]; thus, the initial treatment emphasis, before introducing pharmacotherapy, is on mitigating the modiﬁable lifestyle factors of obesity and physical inactivity [66–68]. Both lifestyle changes and medications may affect MS and CVD risk via an impact on oxidative stress status.

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AND

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Regular exercise training in older adults is associated with signiﬁcant reductions in several metabolic risk factors for CVD [69]. Similar exercise programs may contribute to the prevention of MS, as Ekelund et al. [70] found that the level of energy expenditure in physical activity was inversely associated in a dose-dependent fashion with development of MS signs over 5.6 years in a prospective study of 605 healthy adults (BMI, 26; mean age, 53.2). In a randomized clinical trial, Stewart et al. [71] provided 6 months of supervised exercise training (per the American College of Sports Medicine [72]) to 51 older adults (BMI, 29.4; BP, 140/77; mean age, 63), 22 who presented with MS according to ATP III criteria. In addition to improvements in body composition and ﬁtness, the subjects lost 2.2 kg body weight and reduced their BP by 5.3/3.7. Importantly, no subjects developed MS during the intervention period, and 9 who presented with MS were no longer so classiﬁed. Physical activity can also increase insulin sensitivity. For example, by subjecting 28 MS patients (BMI, 32; mean age, 52) to a 40-minute exercise program for 3 days a week over 8 weeks, Dumortier et al. [68] found that their insulin response improved twofold, and they also noted signiﬁcant decreases in body weight (–2.6 kg), BMI (–0.96), and body fat (–1.55%). Exercise programs can also impact measures of oxidative stress. For example, Vasankari et al. [73] found that a 10-month program of 3 to 5 hours of walking per week decreased the ratio of LDL conjugated dienes to LDL by 16% and enhanced the total antioxidant capacity of LDL by 13.5% in 104 sedentary volunteers (BMI, 29; mean age, 44). Exercise training can also signiﬁcantly reduce measures of lipid peroxidation and inﬂammation in vivo in obese individuals [74]. For example, Roberts et al. [75] reported that 45 to 60 minutes of supervised aerobic exercise at 70 to 85% maximum heart rate over 3 weeks decreased serum 8-iso from 202.6 to 131.3 pg/mL in 31 obese, older men (BMI, 35.4; mean age, 63.3), including 15 presenting with MS and all others with at least one MS factor. At the end of the exercise program, the number of men with MS according to WHO criteria decreased from 15 to 5.

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OXIDATIVE STRESS STATUS

Calorie reduction or restriction is an established approach to reducing body weight, and some studies indicate that success is associated with a reduction in measures of oxidative stress, as well. For example, Dandona et al. [76] found that a 1000-kcal/day diet regimen over 4 weeks induced a 12.3-kg loss of weight in 9 obese patients (BMI, 40.7; mean age, 45.3) and concomitantly signiﬁcant reductions in oxidative damage to lipids (1.68 vs. 1.47 µmol TBARS per L), proteins (1.39 vs. 1.17 µmol protein carbonyls per mg protein), and amino acids (o-tyrosine/phenylalanine, 0.42 vs. 0.36) with no changes in the status of α-tocopherol, β-carotene, or lycopene. Similarly, Davi et al. [26] found that a 1200-kcal/day diet consumed by 11 android obese women was associated with a signiﬁcant 32% reduction in urinary 8-iso; 9 other women in this study who failed to comply with the diet and lost no weight showed no change in their urinary 8-iso. Although drug treatments speciﬁc for MS signs are discussed below, gastrointestinal lipase inhibitors such as orlistat are described here as they are speciﬁcally indicated as adjuncts to hypocaloric, weight-loss diets [77]. Use of orlistat for 6 months in an obese population (BMI, 36.1; WC, 105; mean age, 49.7) not only reduced BMI and WC but also reduced plasma MDA from 2.0 vs. 0.89 µmol/L, the latter value being equivalent to non-obese controls, in direct association with BMI (r = 0.36) [78]. However, Samuelsson et al. [79] observed no change in plasma 8-iso with orlistat and/or hypocaloric diets. As exercise can modulate antioxidant defenses [58], it is worth noting that the combination of orlistat with exercise and a low-calorie diet decreased serum MDA from 1.79 to 1.20 µg/mL in a study of 12 obese subjects (BMI, 39.1; mean age, 37.3), while 11 subjects in the drug-plus-diet group (BMI, 37.9; mean age, 40) showed no such relationship [80]. However, results on oxidative stress from studies of orlistat are confounded by their action in decreasing the absorption of fat-soluble antioxidants such as carotenoids and tocopherols.

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OF

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Although the ﬁrst-line of treatment for MS patients includes lifestyle modiﬁcations, pharmacotherapy is the second line of treatment and speciﬁcally targeted to each of its signs: dyslipidemia, hyperglycemia, and hypertension, as well as obesity (see earlier discussion of lipase inhibitors). With a growing appreciation of the putative role of oxidative stress, supplementation with dietary antioxidants is also being considered as another potential adjunct in the prevention and treatment of MS. Antihyperglycemia Therapy Long-term therapy with thiazolidinediones improves insulin sensitivity and decreases the progression of carotid intima-media thickness [81]. Interestingly, treatment with repaglinide for 2 months in a randomized clinical trial signiﬁcantly enhanced total serum antioxidant capacity and serum SOD activity in 46 type 2 diabetics (BMI, 27.7; mean age, 50.5), initial values of which were lower than age- and sex-matched controls [82]. Although the improvement in these antioxidant defenses may be attributed to improved glycemic control, it is worth noting that this class of drugs is composed of benzoic acid derivatives capable of directly scavenging free radicals. In an 8-week, randomized clinical trial with 15 obese patients, troglitazone was found to signiﬁcantly reduce plasma TBARS as well as increase the resistance of LDL to oxidation in vitro without affecting vitamin E content [83]. Antihypertension Therapy The drugs employed to treat hypertension include thiazide diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium channel blockers, and β-blockers, often in conjunction with dietary modiﬁcations such as reductions in total calorie and sodium intake [84,85]. Saez et al. [85] found that combined drug (ARB or β-blockers) and diet treatments in 89 hypertensive patients (BMI, 29.5; BP 139/88; mean age, 46) were associated with signiﬁcant decreases in MDA and increases in GSH as well as SOD, GSHPx, and catalase activity in blood; however, no signiﬁcant correlation between BP reduction and these biomarkers of oxidative stress was found. In contrast, erythrocyte oxidized/reduced GSH was not altered by either ARB or calcium channel blocker regimens in a randomized trial of 49 nonsmoking, untreated hypertensives (BP, 151/96; BMI, 27; mean age, 52.5), although this ratio was signiﬁcantly higher than that of the 32 placebo controls (BMI, 24.5; mean age, 51) [86]. A clinical trial of ARB conducted in 12 MS patients (BP, 145/85; BMI, 37; mean age, 45.2) similarly failed to ﬁnd signiﬁcant changes in biomarkers of oxidative stress, including plasma TBARS and urinary 8-iso, after the intervention [87]. The hypothesis that an antioxidant supplement combined with antihypertensive therapy might improve clinical outcomes in MS patients was tested by Sola et al. [88] in a trial with an ARB plus 300 mg/day α-lipoic acid. After 4 weeks’ treatment of 15 MS patients (BP, 135/85; BMI, 34; mean age, 48), the drug-plus-antioxidant combination reduced serum 8-iso by 22%, the drug alone decreased it by 15%, and the antioxidant alone had no effect on 8-iso; however, the antihypertensive efﬁcacy of the ﬁrst two groups was quite small and null for α-lipoic acid, despite some indication that it possesses some such activity [89]. Dyslipidemia Therapy Although atherogenic dyslipidemia is characterized by the abnormal proﬁles of many constituent lipids, LDL is the primary target of therapy and statins are the principal class of therapeutic drugs [66,90]. Deedwania et al. [91] examined 2268 dyslipidemia patients and found that the 811 who met the ATP III criteria for MS all beneﬁted from statin treatment, albeit with some differences noted between individual agents. Importantly, all statins possess some antioxidant activity, providing

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them with at least a dual mechanism action in their use for patients with dyslipidemia as well as MS and type 2 diabetes mellitus. For example, 3 months of atorvastain therapy in vitro increased the resistance of LDL to in vitro oxidation in 12 normocholesterolemic type 2 diabetic patients [92]. Similarly, 12 weeks of rosuvastatin therapy reduced ox-LDL by 55% compared to placebo in a trial of 18 patients with familial combined hyperlipidemia (BMI, 28; mean age, 53.9) [93]. Further, Kural et al. [94] reported that a 10-week atorvastatin regimen enhanced total antioxidant capacity and serum PON activity by 7.6 and 23.6%, respectively, in 40 patients (mean age, 53.5) with dyslipidemia. Studies of statins and oxidative stress are confounded by the inhibitory action of these drugs on 3-hydroxy-3-methylglutaryl coenzyme A, a critical step in the pathway not only for cholesterol but also for the synthesis of antioxidant ubiquinols such as coenzyme Q10. Signiﬁcant reductions in the ubiquinol content of LDL and a greater oxidizability of LDL in vitro were found in a trial of 28 men with primary hyperlipidemia and coronary heart disease (BMI, 27.1; BP, 147/88; mean age, 56) who received a 6-week treatment with lovastatin [95]. Similarly, atorvastain has been found in clinical trials to reduce plasma ubiquinol concentrations [96]. Perhaps as a function of their lipid-lowering action, statins have also been reported to decrease vitamin E status [95]. Thus, in addition to supplementing patients taking statins with coenzyme Q10, some investigators have suggested including vitamin E supplements. For example, Manuel-Keenoy et al. [97] supplemented 11 type 1 diabetics receiving atorvastain with 250 IU vitamin E daily for 6 months and found that their α-tocopherol status was markedly enhanced, while 11 patients receiving the drug alone showed a decrease in plasma concentrations of the vitamin. Consistent with these results, the TBARS content of LDL was reduced in the vitamin-E-supplemented group and elevated in the drug-only group. Importantly, several studies have revealed that the antioxidant potency of statins in LDL varies by individual compounds and is independent of their cholesterol-lowering potency (e.g., with atorvastatin and ﬂuvastatin increasing resistance to oxidation but little such action by simvastatin, depending on the assay utilized) [98,99]. Statins have also been shown to beneﬁcially affect biomarkers of oxidative stress other than LDL oxidizability. Among a group of 35 hypercholesterolemic patients (BMI, 29; mean age, 54), Shishehbor et al. [100] found a reduction in plasma measures of protein oxidation independent of improvements in lipid proﬁles (i.e., declines in chlorinated tyrosine, nitrotyrosine, and di-tyrosine by 30, 25, and 32%, respectively) following a 12-week atorvastatin regimen. However, as noted above, studies of statins in MS patients are few, and those that address in a comprehensive way the impact of the therapy on antioxidant defenses and biomarkers of oxidative stress are even more limited. Antioxidant Supplementation A theoretical rationale for antioxidant supplementation in MS can be proffered by examining the effect of these nutrients on each of the four individual components of the syndrome and their contribution to the generation of oxidative stress; however, as little direct evidence is available to test this hypothesis, further research in this area is warranted. For example, as noted above, hypertension increases oxidative stress as indicated by increases in plasma TBARS and urinary 8-iso [31–33]. Conversely, Hajjar et al. [101] have shown in a randomized clinical trial that supplementation with 500 to 2000 mg/day vitamin C for 6 months reduced BP by 4.4/2.8 in 31 hypertensives (BP, 140–180/90–100). Also, Ward et al. [102] obtained a mean decrease of systolic blood pressure (SBP) 1.8 with 500 mg/day vitamin C in a trial of 69 treated hypertensives (SBP, 136.5; BMI, 28.7; mean age, 62) already receiving antihypertensive therapies. The vitamin C supplement did not affect plasma levels of urinary 8-iso or serum ox-LDL. Vitamin E has been well established as a chain-breaking antioxidant effective in reducing lipid peroxidation reactions. Brockes et al. [103] found that LDL in normotensive individuals had a greater resistance to oxidation in vitro than in hypertensives but after 400-IU/day vitamin E

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supplementation for 2 months in both groups signiﬁcant differences in this parameter were eliminated. Vitamin E has also been noted to increase insulin sensitivity via an inhibition of protein kinase C and activation of diacylglycerol kinase [104]. For example, in a randomized clinical trial, Barbagallo et al. [105] supplemented 24 hypertensive patients with normal blood glucose and insulin (BP, >140/90; BMI, 25.3; mean age, 47) with 600 mg/day vitamin E for 4 weeks and found signiﬁcant increases in whole body glucose disposal and the ratio of plasma reduced to oxidized GSH. Investigating 41 overweight subjects (BMI, 32.3; mean age, 47) with normal glycemic status, Manning et al. [106] tested 800 IU/day vitamin E in a randomized clinical trial for 3 months and found signiﬁcant reductions in fasting plasma insulin and lipid peroxides and an increase in insulin sensitivity compared to no change in any of these parameters among the 39 subjects (BMI, 33.2; mean age, 51) receiving placebo. The decrease in plasma insulin was signiﬁcantly correlated with the increase in plasma vitamin E (r = –0.235). In contrast, McSorley et al. [107] found no effect of 800 IU/day vitamin E supplementation for 12 weeks on fasting plasma glucose or insulin sensitivity in 13 adult children of parents with type 2 diabetes with normal glucose tolerance (BMI, 24.8; mean age, 28) in a randomized, crossover trial. Results from Skrha et al. [108] suggested a deleterious effect of 600 mg/day vitamin E administered for 3 months when they observed a 7.3% reduction in insulin sensitivity in 11 obese subjects with type 2 diabetes (BMI, 31.6; mean age, 45). Hildebrandt et al. [109] tested 600 mg/day N-acetylcysteine, a GSH prodrug, for 8 weeks in 11 obese subjects with impaired glucose tolerance (BMI, 35.7; mean age, 45.4) and observed increased plasma thiol status but further reduced glucose tolerance. Like the outcome of the study by Skrha et al. [108], these results suggest that some people may experience untoward results from an antioxidant intervention and caution in future studies is advisable.

CONCLUSION Each component of the constellation of MS signs — dyslipidemia, hyperglycemia, hypertension, and obesity — has been associated, though not unequivocally, with an elevation of oxidative stress. Moreover, reductions in these conditions appear generally associated with attenuation of biomarkers of oxidative stress, although these inverse correlations are not always strong. Although hypotheses can be readily proffered regarding a vicious cycle of free radicals and pathology in the progression of these conditions and the potential for a beneﬁcial impact of antioxidants in slowing the progress of MS toward CVD, few direct data are available to support this approach as an adjunct to established lifestyle modiﬁcations and drug therapies for prevention or treatment. Nonetheless, the biological plausibility of these relationships clearly warrants further research in this area. New research should consider variables that are particular to current approaches to MS; for example, without careful planning, hypocaloric diets can readily be poor in antioxidant nutrients such as carotenoids and vitamin E, particularly when low-fat menus are stressed. Physical activity is to be encouraged, but it is important to recognize that intense exercise can generate free radicals and increase the requirement for antioxidant nutrients. While training regimens can upregulate some antioxidant enzymes, although perhaps not in older adults, this may not obviate the need for greater intake of antioxidant nutrients from food and supplements. Further, some of the drugs used to treat MS interact with the antioxidant defense network (e.g., statins, which inhibit ubiquinol synthesis and reduce vitamin E status), again suggesting a value for supplementation. Of course, the potential for adverse drug–nutrient interactions, particularly with regard to dietary supplements, should always be considered. As it is always a challenge to design antioxidant interventions to alleviate oxidative stress, studies must be undertaken to determine the optimal combinations and doses, together with speciﬁc lifestyle modiﬁcations and drug therapies, as well as the best time to intervene in MS. Importantly, studies must include not only relevant clinical outcomes but also measures of oxidative stress and related pathways such as inﬂammation. These measures not only will serve to provide a biological basis for the mechanisms of action but will also help to identify individual differences between patients and the nature of responders and nonresponders for each intervention.

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Obesity: Epidemiology, Pathophysiology, and Prevention Samuelsson, L., Gottsater, A., and Lindgarde, F., Decreasing levels of tumour necrosis factor alpha and interleukin 6 during lowering of body mass index with orlistat or placebo in obese subjects with cardiovascular risk factors, Diabetes Obes. Metab., 5, 195, 2003. Ozcelik, O. et al., Exercise training as an adjunct to orlistat therapy reduces oxidative stress in obese subjects, Tohoku J. Exp. Med., 206, 313, 2005. Xiang, A.H. et al., Effect of thiazolidinedione treatment on progression of subclinical atherosclerosis in premenopausal women at high risk for type 2 diabetes, J. Clin. Endocrinol. Metab., 90, 1986, 2005. Tankova, T. et al., The effect of repaglinide on insulin secretion and oxidative stress in type 2 diabetic patients, Diabetes Res. Clin. Pract., 59, 43, 2003. Tack, C.J. et al., Troglitazone decreases the proportion of small, dense LDL and increases the resistance of LDL to oxidation in obese subjects, Diabetes Care, 21, 796, 1998. Stafﬁleno, B.A., Treating hypertension with cardioprotective therapies: the role of ACE inhibitors, ARBs, and beta-blockers, J. Cardiovasc. Nurs., 20, 354, 2005. Saez, G.T. et al., Factors related to the impact of antihypertensive treatment in antioxidant activities and oxidative stress by-products in human hypertension, Am. J. Hypertens., 17, 809, 2004. Muda, P. et al., Effect of antihypertensive treatment with candesartan or amlodipine on glutathione and its redox status, homocysteine and vitamin concentrations in patients with essential hypertension, J. Hypertens., 23, 105, 2005. Nashar, K. et al., Angiotensin receptor blockade improves arterial distensibility and reduces exerciseinduced pressor responses in obese hypertensive patients with the metabolic syndrome, Am. J. Hypertens., 17, 477, 2004. Sola, S. et al., Irbesartan and lipoic acid improve endothelial function and reduce markers of inﬂammation in the metabolic syndrome: results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) study, Circulation, 111, 343, 2005. Wollin, S.D. and Jones, P.J., Alpha-lipoic acid and cardiovascular disease, J. Nutr., 133, 3327, 2003. Ballantyne, C.M. et al., Inﬂuence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S, Circulation, 104, 3046, 2001. Deedwania, P.C. et al.; STELLAR Study Group, Effects of rosuvastatin, atorvastatin, simvastatin, and pravastatin on atherogenic dyslipidemia in patients with characteristics of the metabolic syndrome, Am. J. Cardiol., 95, 360, 2005. Oranje, W.A. et al., Effect of atorvastatin on LDL oxidation and antioxidants in normocholesterolemic type 2 diabetic patients, Clin. Chim. Acta, 311, 91, 2001. ter Avest, E. et al., Effect of rosuvastatin on insulin sensitivity in patients with familial combined hyperlipidaemia, Eur. J. Clin. Invest., 35, 558, 2005. Kural, B.V. et al., The effects of lipid-lowering therapy on paraoxonase activities and their relationships with the oxidant-antioxidant system in patients with dyslipidemia, Coronary Artery Dis., 15, 277, 2004. Palomaki, A., Malminiemi, K., and Metsa-Ketela, T., Enhanced oxidizability of ubiquinol and alphatocopherol during lovastatin treatment, FEBS Lett., 410, 254, 1997. Mabuchi, H. et al., Reduction of serum ubiquinol-10 and ubiquinone-10 levels by atorvastatin in hypercholesterolemic patients, J. Atheroscler. Thromb., 12, 111, 2005. Manuel-Keenoy, B. et al., Impact of vitamin E supplementation on lipoprotein peroxidation and composition in type 1 diabetic patients treated with atorvastatin, Atherosclerosis, 175, 369, 2004. Zhang, B. et al., A comparative crossover study of the effects of ﬂuvastatin and pravastatin (FP-COS) on circulating autoantibodies to oxidized LDL in patients with hypercholesterolemia, J. Atheroscler. Thromb., 12, 41, 2005. Thallinger, C. et al., The ability of statins to protect low density lipoprotein from oxidation in hypercholesterolemic patients, Int. J. Clin. Pharmacol. Ther., 43, 551, 2005. Shishehbor, M.H. et al., Statins promote potent systemic antioxidant effects through speciﬁc inﬂammatory pathways, Circulation, 108, 426, 2003. Hajjar, I.M. et al., A randomized, double-blind, controlled trial of vitamin C in the management of hypertension and lipids, Am. J. Ther., 9, 289, 2002. Ward, N.C. et al., The combination of vitamin C and grape-seed polyphenols increases blood pressure: a randomized, double-blind, placebo-controlled trial, J. Hypertens., 23, 427, 2005.

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Brockes, C. et al., Vitamin E prevents extensive lipid peroxidation in patients with hypertension, Br. J. Biomed. Sci., 60, 5, 2003. Azzi, A. et al., Non-antioxidant molecular functions of alpha-tocopherol (vitamin E), FEBS Lett., 519, 8, 2002. Barbagallo, M. et al., Effects of vitamin E and glutathione on glucose metabolism: role of magnesium, Hypertension, 34, 1002, 1999. Manning, P.J. et al., Effect of high-dose vitamin E on insulin resistance and associated parameters in overweight subjects, Diabetes Care, 27, 2166, 2004. McSorley, P.T. et al., Endothelial function, insulin action and cardiovascular risk factors in young healthy adult offspring of parents with type 2 diabetes: effect of vitamin E in a randomized doubleblind, controlled clinical trial, Diabet. Med., 22, 703, 2005. Skrha, J. et al., Insulin action and ﬁbrinolysis inﬂuenced by vitamin E in obese type 2 diabetes mellitus, Diabetes Res. Clin. Pract., 44, 27, 1999. Hildebrandt, W. et al., Effect of thiol antioxidant on body fat and insulin reactivity, J. Mol. Med., 82, 336, 2004.

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and 12 Obesity Type 2 Diabetes Subhashini Yaturu and Sushil K. Jain CONTENTS Introduction ....................................................................................................................................139 Prevalence.......................................................................................................................................140 Diagnostic Criteria for Diabetes ....................................................................................................141 Trends in Weight, Body Mass Index, and Type 2 Diabetes .........................................................141 Obesity and Comorbidities ............................................................................................................141 Impact of Diabetes and Obesity on Cardiovascular Disease ........................................................142 Impact of Obesity on Type 2 Diabetes..........................................................................................142 Impact of Childhood Obesity on Type 2 Diabetes........................................................................142 Impact of Catch-Up Growth ..........................................................................................................142 Obesity and Dyslipidemia..............................................................................................................143 Pathophysiology of Diabetes: Obesity, Type 2 Diabetes, and Insulin Resistance .......................143 Free Fatty Acids, Obesity, and Diabetes .......................................................................................143 Visceral Adiposity, Obesity, Insulin Resistance, and Type 2 Diabetes.........................................143 Visceral Fat Tissue as a Proinﬂammatory Tissue and Its Role in Insulin Resistance .................144 Insulin Resistance in Type 2 Diabetes and Obesity......................................................................144 Adipocyte Hormones, Obesity, Insulin Resistance, and Progression to Diabetes .......................144 Fatty Liver ......................................................................................................................................145 Beneﬁts of Weight Loss in Type 2 Diabetes.................................................................................146 Pharmacotherapy for Obesity and Improvement in Metabolic Risk Factors and Diabetes .........146 Prevention of Type 2 Diabetes by Weight Reduction ...................................................................147 Mouse Models for Obesity-Induced Diabetes...............................................................................148 Conclusions ....................................................................................................................................148 Acknowledgments ..........................................................................................................................149 References ......................................................................................................................................149

INTRODUCTION Obesity and diabetes are emerging pandemics in the 21st century. Both are major public health problems throughout the world and are associated with signiﬁcant, potentially life-threatening comorbidities. A strong association exists between obesity and type 2 diabetes. The increase in the prevalence of diabetes parallels that of obesity. Some experts call this dual epidemic diabesity. Not all subjects with type 2 diabetes are obese, and many obese subjects do not have diabetes, but most of the subjects with type 2 diabetes are overweight or obese. A signiﬁcant number of obese individuals have diabetes. Both obesity and type 2 diabetes feature insulin resistance and similar atherogenic lipid proﬁles such as increased triglycerides and decreased high-density lipoprotein cholesterol (HDL-C). The genetic basis of human obesity predisposing individuals to insulin resistance and development of type 2 diabetes is multigenic rather than monogenic. 139

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Obesity Trends* Among U.S. Adults BRFSS, 1991, 1996, 2004 (* BMI ≥30, or about 30 lb overweight for 5ʼ4”person) 1991

1996

2004

No Data

<10%

10%–14%

15%–19%

20%–24%

25%

FIGURE 12.1 Obesity and diabetes mellitus in U.S. adults. Over the 10-year period from 1991 to 2001, the prevalence of obesity and diabetes among U.S. adults increased in every region of the nation. Obesity is associated with the development of type 2 diabetes mellitus and may be the root cause underlying the increased prevalence of type 2 diabetes.

PREVALENCE In the United States, diabetes affects at least 20.8 million adults (7.0% of the population), which includes 14.6 million diagnosed and 6.2 million undiagnosed people [5]. Type 2 diabetes is the predominant form of diabetes worldwide, accounting for 90% of cases [6,7]. Figure 12.1 shows that the prevalence of diabetes, overweight, and obesity are increasing worldwide, with a 49% increase between 1991 and 2004. The age-adjusted prevalence of obesity ranges from 13.1 to 30.0% and that of type 2 diabetes from 3.3 to 9.2% [8]. In the United States, the Centers for Disease Control and Prevention (CDC) analyzed the prevalence of overweight and obesity among U.S. adults ≥20 years old with previously diagnosed diabetes by using data from two surveys: the Third National Health and Nutrition Examination Survey (NHANES III) 1988–1994 and NHANES 1999–2002 [9]. Their report summarized the results of that analysis, which indicated that most adults with diagnosed diabetes were overweight or obese. During the period from 1999 to 2002, the prevalence of overweight or obesity was 85.2%, and the prevalence of obesity was 54.8%. The prevalence of obesity among adults overall in the United States increased from 22.9% (during the period from 1988 to1994) to 30.5% (during the period from 1999 to 2002). The prevalence of obesity among adults with diagnosed diabetes remained high, at 45.7% (1988 to 1994) and 54.8% (1999 to 2002). Obesity and overweight are often deﬁned by the World Health Organization (WHO) in terms of excess weight for a given height [1,10]. Overweight is deﬁned as a body mass index (BMI) of 25.0 to 29.9 and obesity as a BMI of ≥30.0. The BMI, calculated by dividing weight (kg) by height (m2) and adjusted for height, is used as a measure of weight standards.

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141 93.2

100 Women Men

Age-adjusted relative risk of type 2 diabetes

70

54.0 42.1

40.3 27.6

40 15.8 10

21.3 11.6

8.1 6.7 4.3

5

0

5.0

2.9 1.5

4.4 2.2

1.0

1.0

1.0

<22

<23

23– 24– 25– 27– 29– 31– 33– 23.9 24.9 26.9 28.9 30.9 32.9 34.9

35+

Body mass index (kg/m2)

FIGURE 12.2 Relationship between body mass index and type 2 diabetes in adult men and women in the United States. The vertical line separates underweight and lean subjects (left side) from overweight and obese subjects (right side). The data demonstrate that the risk of diabetes begins to increase at the upper end of the lean BMI category. (From Larsen, P.R. et al., Williams Textbook of Endocrinology, 10th ed., Saunders, Philadelphia, 2002. With permission.)

DIAGNOSTIC CRITERIA FOR DIABETES The criteria for diagnosis of diabetes mellitus as recommended by the American Diabetes Association (ADA) include a fasting plasma glucose (FPG) value after an 8-hour fast that is higher than 126 mg/dL, a 2-hr post-load glucose (PG) level that is ≥200 mg/dL, or symptoms of diabetes mellitus and a random plasma glucose concentration that is ≥200 mg/dL [11].

TRENDS IN WEIGHT, BODY MASS INDEX, AND TYPE 2 DIABETES The increasing prevalence of obesity is said to play a signiﬁcant role in the increase in cases of type 2 diabetes [12]. Data from NHANES III indicate that two thirds of adults, both men and women, had BMI values greater than 27 kg/m2 [13]. The risk of diabetes increases linearly with BMI; the prevalence of diabetes increased from 2% in those with a BMI of 25 to 29.9 kg/m2 to 8% in those with a BMI of 30 to 34.9 kg/m2 and, ﬁnally, to 13% in those with a BMI greater than 35 kg/m2 [14]. As shown in Figure 12.2, the risk of type 2 diabetes increases with an increase in BMI to >22 kg/m2 [12,15]. More than generalized obesity, the risk of obesity increases with increase in waist circumference, waist-to-hip ratio, visceral adiposity, or abdominal obesity [16–18].

OBESITY AND COMORBIDITIES Obesity is becoming a major public health problem throughout the world and is associated with signiﬁcant, potentially life-threatening comorbidities. Either obesity itself or comorbidities of obesity are responsible for increased cardiovascular risk. Obesity is associated with most of the components of metabolic syndrome, the leading cause of type 2 diabetes. The comorbidities of obesity and type 2 diabetes associated with insulin-resistance syndrome include obstructive sleep apnea, hypertension, polycystic ovary syndrome, nonalcoholic fatty liver disease, and certain forms of cancer.

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IMPACT OF DIABETES AND OBESITY ON CARDIOVASCULAR DISEASE Cardiovascular disease (CVD) is a major cause of morbidity and mortality among subjects with type 2 diabetes and is responsible for up to 75% of deaths among them. The risk of coronary artery disease (CAD) in subjects with type 2 diabetes is considered equivalent to that in nondiabetic subjects who have CAD [19,20].

IMPACT OF OBESITY ON TYPE 2 DIABETES Although an increase in weight or BMI is a major risk factor for diabetes [22], an increase in BMI is a better predictor of diabetes. Prospective studies in nondiabetic overweight adults noted a 49% increase in the incidence of diabetes over 10 years for every 1-kg/year increase in body weight; similarly, each 1 kg of weight lost annually over 10 years was associated with a 33% lower risk of diabetes in the subsequent 10 years [23]. Similar studies in Pima Indians reported that weight gain was signiﬁcantly related to diabetes incidence only in those who were not initially overweight (BMI, <27.3 kg/m2) [24]. Similarly, in the Behavioral Risk Factor Surveillance System (BRFSS) for 1991 to 1998, Mokdad et al. [25] reported that every 1-kg increase in average self-reported weight was associated with a 9% increase in the prevalence of diabetes.

IMPACT OF CHILDHOOD OBESITY ON TYPE 2 DIABETES The prevalence of obesity is on the rise in children and adolescents. As deﬁned by a BMI greater than the 95th percentile for age and gender from the revised National Center for Health Statistics growth charts, 10 to 15% of 6- to 17-year-old children and adolescents are overweight in the United States [13] and worldwide [62]. Similar to the situation observed in adults, diseases that are commonly associated with obesity, such as type 2 diabetes, hypertension, hyperlipidemia, gallbladder disease, nonalcoholic steatohepatitis, sleep apnea, and orthopedic complications, are now increasingly observed in children [26,27]. Evidence suggests that the prenatal, early-childhood, and adolescent periods are critical in the development of obesity. Signiﬁcant negative health outcomes are associated with childhood obesity, including the presence of cardiovascular risk factors and greater prevalence of various medical problems such as insulin resistance, type 2 diabetes mellitus, metabolic syndrome, orthopedic problems, and pseudotumor cerebri. Of further concern is the increased risk for obesity in adulthood with its attendant comorbidities. BMIs in childhood change substantially with age and are not applicable when deﬁning childhood obesity [28,29]. In the United States, the 85th and 95th percentiles of BMI for age and sex based on nationally representative survey data have been recommended as cut-off points to identify overweight and obesity [26,30]. The increasing prevalence of type 2 diabetes in adolescents is linked to the epidemic of childhood obesity in the United States and around the world [31,32]. Altered glucose metabolism, manifested as impaired glucose tolerance (IGT), appears early in obese children and adolescents. Obese young people with IGT are characterized by marked peripheral insulin resistance and a relative β-cell failure [33]. Caucasian adolescent subjects with obesity without diabetes were noted to have approximately 50% lower levels of adiponectin [34]. In addition, the study noted that hypoadiponectinemia was a strong and independent correlate of insulin resistance, β-cell dysfunction, and increased abdominal adiposity [34].

IMPACT OF CATCH-UP GROWTH Maternal insulin resistance promotes the transfer of nutrients to the fetus. Accelerated childhood growth is another risk factor for adiposity and insulin resistance, especially in children with low birth weight [35]. The risk of type 2 diabetes is high among adults with low birth weight (small for gestational age) who were also overweight during childhood [36–39].

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OBESITY AND DYSLIPIDEMIA Obesity and insulin resistance often coexist along with other abnormalities such as hypertension and dyslipidemia. The original description of metabolic syndrome by Reaven consisted of obesity, insulin resistance, hypertension, impaired glucose tolerance or diabetes, hyperinsulinemia, and dyslipidemia characterized by elevated triglyceride and low HDL concentrations [3,40]. The primary dyslipidemia related to obesity is characterized by increased triglycerides, decreased HDL levels, and abnormal small, dense low-density lipoprotein composition, which seem to be closely related to insulin resistance. The dyslipidemia associated with obesity no doubt plays a major role in the development of atherosclerosis and CVD. All of the components of dyslipidemia, including higher triglycerides, decreased HDL levels, and increased LDL particles, have been shown to be atherogenic. Combined weight loss and exercise, even if they do not result in normalization of body weight, can improve dyslipidemia and thus reduce CVD risk. In obesity and type 2 diabetes, the altered communication between adipose tissue and the liver results in the altered regulation of VLDL production. A number of studies indicate that adipocytokines, in particular adiponectin, may be seminal players in the regulation of fat metabolism in the liver [41].

PATHOPHYSIOLOGY OF DIABETES: OBESITY, TYPE 2 DIABETES, AND INSULIN RESISTANCE Normal glucose homeostasis is maintained by a delicate balance between insulin secretion by the pancreatic β-cells and insulin sensitivity of the peripheral tissues (muscle, liver, and adipose tissue). Decreased insulin sensitivity and impaired β-cell function are the two key components in type 2 diabetes pathogenesis based on long-term experience in adults [42,43]. Insulin resistance is frequently observed in obese subjects and has been established as an independent risk factor for the development of both type 2 diabetes and coronary artery disease [2,44–47].

FREE FATTY ACIDS, OBESITY, AND DIABETES Studies have shown that both obesity and type 2 diabetes impair insulin-induced suppression of glycogenolysis and gluconeogenesis and that the degree of impairment correlates with plasma free fatty acid (FFA) concentrations [48,49]. Plasma FFA concentrations correlate with rates of gluconeogenesis and glycogenolysis, suggesting that they inﬂuence the regulation of both processes. The hepatic insulin resistance associated with obesity and type 2 diabetes results in impaired insulininduced suppression of glycogenolysis and gluconeogenesis. A growing body of evidence indicates that obesity and diabetes both cause hepatic insulin resistance [48,50–53].

VISCERAL ADIPOSITY, OBESITY, INSULIN RESISTANCE, AND TYPE 2 DIABETES Obesity-related metabolic abnormalities are signiﬁcantly associated with overall accumulation of fat in the body; substantial evidence indicates that central obesity is a better predictor of morbidity than excess fat in the lower body [2,44,47]. Accumulation of fat in abdomen regions has major implications for metabolism and particularly for insulin sensitivity [2,44,47]. This high prevalence of comorbidities relates more to waist circumference than to BMI. Visceral or abdominal obesity is associated with an increased risk of cardiovascular disease and type 2 diabetes. A high prevalence of obesity and abdominal obesity in Mexicans is associated with a markedly increased incidence of diabetes and hypertension [54]. Visceral adiposity is considered a risk factor for insulin resistance in children [33,55–57] and metabolic syndrome [58] and type 2 diabetes in adults [59], as well as in ﬁrst-degree relatives of patients with type 2 diabetes with normal glucose levels [60]. Adipocytokines, hormones secreted by the visceral adipocytes, generate the insulin-resistant state and the chronic inﬂammatory proﬁle that frequently goes along with visceral obesity [61].

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VISCERAL FAT TISSUE AS A PROINFLAMMATORY TISSUE AND ITS ROLE IN INSULIN RESISTANCE When analyzed using stepwise multivariate analysis, age, sex, fasting plasma glucose, and BMI seem to be the most important factors contributing to the variation of vascular reactivity [63]. Visceral fat exhibits accelerated lipolytic activity with increased release of free fatty acids, which can adversely affect insulin action and glucose disposal in several tissues [64–68]. These increases in circulating FFA levels may also result in the development of triglyceride reservoirs in both muscle and liver, depressing insulin action and increasing hepatic very-low-density lipoprotein output [69,70]. Conversely, declines in visceral adiposity and reduced FFA levels following weight-loss diets have been associated with enhanced insulin sensitivity [71,72]. Tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) are expressed in adipose tissues [73], with visceral fat being responsible for more TNFα production than subcutaneous fat [74]. These cytokines inhibit insulin signaling [75], and TNFα may play a crucial role in the systemic insulin resistance of type 2 diabetes [76]. TNFα inhibits tyrosine kinase phosphorylation of the insulin receptor, resulting in defects in insulin signaling and ultimately leading to insulin resistance and impaired glucose transport [77]. An imbalance in favor of proinﬂammatory cytokines from adipose tissue (hypoadiponectinemia and increased levels of IL-6) and other sources may trigger C-reactive protein (CRP) secretion. CRP levels are related strongly to insulin resistance and adiposity, and elevated levels of CRP correlate with impaired endothelial dysfunction (ED) and CAD. This in turn can exacerbate mild insulin resistance and accentuate other metabolic abnormalities that together constitute metabolic syndrome. Thus, insulin resistance itself appears to be an endothelial dysfunction risk equivalent. The pathways are clearly intertwined with and sparked by obesity, in large part by excess adipokine production. Abnormalities in vascular reactivity and biochemical markers of endothelial cell activation are present early in individuals at risk of developing type 2 diabetes. The association of endothelial dysfunction with insulin resistance in the absence of overt diabetes or metabolic syndrome provides evidence that the atherosclerosis may actually begin earlier in the spectrum of insulin resistance, ultimately resulting in a progression of metabolic syndrome to prediabetes and then to type 2 diabetes [78].

INSULIN RESISTANCE IN TYPE 2 DIABETES AND OBESITY Insulin is a critical regulator of virtually all aspects of adipocyte biology, and adipocytes are one of the most highly insulin-responsive cell types [79]. Insulin resistance is a fundamental aspect of the etiology of type 2 diabetes and is also linked to a wide array of other pathophysiologic sequelae, including hypertension, hyperlipidemia, atherosclerosis (i.e., metabolic syndrome, or syndrome X), and polycystic ovary syndrome [80]. The association between obesity and type 2 diabetes has been well recognized for decades, and the major link is insulin resistance. In the natural history of diabetes, obesity and insulin resistance precede abnormal glucose (Figure 12.3). Insulin resistance in both obesity and type 2 diabetes is manifested by decreased insulin-stimulated glucose transport and metabolism in adipocytes and skeletal muscle and by impaired suppression of hepatic glucose output [80]. Type 2 diabetes is characterized by four major metabolic abnormalities: obesity, impaired insulin action, insulin secretory dysfunction, and increased endogenous glucose output (EGO) [43,81]. Insulin resistance is the earliest observable abnormality in individuals who are predisposed to, and who later develop, type 2 diabetes.

ADIPOCYTE HORMONES, OBESITY, INSULIN RESISTANCE, AND PROGRESSION TO DIABETES Adipose tissue is a highly active metabolic and endocrine organ. The important endocrine function of adipose tissue is emphasized by the adverse metabolic consequences of both adipose tissue excess and its deﬁciency [82]. Adipose tissue produces several proteins (adipocytokines), such as

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IGT*

Diabetes

Uncontrolled Hyperglycemia

Post-meal Glucose

Plasma Glucose

Fasting Glucose

120 (mg/dL) Relative β-Cell Function

Insulin Resistance

100 (%)

Insulin Level –20

–10

0

10

20

30

Years of Diabetes *IGT = impaired glucose tolerance

FIGURE 12.3 Diabetes, obesity, and insulin resistance precede abnormal glucose. (Adapted from International Diabetes Center, Minneapolis, MN.)

leptin, adiponectin, resistin, TNFα, and IL-6, which modulate insulin sensitivity and appear to play important roles in the pathogenesis of insulin resistance, diabetes, dyslipidemia, inﬂammation, and atherosclerosis [82–84]. During the progression from normal weight to obesity and then to overt diabetes, the adipocyte-derived factors contribute to the occurrence and development of β-cell dysfunction and type 2 diabetes. In addition to inducing insulin resistance in insulin-responsive tissues, adipocyte-derived factors play an important role in the pathogenesis of β-cell dysfunction. Leptin, free fatty acids, adiponectin, TNFα, and IL-6 are all produced and secreted by adipocytes and may directly inﬂuence aspects of β-cell function, including insulin synthesis, secretion, insulin cell survival, and apoptosis [85]. Adiponectin is a protein secreted by adipocytes only and accounts for approximately 0.01% of total plasma protein. In healthy patient populations, adiponectin can be found in concentrations of 7 to 12 mg/L. Adiponectin correlates with decreased free fatty acid blood concentrations and reduced BMI or body weight. Adiponectin may be the molecular link between obesity and insulin resistance and may serve as a biomarker for metabolic syndrome [86]. Association of altered levels of adiponectin with insulin resistance and free fatty acid metabolism is well established. Interventions to reduce insulin resistance by increasing adiponectin concentrations may be particularly effective in obese, insulin-resistant individuals [86]. Although adiponectin replacement in humans may represent a promising approach to prevent or treat obesity, insulin resistance, and type 2 diabetes, clinical studies with adiponectin administration must be conducted to conﬁrm this hypothesis [87]. Plum treatment (plum juice) signiﬁcantly increased plasma adiponectin concentrations and peroxisome proliferator-activated receptor γ (PPARγ) mRNA expression in adipose tissue from Wistar fatty rats [88]. Visfatin (also known as pre-B-cell colony-enhancing factor, or PBEF) is a cytokine highly expressed in visceral fat whose blood levels correlate with obesity. Increasing concentrations of visfatin were independently and signiﬁcantly associated with type 2 diabetes [89].

FATTY LIVER Fatty liver is common in type 2 diabetes, with estimates of prevalence ranging from 21 to 78% [90–92]. The risk factors for fatty liver include obesity, insulin resistance, and increased concentrations of plasma fatty acids; each of these metabolic factors is also characteristic of type 2 diabetes. Fatty liver is relatively common in overweight and obese subjects with type 2 diabetes and is an aspect of body composition related to severity of insulin resistance, dyslipidemia, and inﬂammatory markers [39]. Nonalcoholic fatty liver disease (NAFLD) is very common in subjects with morbid

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TABLE 12.1 Benefits of Weight Loss in Type 2 Diabetes Improved glucose levels Improved glycemic control Reduced fasting insulin Increased insulin sensitivity Reduced upper-body adiposity Improved atherogenic lipid proﬁle: Decreased triglycerides Increased high-density lipoprotein (HDL) cholesterol Larger, less small, more dense low-density lipoprotein (LDL) cholesterol particles Reduced blood pressure Improved mortality

obesity [93,94]. The fatty liver may help to explain why some but not all obese individuals are insulin resistant and why even lean individuals may be insulin resistant and thereby at risk of developing type 2 diabetes and cardiovascular disease [95].

BENEFITS OF WEIGHT LOSS IN TYPE 2 DIABETES Weight loss is an important therapeutic objective for individuals with type 2 diabetes [113]. Both short-term and long-term weight loss in overweight or obese type 2 diabetic subjects on very low calorie diets was shown to decrease insulin resistance, improve measures of glycemic control, improve lipid abnormalities, and reduce blood pressure [114–116]. Recommendations from a National Institutes of Health (NIH) consensus conference indicate that a weight loss of 5 to 10% can signiﬁcantly improve risk factors for obesity-related diseases [96]. Weight reduction has been shown to improve glycemic control and cardiovascular risk factors associated with insulin resistance in obese individuals with type 2 diabetes. A list of beneﬁts is shown in Table 12.1. The most effective interventions include comprehensive behavioral management, dietary modiﬁcation, exercise, pharmacotherapy, and bariatric surgery. Bariatric surgery for severe obesity results in longterm weight loss, which leads to an improved lifestyle and recovery from diabetes [121,122], hypertriglyceridemia, low levels of HDL cholesterol, hypertension, and hyperuricemia [122–124]. The most widely investigated drugs, sibutramine and orlistat, result in modest, clinically worthwhile weight loss, with demonstrable improvements in comorbidities, among which is type 2 diabetes. Observational and interventional studies have clearly shown that type 2 diabetes can be prevented by lifestyle measures, including reduced energy intake to induce a modest but sustained weight reduction, together with changes in diet composition [97]. Even in elderly individuals, dietinduced weight loss results in improved insulin sensitivity and improved β-cell function [98]. In short-term [99] as well as long-term studies [100], the use of a low-carbohydrate diet in obese subjects with type 2 diabetes has improved glucose proﬁles and insulin sensitivity and lowered plasma triglyceride and cholesterol levels.

PHARMACOTHERAPY FOR OBESITY AND IMPROVEMENT IN METABOLIC RISK FACTORS AND DIABETES Orlistat, a gastrointestinal lipase inhibitor drug, has been used effectively and safely in the treatment of obesity [101]. Orlistat signiﬁcantly reduces body weight and improves glycemic control and several cardiovascular risk factors in overweight and obese subjects with type 2 diabetes [102–104].

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In type 2 diabetic patients, orlistat also attenuates postprandial increases in triglycerides, remnantlike particles, cholesterol, and free fatty acids [105]. The antihyperglycemic effect of orlistat has been attributed to weight loss associated with a decrease in insulin resistance [104] and augmentation of the postprandial increases in plasma levels of glucagon-like peptide 1 (GLP-1) [106]. Rimonabant is a selective cannabinoid-1 (CB1) receptor blocker with both central and peripheral actions [107]. In the RIO–Europe study [108], a 2-mg/day dose of rimonabant along with a lowcalorie diet resulted in signiﬁcant weight reduction and improvement in cardiovascular risk factors such as waist circumference, HDL cholesterol, triglycerides, insulin resistance, and the incidences of metabolic syndrome. In another study [109], rimonabant use at a daily dose of 20 mg resulted in an increase in plasma adiponectin levels that was partly independent of weight loss alone. Sibutramine is an anti-obesity drug that induces satiety and thermogenesis [110]. Sibutramine use has been shown to reduce weight, lower the levels of nonesteriﬁed fatty acids, decrease hyperinsulinemia, and reduce insulin resistance. It has been used as an effective adjunct to oral hypoglycemic therapy in obese subjects with type 2 diabetes [111]; however, the magnitude of weight loss was modest, and the long-term health beneﬁts and safety remain unclear [112]. Metformin, an oral hypoglycemic agent, decreases calorie intake in a dose-dependent manner and leads to a reduction in body weight in subjects with type 2 diabetes and obesity [117–119]. Exenatide, a member of a new class of agents known as incretin mimetics, is currently in development for the treatment of type 2 diabetes. In short-term studies, exenatide improved glycemic control and helped to reduce body weight over 28 days in patients with type 2 diabetes who had been treated with diet and exercise or metformin [120]. Studies have shown that adiponectin administration in rodents has insulin-sensitizing, antiatherogenic, and antiinﬂammatory effects and under certain settings also decreases body weight. Adiponectin replacement in humans may represent a promising approach to prevent or treat obesity, insulin resistance, and type 2 diabetes; however, clinical studies with adiponectin administration must be conducted to conﬁrm this hypothesis.

PREVENTION OF TYPE 2 DIABETES BY WEIGHT REDUCTION Several interventional studies have demonstrated that signiﬁcant weight reduction could lead to a decreased incidence of progression to type 2 diabetes: •

•

Finnish study [125] — This study from Finland included middle-aged obese subjects with impaired glucose tolerance who were randomized to receive either brief diet and exercise counseling (control group) or intensive individualized instruction on weight reduction, food intake, and guidance on increasing physical activity (intervention group). After an average follow-up of 3.2 years, a 58% relative reduction in the incidence of diabetes was observed in members of the intervention group compared with the control subjects. Diabetes Prevention Program (DPP) [126] — This was a multicenter study that enrolled subjects with impaired glucose intolerance who were slightly younger and more obese. Approximately 45% of the study subjects were recruited from minority groups (e.g., African-Americans, Hispanics) and 20% of subjects were ≥60 years old. Subjects were randomized to one of three intervention groups: the intensive nutrition and exercise counseling (lifestyle) group or either of two masked medication treatment groups (the metformin group or the placebo group). Participants in both the placebo group and the metformin group received standard diet and exercise recommendations. After an average follow-up of 2.8 years, compared with the control group, a 58% relative reduction in the progression to diabetes was observed in the lifestyle group and a 31% relative reduction in the metformin group. On average, 50% of the subjects in the lifestyle group achieved

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the goal of ≥7% weight reduction, and about 74% maintained at least 150 min/week of moderately intense activity. Da Qing Study [127] — This study from China included subjects with impaired glucose tolerance, as determined by oral glucose tolerance tests, who were randomized to a control group or to one of three active treatment groups: diet only, exercise only, or diet plus exercise. Subjects were followed biannually. After an average of 6 years’ followup, the diet, exercise, and diet plus exercise interventions were associated with 31, 46, and 42% reductions, respectively, in the risk of developing type 2 diabetes. Xenical in the Prevention of Diabetes in Obese Subjects (XENDOS) Study [128] — This study addressed the beneﬁt of weight reduction achieved by the addition of orlistat to lifestyle change with regard to delaying the progression of type 2 diabetes in a group with BMIs ≥30 kg/m2 with or without impaired glucose tolerance. After 4 years of treatment, the effect of adding orlistat corresponded to a 45% reduction in risk factors in the IGT group, with no effect observed in those without IGT [128].

MOUSE MODELS FOR OBESITY-INDUCED DIABETES Obesity-driven type 2 diabetes (diabesity) involves complex genetic and environmental interactions that trigger the disease. The New Zealand Obese mouse (NZO/HlLt) represents one such model. These mice are hyperphagic and develop juvenile-onset obesity, even when fed a low-fat (4 to 6%) diet. Approximately 50% of NZO/HlLt males transit from impaired glucose tolerance to diabetes by 24 weeks of age [129]. The new mouse models of obesity-induced diabetes (diabesity models) have been created by combining independent diabetes risk-conferring quantitative trait loci from two unrelated parental strains: New Zealand Obese (NZO/HlLt) and Nonobese Nondiabetic (NON/Lt) [130–132]. Recombinant congenic strains are particularly useful for the analysis of polygenic syndromes. The NZO strain, selected for polygenic obesity, is known to contribute obesity/diabetes quantitative trait loci (QTL) on chromosomes (Chr) 1, 2, 4, 5, 6, 7, 11, 12, 13, 15, 17, and 18. Recombinant congenic strain (RCS)-10 recreates the 100% incidence seen in (NZO×NON) F1 males, but with less weight gain. Similarly, RCS-6, -7, -8, and -9 represent diabetes-prone strains with different combinations of diabetogenic QTL [129]. M16 mice represent an outbred animal model used to facilitate gene discovery and elucidate the pathways controlling early-onset polygenic obesity and type 2 diabetic phenotypes. Phenotypes prevalent in the M16 model, with obesity and diabesity exhibited at a young age, closely mirror current trends in human populations [133].

CONCLUSIONS The dramatic increase in obesity in adults and children has reached epidemic proportions. The resultant comorbidities are associated with signiﬁcant health and ﬁnancial burdens, warranting vigorous and comprehensive preventive efforts. Obesity is strongly associated with insulin resistance and vascular inﬂammation, as well as with a cluster of numerous risk factors, including atherosclerosis, hypertension, and diabetes. Prevention of overweight is critical, because long-term outcome data for successful treatment approaches are limited. Knowledge of the genetic basis for differences among the complex of hormones and neurotransmitters (including growth hormones, leptin, ghrelin, neuropeptide Y, melanocortin, and others) responsible for regulating satiety, hunger lipogenesis, lipolysis, and growth will eventually reﬁne our understanding of obesity and lead to more effective therapies [134]. The American Diabetes Association recommends changes in lifestyle, such as weight loss to a desirable BMI, increased physical activity, and healthy eating habits [135]. Dietary nutrients known to lower inﬂammatory mediators include omega-3 fatty acids, vitamin E, chromium, ﬂavonoids, coumarins, and anthocyanins. Dietary nutrients that tend to raise

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inﬂammatory markers include omega-6 fatty acids, iron, trans fats, and cholesterol. Optimal approaches to prevent the development of diabetes in obese adults and children should combine dietary and physical interventions.

ACKNOWLEDGMENTS SKJ was supported by a grant from NIDDK and the Ofﬁce of Dietary Supplements of the National Institutes of Health (RO1 DK064797). The authors thank Ms. Georgia Morgan First for the excellent editing of this manuscript.

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Obesity: Epidemiology, Pathophysiology, and Prevention Reifsnyder, P.C. and Leiter, E.H., Deconstructing and reconstructing obesity-induced diabetes (diabesity) in mice, Diabetes, 51(3), 825–832, 2002. Leiter, E.H. et al., Differential endocrine responses to rosiglitazone therapy in new mouse models of type 2 diabetes, Endocrinology, 147(2), 919–926, 2006. Mathews, C.E., Bagley, R., and Leiter, E.H., ALS/Lt: a new type 2 diabetes mouse model associated with low free radical scavenging potential, Diabetes, 53(Suppl. 1), S125–S129, 2004. Leiter, E.H. and Reifsnyder, P.C., Differential levels of diabetogenic stress in two new mouse models of obesity and type 2 diabetes, Diabetes, 53(Suppl. 1), S4–S11, 2004. Allan, M.F., Eisen, E.J., and Pomp, D., The M16 mouse: an outbred animal model of early onset polygenic obesity and diabesity, Obes. Res., 12(9), 1397–407, 2004. Krebs, N.F., Baker, R.D., Greer, F.R. et al., American Academy of Pediatrics policy statement: prevention of pediatric overweight and obesity, Pediatrics, 112, 424–430, 2003. Kahn, R., Buse, J., Ferrannini, E. et al., The metabolic syndrome: time for a critical appraisal, joint statement from the American Diabetes Association and the European Association for the Study of Diabetes, Diabetes Care, 28, 2289–2304, 2005.

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13 Angiogenesis-Targeted Redox-Based Therapeutics Shampa Chatterjee, Debasis Bagchi, Manashi Bagchi, and Chandan K. Sen CONTENTS Introduction ....................................................................................................................................155 Adipokines, Adipokinomes, Inﬂammation, and White Adipose Tissue .......................................156 Hypoxia, Cancer, and Angiogenesis..............................................................................................157 Role of Leptin, Product of the ob Gene, in Angiogenesis............................................................157 Antiangiogenic Therapeutic Strategies to Regulate Obesity.........................................................158 Redox Control of Angiogenesis: Oxidants as Inducers of Angiogenic Factors and Angiogenesis....................................................................................159 Antiangiogenic Function of Antioxidants .....................................................................................160 Antiangiogenic Antioxidant Nutrients ...........................................................................................160 Obesity, Angiogenesis, and Cancer ...............................................................................................161 Conclusions ....................................................................................................................................161 Acknowledgment............................................................................................................................161 References ......................................................................................................................................161

INTRODUCTION Obesity is now a worldwide epidemic [1–3]. The prevalence of overweight and obesity in the United States and other industrialized and developing countries is increasing exponentially (Table 13.1) [1–6]. Approximately half a billion of the world’s population is now considered overweight (body mass index [BMI], 25–29 kg/m2) or obese (BMI, >30 kg/m2) [1–3,9]. Genetic predisposition, inadequate energy expenditure, increased caloric intake, environmental and social factors, and sedentary lifestyle represent major contributors to obesity [1–9]. Recent studies have shown that approximately a third of the variance in adult body weights is secondary to genetic inﬂuences [10]. Leptin, an adipocyte- and placenta-derived circulating protein, regulates, to some extent, the magnitude of fat stores in the body causing obesity [11]. Gastrointestinal peptides, neurotransmitters, and adipose tissue may also have an etiologic role in obesity [12]. Low caloric diets with or without exercise can help with temporary weight loss; nevertheless, diet and exercise alone have not proven universally successful for long-term solutions in weight management. In addition, supplementation with drugs that suppress appetite, reduce food intake, increase energy expenditure, or inﬂuence nutrient partitioning or metabolism have potential efﬁcacy, but unfortunately they are accompanied by adverse side effects, some life threatening [13,14].

155

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TABLE 13.1 Percentage of Population Obese Worldwide Country United Kingdom Spain Finland Denmark Sweden France Italy United States

Adults (%)

Children (%)

22 13 11 10 9 9 9 31

22 30 13 18 18 18 36 15

The genesis and development of metabolic syndromes such as obesity are directly fed by angiogenesis. Angiogenesis, the growth or formation of new blood vessels by capillary sprouting from preexisting vessels, is critical to the expansion of adipose tissue. New blood vessels, by providing nutrients and oxygen deep into the adipose tissue, spur the development and maturation of adipocytes [15–18]. This is further enhanced as adipocytes themselves induce angiogenic factors such as vascular endothelial growth factor (VEGF), monobutyrin, and leptin [15]. In addition, adipocytes also induce endothelial cell-speciﬁc mitogens that cause proliferation of endothelial cells lining the vasculature of these vessels. Such endothelial cell proliferation and differentiation within the fat tissue are presumed to be involved in the development and maintenance of adipose tissue [15–17]. Endothelial cells also interact with adipocytes and promote their maturation and proliferation. These cells secrete basic ﬁbroblast growth factors, platelet-derived endothelial cell growth factor, and other soluble matrix-bound preadipocyte mitogens, which stimulate preadipocyte replication and promote differentiation [15–17]. Thus, newly formed adipose tissue depends on continued angiogenesis for further growth [15]. The interaction between microvascular endothelial cells and preadipocytes promotes the expansion of adipose tissue [16,18,19]; therefore, the development of adipose tissue, also known as adipogenesis, is intrinsically associated with angiogenesis. In other words, the expanding adipose tissue in adults represents one of the few sites of active angiogenesis.

ADIPOKINES, ADIPOKINOMES, INFLAMMATION, AND WHITE ADIPOSE TISSUE Conventionally, white adipose tissue or fat was known to provide thermal and mechanical insulation to the body [17,20]. In addition, it serves as an energy storage depot for mammals [16]. The white adipose tissue has now emerged as a dynamic, multifunctional endocrine organ involved in a wide range of physiological and metabolic processes [15–17]. The tissue acts as a central reservoir of lipids subject to deposition and the release of fatty acids [15–18,20]. White adipocytes secrete several major hormones, most importantly leptin and adiponectin, and a diverse range of signaling mediators collectively known as adipokines or adipocytokines [17–20]. The total number of adipokines is now well over 50, and their main functional categories include appetite and energy balance, immunity, insulin sensitivity, angiogenesis, homeostasis, lipid metabolism, and blood pressure [16,20]. Furthermore, a growing list of adipokines is involved in inﬂammation: tumor necrosis factor α (TNFα), interleukin 1β (IL-1β), IL-6, IL-8, IL-10, transforming growth factor β (TGF-β), plasminogen activator inhibitor 1 (PAI-1), haptoglobin, and serum amyloid A [15–19]. Under conditions of obesity, the production of these inﬂammatory

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adipokines by adipose tissue is increased. This has led to the hypothesis that obesity is characterized by a state of chronic low-grade inﬂammation and that this provides a link to insulin resistance and metabolic syndrome [15,17]. The term adipokinome refers to proteins involved in lipid metabolism, insulin sensitivity, the alternative complement system, vascular homeostasis, regulation of blood pressure and energy balance, and angiogenesis [16,17,20]; however, the extent to which adipose tissue contributes quantitatively to the elevated circulating levels of these inﬂammatory adipokines in obesity is unclear. Moreover, it is also unknown whether this is a generalized or local state of inﬂammation [17,20]. Overall, increased production of inﬂammatory cytokines and acute-phase proteins by the adipose tissue in obesity primarily relates to localized events within the expanding fat depots [16].

HYPOXIA, CANCER, AND ANGIOGENESIS Hypoxia or low levels of oxygen availability to the adipose tissue, as might happen to the peripheral white fat mass ahead of angiogenesis, could be a key trigger for the inﬂammationrelated events in white adipose tissue in obesity [17–20]. Adipose-derived inﬂammatory cytokines may directly stimulate angiogenic factors, such as VEGF and leptin, or induce them through activation of the transcription factor hypoxia-inducible factor 1 (HIF-1) [18,20]. HIF-1 controls the cellular response to hypoxia by activating numerous genes, as a recent study of global gene expression using DNA microarrays has shown [21]. Immunohistochemical analysis of human tumor biopsies has revealed stabilization of HIF-1α in neoplastic tissues [22]. High HIF-1α levels in tumors reﬂect the frequent presence of intratumoral hypoxia and the fact that many common genetic alterations in cancer cells affect HIF-1α expression [23]. Because HIF-1α binds to and activates transcription of the gene encoding VEGF [23], there seems to be a link between HIF, oncogene gain-of-function, and tumor vascularization. In addition, the remarkable frequency with which common genetic alterations in cancer cells are associated with increased HIF-1 α expression suggests that HIF-1α stabilization could contribute to the accumulation of mutations during tumor progression. This hypothesis is supported both by mechanistic studies in animal models of cancer and by clinical studies demonstrating that HIF-1 α stabilization is associated with increased risk of mortality in a variety of human cancers [24]. HIF-1 also plays critical roles in angiogenesis by directly activating transcription of the VEGF gene [25]. HIF-1-controlled VEGF production leads to autocrine signal transduction that is critical for angiogenesis, and many of the biological processes in angiogenesis, extracellular matrix invasion, and tube formation by endothelial cells are stimulated through HIF-1 [21,26].

ROLE OF LEPTIN, PRODUCT OF THE ob GENE, IN ANGIOGENESIS Leptin, an adipocyte-derived 16,000 molecular weight cytokine-like hormone, plays a pivotal role in the regulation of body weight and obesity, as well as in the control of food consumption, sympathetic nervous system activation, thermogenesis, and proinﬂammatory immune responses [27]. Because angiogenesis and adipogenesis are integrally linked during embryonic development of adipose tissue mass, Bouloumié et al. [27] evaluated the regulatory role of leptin in the growth of the vasculature using human umbilical vein endothelial cells (HUVECs) and porcine aortic endothelial cells. Leptin, via activation of the endothelial leptin receptor (Ob-R), generates a growth signal involving a tyrosine-kinase-dependent intracellular pathway and promotes angiogenic processes [16,27]. This leptin-mediated stimulation of angiogenesis is viewed as a prime event in the development of obesity [15,16,27]. Leptin also contributes to the modulation of growth under physiological and pathophysiological conditions in other tissues [15–17,27].

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ANTIANGIOGENIC THERAPEUTIC STRATEGIES TO REGULATE OBESITY Rupnick et al. [28] explored the corelationships between adipose tissue growth, angiogenesis, and leptin levels in ob/ob mice, which rapidly accumulate adipose tissue and develop spontaneous obesity because of a lack of functional leptin. The authors also examined endothelial cell proliferation, apoptotic cell death in adipose tissue, and metabolic consequences in these mice following treatment with antiangiogenic inhibitor TNP-470, a synthetic analog of fumagillin, which is also an inhibitor of endothelial cell proliferation in vitro [28]. TNP-470-treated ob/ob mice dosedependently lost body weight and adipose tissue weights as compared to the control animals. Obesity-associated hyperglycemia, serum glucose levels, and appetite levels were also reduced. TNP-470-treated mice also had the lowest average lean mass [28]. Several angiogenesis inhibitors, including endostatin, Bay12-9566 (a matrix metalloproteinase inhibitor), thalidomide, angiostatin, and TNP-470, were tested on ob/ob mice, and all treatment groups gained less or lost weight compared to the control animals [28]. Mice from other obesity models also yielded similar results. The authors also treated 3T3-L1 preadipocytes with different concentrations of TNP-470 to evaluate whether suppression of preadipocyte proliferation contributes to this effect, and the results demonstrate that both endothelial-mediated mechanisms and preadipocyte suppression are involved in this pathophysiology [28]. When cell proliferation and apoptosis were assessed in epididymal fat sections from TNP-470-treated and control ob/ob mice, TNP-470 decreased endothelial cell proliferation and increased apoptosis. Furthermore, basal metabolic rate (as measured by oxygen consumption, VO2max) was also increased in TNP-470-treated ob/ob mice [28]. Brakenhielm et al. [29] evaluated the effect of TNP-470 on C57Bl/6 wt and ob/ob mice fed a high-fat diet. Systemic administration of TNP-470 prevented obesity in high-caloric-diet-fed C57Bl/6 wt mice as well as in genetically leptin-deﬁcient ob/ob mice. This containment of obesity in mice was accompanied by a reduction of vascularity in the adipose tissue [29]. TNP-470 selectively affected the growth of adipose tissue as measured by the ratio between total fat and lean body mass, as well as decreased serum levels of low-density lipoprotein (LDL) cholesterol [29]. Furthermore, TNP-470 increased insulin sensitivity as demonstrated by reduced insulin levels, suggesting the therapeutic role of a potent angiogenesis inhibitor in the prevention of type 2 diabetes [15,29]. The investigators demonstrated that adipose tissue growth is dependent on angiogenesis and that potent antiangiogenic compounds may serve as novel therapeutic agents for the prevention of obesity and symptoms of metabolic syndrome [29]. Voros et al. [30] studied the intricate aspects of the development of vasculature and mRNA expression of 17 pro- and antiangiogenic factors during adipose tissue development in nutritionally induced or genetically predisposed murine obesity models. Male C57Bl/6 mice were maintained either on a standard food diet (SFD) or on high-fat diet (HFD), and male ob/ob mice were maintained on a SFD over a period of 15 weeks. The ob/ob mice and male C57BL/6 mice on the HFD had signiﬁcantly larger subcutaneous and gonadal fat pads, accompanied by signiﬁcantly higher blood content, increased total blood vessel volume, and higher number of proliferating cells [30]. Fat pad growth was accompanied by increased vascularization. Both mRNA and the protein levels of angipoietin-1 were downregulated, whereas those of thrombospondin-1 were upregulated in the developing adipose tissue in both obesity models. Angiopoietin-1 mRNA levels correlated negatively with adipose tissue weight in the early phase of nutritionally induced obesity as well as in genetically predisposed obesity [30]. Placental growth factor and angiopoietin-2 expression were increased in subcutaneous adipose tissue of ob/ob mice, and thrombospondin-2 expression was increased in both subcutaneous and gonadal fat pads. No changes were observed in the mRNA levels of VEGF-A isoforms VEGF-B; VEGF-C; VEGF receptor-1, -2, and -3; and neuropilin-1 [30]. Neels et al. [18] examined the angiogenic process using the 3T3-F442A model of adipose tissue development. These investigators subcutaneously implanted 3T3-F442A preadipocytes into athymic Balb/c nude mice to study the neovascularization of developing adipose tissue [18]. These cells

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FAT MASS •VEGF •Leptin •Monobutyrin

Proliferation of •endothelial cells •smooth muscles •preadipocytes •adipocytes

159

FAT MASS ANTIANGIOGENIC THERAPY •Nonproliferation of endothelial cells •Diminished growth of vasculature

CONTROL OF FAT EXPANSION Growth of vasculature, new vessels EXPANDING FAT MASS

FIGURE 13.1 Pathophysiology of angiogenesis in expanding fat mass and signiﬁcance of antiangiogenic therapy.

developed into highly vascularized fat pads over the next 14 to 21 days, and these fat pads were morphologically similar to normal subcutaneous adipose tissue. Histological studies demonstrated that a new microvasculature comes up as early as 5 days after cell implantation, and real-time polymerase chain reaction (RT-PCR) quantitative analyses indicated that the expression of endothelial cell markers and adipogenesis markers increased simultaneously in parallel during fat pad development [13]. Thus, neovasculature originates by sprouting from larger host-derived blood vessels that run parallel to peripheral nerves, and the endothelial progenitor cells play a minor role in this process [18]. Figure 13.1 demonstrates the key factors involved in adipose tissue development and the inﬂuence of antiangiogenic therapy.

REDOX CONTROL OF ANGIOGENESIS: OXIDANTS AS INDUCERS OF ANGIOGENIC FACTORS AND ANGIOGENESIS Endothelial cells (ECs) lining the blood vessels generate reactive oxygen species (ROS) such as O2•– and H2O2, which play a role in physiological and pathophysiological responses. High concentrations of ROS cause apoptosis and cell death [31]. In addition, ROS-induced oxidative stress is associated with cardiovascular diseases such as atherosclerosis and diabetes. However, low levels of ROS, as perhaps produced in response to growth factor, hypoxia, or ischemia, function as signaling molecules to mediate EC proliferation and migration which may contribute to angiogenesis in vivo [32,33]. Cellular ROS can be generated from a number of sources, including the mitochondrial electron transport system, xanthine oxidase, cytochrome P450, NADPH oxidase, and nitric oxide synthase (NOS). NADPH oxidase is one of the major sources of ROS in vasculature [31]. Neutrophil NADPH oxidase releases large amounts of O2– in bursts, whereas vascular NADPH oxidases continuously produce low levels of O2•– intracellularly in the basal state, yet production can be further stimulated acutely by various agonists and growth factors [31]. NADPH oxidase is activated by numerous stimuli such as VEGF, angiopoietin-1, cytokines, shear stress, hypoxia, and G-protein-coupled receptor agonists, including angiotensin II in ECs [31,34,35]. ROS produced via activation of

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NADPH oxidase stimulate diverse redox signaling pathways leading to angiogenic responses in ECs as well as postnatal neovascularization in vivo [33]. In addition to ECs, ROS stimulates the induction of VEGF in various other cell types including vascular smooth muscle cells to promote cell proliferation and migration [32,36], cytoskeletal reorganization, and tubular morphogenesis in ECs [37]. Hypoxia and the adhesion of activated polymorphonuclear leukocytes to ECs cause ROS production, which results in capillary tube formation [38,39]. Angiogenesis growth factors such as VEGF and angiopoietin-1 increase ROS and thus induce EC migration and proliferation [31,34,35]. Compounds that cause ROS formation often stimulate angiogenesis. Ethanol stimulates actin cytoskeletal reorganization, cell motility, and tube formation in a ROS-dependent manner in ECs [40]. Leptin, a circulating adipocytokine, upregulates VEGF mRNA and stimulates cell proliferation through an increase in ROS in ECs [41]. A strong correlation exists among ROS production, neovascularization, and VEGF expression in the eyes of diabetics [42,43] and in balloon-injured arteries [44]. The generation of ROS during ischemia/reperfusion can also lead to angiogenesis. Reperfusion of the ischemic retina has been reported to upregulate VEGF mRNA [45]. Short periods of ischemia/reperfusion induce an increase in ROS, thereby stimulating myocardial angiogenesis in the ischemic noninfarcted heart [46]

ANTIANGIOGENIC FUNCTION OF ANTIOXIDANTS Because ROS is involved in angiogenesis, antioxidants that scavenge ROS should inhibit formation of new vessels. It has been reported that antioxidants such as pyrrolidine dithiocarbamate [47], epigallocatechin-3-gallate [48], resveratrol (a novel phytoalexin found in grapes, red wine, and diverse functional foods), and other natural polyphenols inhibit neovascularization in the mouse model [49,50]. Green tea catechins, vitamin E, etc. also inhibit angiogenic responses in ECs [51]. Antiangiogenic therapy also reduces plaque growth and intimal neovascularization [52], and antioxidants such as vitamins C and E are reported to reduce vascular VEGF and VEGFR-2 expression in apolipoprotein-E-deﬁcient (apoE–/–) mice [53]. ROS are also involved in neovascularization during tumor growth. The thiol antioxidant N-acetylcysteine (NAC) attenuates EC invasion and angiogenesis in a tumor model in vivo [54].

ANTIANGIOGENIC ANTIOXIDANT NUTRIENTS Tumor vascularization is a key step in the development of solid tumors, and the vast majority of pharmaceutical activity surrounding angiogenesis relates to the development of therapeutic strategies to destroy existing tumor vasculature and to prevent neovascularization [16–19]. Thus, antiangiogenic approaches to treat cancer represent a prime area in vascular tumor biology. Antioxidant nutrients demonstrate potent antiangiogenic functions. Catechin derivatives exhibited novel antiangiogenic properties in three different in vitro bioassays with concentrations ranging from 1.56 to 100 µM [55,56]. Epigallocatechin-3-gallate (EGCG) exhibited the most potent antiangiogenic activity in all three assays among all catechins tested. EGCG inhibited the binding of VEGF to HUVECs in a concentration-dependent manner [55,56], and resveratrol and quercetin exhibited antiangiogenic properties in a concentration-dependent manner (6 to 100 µM) [50]. Pure ﬂavonoids, including rutin, kaempferol, ferrulic acid, genistein, ﬁsetin, and luteolin, also exhibited novel antiangiogenic properties [57,58]. These studies demonstrate that functional foods are effective in limiting angiogenesis in vivo [55–58]. OptiBerry, a blend of six edible berry extracts (blueberry, bilberry, cranberry, elderberry, raspberry seeds, and strawberry), was recently developed in our laboratories [58,59]. OptiBerry was shown to possess a high antioxidant capacity, low cytotoxicity, and potent antiangiogenic properties. In terms of antiangiogenic properties, OptiBerry was superior to individual berry anthocyanins, thus highlighting the synergistic power of the blend. OptiBerry signiﬁcantly inhibited both

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H2O2 as well as TNFα-induced VEGF expression by human keratinocytes [58,59]. Angiogenesis as monitored by Matrigel assay using human microvascular endothelial cells was also impaired in the presence of OptiBerry [58,59]. In addition to these in vitro cell models, OptiBerry signiﬁcantly inhibited inducible transcription factor NF-κB in an in vivo model [35]. In 129 P3 mice, endothelioma cells pretreated with OptiBerry showed a diminished growth of neoplastic vasculature by more than 50% [59]. These studies highlight the novel antiangiogenic and anticarcinogenic potential of select natural food constituents, including catechin derivatives, curcumin (comprising about 40% of the spice turmeric), selected ﬂavonoids (e.g., quercetin, rutin, kaempferol, ferrulic acid, genistein, ﬁsetin, luteolin, resveratrol), and berry anthocyanins [55–59].

OBESITY, ANGIOGENESIS, AND CANCER The link between obesity and angiogenesis illuminates the complex association between obesity and cancer. As mentioned earlier, adipocytes can accelerate tumor vascularization by triggering an angiogenic signaling cascade; however, the exact mechanisms behind its multifaceted functions remain unknown. Obesity itself develops via complex mechanisms involving an interplay among heredity, nutrition, and physical lifestyle. In addition to the role of adipocytes in increasing vascularization and inﬂammation, fat deposits can also cause hormonal imbalances. High levels of estrogens contribute to the proclivity toward cancer. The increased risk of breast cancer after menopause in obese women is believed to be caused by increased levels of estrogens as fat tissues replace ovaries to become the primary source of estrogen [60]. Obesity is often associated with the development of insulin resistance with high circulating levels of insulin and insulin-like hormones [61]. Insulin is known to stimulate cell proliferation, suggesting that an overproduction or high concentrations may be responsible, at least to some extent, for cancer development. High insulin and insulin-like hormone levels are closely associated with an increased risk for breast cancer and poorer survival after breast cancer diagnosis [62].

CONCLUSIONS Overweight and obesity pose epidemic threats to human health, especially in the Western world. Healthy diet, proper nutrition, and exercise represent the fundamental prerequisites to ﬁghting such threats. Growth of adipose tissue depends on the blood vessels that feed the fat mass. Emergent studies reveal that the growth of adipose tissue may be regulated by inhibiting the development of vasculature. Antiangiogenic therapeutics show signiﬁcant promise to manage the undesired expansion of fat mass. Given that oxidants stimulate angiogenesis, it is understandable why antioxidants also possess antiangiogenic properties. Antiangiogenic nutrients provide a safe and potentially effective strategy to directly ﬁght obesity and thus have an effect on controlling cancer. Several polyphenolic antioxidants, especially berry anthocyanins, possess potent antiangiogenic properties and should be considered as countermeasures for managing obesity in humans.

ACKNOWLEDGMENT This work was supported in part by NIH-GM069589.

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as an Occult Risk 14 Obesity Factor for Drug and Chemical Toxicities George B. Corcoran CONTENTS Introduction ....................................................................................................................................165 Animal Models of Human Obesity ...............................................................................................166 Roles of Genetics and Environment ..............................................................................................167 Overfed Rat Model vs. Zucker Rat Model....................................................................................167 Toxicity of Drugs and Chemicals ..................................................................................................168 Perspective......................................................................................................................................170 Acknowledgments ..........................................................................................................................171 References ......................................................................................................................................171

INTRODUCTION It is widely accepted in the medical community that obesity is a leading disease that has far-reaching negative health consequences. Despite this general agreement, the full implications of obesity, particularly its adverse impacts, are underappreciated more often than not. Large percentages of populations in Western countries qualify as substantially overweight, obese, or morbidly obese. Obesity is the most common disease in the United States. Bray [1] noted that the current worldwide epidemic of obesity will be followed by an epidemic of diabetes, a disease closely linked to metabolic syndrome seen in most obese individuals [2–4]. In investigating the recent surge in childhood obesity, Bray and colleagues observed a direct correlation with increased consumption of beverages rich in high-fructose corn syrup [5]. It is deeply troubling that the Worldwatch Institute reported in 2004 that, for the ﬁrst time, the number of overfed and obese people, about 1.1 billion and growing, would soon outnumber the number of underfed people in the world, about 1.1 billion and stable or declining. Overweight and obesity are estimated to account for 4 to 9% of total healthcare costs annually [6] and 30% of the increase in healthcare costs seen since 1987 [7]. Life expectancy has increased from 73.7 years in 1980 to 77.0 years in 2000 [8]; however, we may live to see the ﬁrst generation in this country to experience a decline in life expectancy [9]. Obesity and morbid obesity (body mass index [BMI] ≥30 and ≥40, respectively) result in substantially increased morbidity and mortality, arising from many different sources. The death rate rises when body weight exceeds the desired value for height by a little as 20% [10]. As noted in the Framingham Heart Study [11], the risk of death in 26 years is increased by 1% for each extra pound of body weight at ages 30 to 41 and increased by 2% for each extra pound of body weight at ages 50 to 62. It was only 20 years ago that obesity was ofﬁcially declared a disease, distinct

165

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from the large number of well-known comorbidities, including heart and liver disease, hypertension, diabetes, and numerous cancers [12,13]. Total cancer mortality is increased by obesity in men by a relative risk of 1.52. Speciﬁc cancer increases include liver (4.52), pancreas (2.61), stomach (1.94), colon and rectum (1.84), and gallbladder (1.76). Total cancer mortality shows a greater increase in obese women (1.88) [14]. Liver disease is a hallmark of obesity, particularly morbid obesity. Why many forms of liver disease are increased is not well understood, but it may involve increased injury by drugs and chemicals. Wanless and Lentz [15] reported large differences between the livers of obese vs. lean humans: steatosis (70% vs. 35%), nonalcoholic steatohepatitis (18.5% vs. 3%), and cirrhosis (2–3% vs. 0%). A factor that may contribute to increased liver and other organ disease may be exaggerated drug toxicity. It is well known, for example, that obese patients and rats undergoing surgical anesthesia with halothane, methoxyﬂurane, and enﬂurane suffer higher rates of liver and kidney damage due to increased toxic metabolite formation [16–18]. Additional clinical studies show that obesity increases the clearance of many drugs that are eliminated primarily by metabolism in the liver [19,20], including acetaminophen [21] and lorazepam [22]. This increased metabolic activity is also capable of activating drugs and chemical to toxic metabolites at increased rates in obese individuals. This chapter considers ﬁndings, primarily from historical data, that support the hypothesis that obese individuals are at substantially increased risk of drug toxicity. This increased risk arises from varied sources. These sources include higher rates of toxic metabolite formation, greater accumulation of the toxic form of a drug, and increased susceptibility due to decreased defenses, including those related to glutathione. The chapter does not consider or present the quite substantial body of evidence showing that many drugs also induce higher incidences of toxicity due to inappropriately high doses of drugs administered to obese individuals. In these cases, dosing is based on total body mass or other values that systematically overestimate actual distribution and clearance values in obese individuals. This also results in acute or chronic exposure to higher and more prolonged drug concentrations and an increased frequency of drug-related toxicities.

ANIMAL MODELS OF HUMAN OBESITY It can be quite difﬁcult and in many cases impossible to perform studies that would be a direct test of one’s working hypothesis in human volunteers or patients due to ethical and other considerations. For this and other reasons, it is often necessary to perform some or most studies with models that duplicate the human condition. In the case of obesity, a wide variety of models exists today. Each has a different array of strengths, weaknesses, and distinguishing attributes. Models divide into those primarily of genetic origin and those primarily of environmental origin [2]. By selecting a model, the implications of the study results become thus speciﬁed, as do the possible relevance of results for drug-related mortality or morbidity in obese humans. When the hypothesis that drugs are more toxic in obesity ﬁrst came under examination, some key animal models that exist today were poorly characterized or were not available because they had not been developed. Although models based on leptin defects, including the leptin null (ob/ob) mouse and the leptin receptor null (db/db) mouse, were in use, the genetic bases of these models were not understood. Some current models that exploit melatonin defects — AGR Agouti, ART Agouti-related protein, melanocortin-4 receptor (MC4R), proopiomelanocortin (POMC), carboxypeptidase, and tubby mice — were available, but others were not [23]. Other environmental models in which mice or rats acquire obesity include dietary models (cafeteria diet, force feeding, overfeeding), surgical models (hypothalamic lesion), and chemically induced models (gold thioglucose). Rat models offer many advantages for studying drug disposition and toxicity, including the ability to obtain multiple blood samples from the same animal to estimate pharmacokinetic parameters. Leading rat models of obesity include the Zucker rat (a genetic model) and the overfed rat (a model in which obesity is acquired).

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TABLE 14.1 Content of Pellet Control and Energy-Rich Dietsa Diet Component Fat Protein Carbohydrate Moisture Fiber Ash Energy content (kcal/g)b

Pellet Control Diet

Energy-Dense Diet

6.5 14.5 57.5 10.0 4.0 7.5 3.47

60.0 24.5 7.5 1.0 2.0 5.0 6.68

a

Shown as percentage (w/w) and based on representative lot analysis of Prolab R-M-H 1000 by the manufacturer (Agway, Inc.; Syracuse, NY) and a description of an energy-dense diet adapted from Schemmel et al. [29]. b Calculated from 9, 4, and 4 kcal/g for fat, protein, and carbohydrate, respectively.

ROLES OF GENETICS AND ENVIRONMENT It is widely understood that both genetic and environmental factors contribute to the majority of human obesity. Obesity is a complex disorder in which genetic predisposition interacts with environmental factors, which together produce an array of different human phenotypes of the disease [24]. The pioneering studies of Stunkard and others [25–27] who observed monozygotic and dizygotic twin pairs, as well as adopted twins raised apart, showed that at least 50%, and possibly as high as 90%, of obesity is heritable. The heritability of obesity is polygenetic. Only 173 human obesity cases have been shown to be due to single-gene mutations occurring in 10 genes [28]. Although some studies present data showing low rates of cultural transmission of obesity, these stand in direct opposition to a well-established body of ﬁndings showing strong socioeconomic determinants of obesity. It can be said with some certainty that both genetic predisposition and environmental factors are important keys to successful modeling of human obesity.

OVERFED RAT MODEL VS. ZUCKER RAT MODEL The goal of using animal models to examine a given mechanism involved in human obesity should not be sidetracked by the desire to work with a near-perfect model but to employ one that will be informative and relevant for the question at hand. It is likely that some models are better mimics of drug disposition than others. This guided our thinking in selecting and then characterizing the overfed rat model of human obesity for pharmacokinetics and metabolism studies. This model seemed to start with recapitulating a key environmental factor contributing to human obesity, the increasing percentage of daily caloric intake that has been represented by dietary fat over the past 5 decades. Sprague–Dawley rats become obese when maintained for more than 12 weeks on an energy-dense diet developed by Schemmel et al. [29] (see Table 14.1 and Figure 14.1). Overfed rats that became obese on an energy-rich diet were compared to Zucker rats, genetically obese rodents that inherit obesity through an autosomal recessive trait caused by a mutation of the leptin receptor gene [30]. The latter mechanism accounts for no more than a fraction of a percent of human obesity. Comparisons showed that overfed rats resembled obese humans in 11 of 12 characteristics selected for their importance to drug disposition and toxicity, including those that control drug clearance and volume of distribution. Zucker rats resembled obese humans in only 5 of 12 characteristics, and the discrepancies were highly meaningful. There were no increases in

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FIGURE 14.1 Pellet control rat vs. obese overfed rat. Pictured animals are representative of groups of rats that were fed a standard pellet diet (#4) or an obesity-inducing energy-rich diet (#5) for 57 weeks. Total body mass differed signiﬁcantly between the group fed the pellet diet (705 ± 110 g, n = 7) vs. the energy-dense diet (1086 ± 186 g, n = 9) at p < 0.05. Other pharmacokinetic characteristics differed substantially between pellet control and obese rats [28].

fat-free mass or creatinine clearance, while thyroid function was abnormally depressed [31]. Differences of the greatest signiﬁcance involved hepatic cytochrome P450, which increased in proportion to total body mass in obese overfed rats but remained unchanged in obese Zucker rats and refractory to induction by phenobarbital. Although P450 status is not fully characterized in obese humans, many reports show increased drug oxidation in obese individuals, consistent with increased P450 levels.

TOXICITY OF DRUGS AND CHEMICALS Being ill more often, obese individuals receive drug treatment more frequently and beginning earlier in life than those of normal weight. Ironically, information to guide the appropriate treatment of this substantial population has only recently begun to accrue, and tools to adjust drug dosing for obese patients remain limited in number and application. Uncertainty in selecting the correct dose of a drug for an obese patient is a problem that has become more acute rather than better understood. Because of higher rates of morbidity, obese individuals are over-represented among those receiving medical attention and drug treatment. Studies with the obese overfed rat demonstrate that representative drugs and chemicals are more toxic to obese animals, even when dosing biases are eliminated by dosing according to fatfree body mass. Experiments with acetaminophen (Table 14.2) show that this analgesic produces greater liver and kidney necrosis in obese overfed rats when compared to pellet control rats, independent of whether animals are dosed according to total body mass or to fat-free mass [32]. The latter indicates that obese rats are intrinsically more susceptible to acetaminophen-induced necrosis in both of these organs. Rats maintained on the energy-dense diet showed increased glucuronidation and decreased sulfation of acetaminophen (Figure 14.2) [32]. Prior studies demonstrated that these dosing regimens produced initial acetaminophen plasma concentrations that were not statistically different, but elimination curves differed between control and obese animals, reproducing the same increase in metabolic clearance in obese rats as seen in obese humans [33]. Acetaminophen activation to its toxic metabolite is increased 28% per mg hepatic microsomal protein from obese overfed rats, and immunodetectable CYP2E1, the primary catalyst of acetaminophen bioactivation, is overtly elevated in obese rats [34].

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TABLE 14.2 Increased Acetaminophen-Induced Liver and Kidney Necrosis in Obese Overfed Rats Relative Incidence and Extent of Necrosis (%)

Group a

Pellet control Energy-dense lean Energy-dense obesea dosed to total body minerals (TBM) Energy-dense obeseb dosed to fat-free mass (FFM)

Liver

Kidney

48-Hour Survival

0

1+

2+

3+

0

1+

2+

3+

4+

9/9 7/9 4/9

100 86 25

— — 25

— 14 25

— — 25

89 43 —

11 29 —

— 14 —

— 14 50

— — 50

4/9

25

25

50

—

—

33

—

33

33

Note: Three groups of rats received 710 mg/kg acetaminophen i.p. and resided in metabolism cages for 24 hours. The last group (dosed to FFM) received the same dose as energy-dense lean animals on a fat-free mass basis (i.e., 955 mg/kg of FFM). Animals were sacriﬁced at 48 hr and portions of liver and kidney were prepared for light microscopic analysis. Hepatic and renal necrosis in surviving animals was graded from 0 (absent) to 4+ (>50%) according to the abundance of dead parenchymal or renal epithelial cells in sections stained with hematoxylin and eosin. Values represent the percentage of surviving animals within a group exhibiting each grade of injury. Differences in distribution of enumerated necrosis scores were detected by nonparametric analysis of variance and Tukey-like multiple comparison test. a

Values bearing the same superscript were different at p < 0.05. Both liver and kidney scores differed between pellet control and obese animals dosed to TBM. b One kidney histology sample was lost during processing. Source: Corcoran, G.B. and Wong, B.K., J. Pharmacol. Exp. Ther., 241, 921, 1987. With permission.

Oxidation of ethanol by the microsomal ethanol-oxidizing system (MEOS) system is elevated by 28% in hepatic microsomes from obese overfed rats compared to rates in microsomes from pellet control animals [35]. It is possible that this elevation in ethanol oxidation by the MEOS system could be a contributing factor to the high incidence of liver pathology in obese individuals. This potential relationship bears further investigation.

Percent of Administered Dose

80 Pellet Lean

60

Obese-TBM Obese-FFM

40

* *

20 * * * 0

A-Gluc

A-Sulf

APAP

Total

FIGURE 14.2 Effects of obesity and dosing normalization on metabolic fate of acetaminophen. Values are the sum of acetaminophen and metabolites that were excreted into urine plus those remaining in the carcass at the time of sacriﬁce. The latter values were estimated by multiplying the terminal plasma concentration by the volume of distribution. Differences were detected by analysis of variance and Tukey’s multiple comparison test (* = p < 0.05). Results are expressed as mean ± S.E.M. (From Corcoran, G.B. and Wong, B.K., J. Pharmacol. Exp. Ther., 241, 921, 1987. With permission.)

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TABLE 14.3 Increased Furosemide-Induced Liver and Kidney Necrosis in Obese Overfed Rats Dosed According to Fat-Free Mass Relative Incidence and Extent of Necrosis (%)

Group Pellet controla Energy-dense obesea dosed to fat-free mass (FFM)

Livera

Kidney

24-Hour Survival

0

1+

2+

3+

0

1+

2+

3+

6/6 9/9

83 —

17 44

— 44

— 11

67 33

17 22

17 22

— 22

Note: Control and obese rats were dosed with furosemide at 450 mg/kg fat-free mass (519 ± 82 g vs. 589 ± 36 g, respectively). Animals were sacriﬁced at 24 hours, and portions of liver and kidney were prepared for light microscopic analysis. Hepatic and renal necrosis in surviving animals was graded from 0 (absent) to 4+ (>50%) according to the abundance of dead parenchymal or renal epithelial cells in sections stained with hematoxylin and eosin. Values represent the percentage of surviving animals within a group exhibiting each grade of injury. Differences in the distribution of enumerated necrosis scores were detected by nonparametric analysis of variance and Tukey-like multiple comparison test. a

Liver but not kidney scores differed between pellet control dosed according to FFM and energy-dense obese dosed according to FFM at p < 0.05.

Source: Corcoran, G.B. et al., Toxicol. Appl. Pharmacol., 98, 12, 1989. With permission.

The loop diuretic furosemide (LASIX®) also undergoes hepatic metabolism to a toxic metabolite that accounts for both liver and kidney necrosis and organ failure. In the obese overfed rat, furosemide is more toxic when dosed on a total body mass basis as well as on a fat-free body mass basis, again indicating the greater intrinsic susceptibility of the obese liver to damage by drugs undergoing P450 bioactivation [36] (see Table 14.3). Gentamicin, a powerful aminoglycoside antibiotic that is reserved for the treatment of severe or life-threatening Gram-negative infection, has a narrow therapeutic index due to nephrotoxicity and ototoxicity. For this reason, its use is typically reserved for critically ill patients. An analysis of critically ill patients treated with aminoglycoside antibiotics shows that the incidence of renal injury is higher in patients who are substantially overweight [37]. This raised the possibility that drugs that do not require bioactivation by P450 also are more toxic in obese individuals. Because obese overfed rats exhibit urinary acidiﬁcation that perhaps could affect gentamicin renal accumulation and therefore toxicity, a group of obese rats was returned to the pellet diet for 7 days to restore normal urinary pH. pH-normalized animals were dosed with gentamicin according to ideal body mass plus 40% of excess body mass, the dosing adjustment used clinically for obese patients. N-Acetyl-hexosaminidase (NAH) is a sensitive biomarker of renal epithelial necrosis. When this index of injury was normalized to creatinine excretion, obese rats demonstrated increased renal injury over pellet controls and obese rats dosed to fat-free mass (Figure 14.3) [38]. Increased toxicity was accompanied by increased renal accumulation of gentamicin over pellet controls. Again, obesity was found to potentiate drug-induced organ injury.

PERSPECTIVE Obesity is a mounting public health problem in the United States and other industrialized countries. This chapter offers complementary ﬁndings that obesity predisposes rats to liver and kidney damage by chemicals and drugs acting through different toxic mechanisms. These ﬁndings also offer several lines of evidence that support the hypothesis that obesity predisposes humans to drug and chemical toxicities that may explain, in part, high incidences of liver, kidney, and other organ damage. The

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171

Creatinine-Adjusted Urinary NAH (U/mg)

0.60

*

Control Obese/pH Restored Obese/pH Restored IBM + 40% XSBM 0.30 * * 0.00 –1

0

1

2

3

4

5

Time (days)

FIGURE 14.3 The effects of obesity on creatinine-adjusted urinary excretion of N-acetyl-hexosaminidase (NAH) after chronic gentamicin dosing based on ideal body mass plus 40% excess body mass. Creatinineadjusted urinary excretion of NAH was determined over time for three groups of animals. Control rats were ). The urine pH of treated with 30 mg/kg gentamicin i.p. twice daily for 5 days based on ideal body mass ( obese rats was restored to control values (7.25 ± 0.24) by placing animals on a pellet diet for 7 days. These ) or ideal body mass plus obese, pH-restored rats were treated with gentamicin based on ideal body mass ( ). Results are expressed as mean ± standard deviation of six to eight animals 40% of excess body mass ( per group (*p < 0.05 vs. control by analysis of variance and Tukey’s test). (From Corcoran, G.B. and Salazar, D.E., J. Pharmacol. Exp. Ther., 248, 17, 1989. With permission.)

higher rates of injury in obese overfed rats do not appear to arise because obese organs were exposed to higher drug concentrations than organs of lean controls. This latter observation points to the importance of underlying susceptibility factors, such as increased cytochrome P450 activities, diminished defenses by glutathione and other protective mediators, and other mechanisms. It is possible that increased liver damage and perhaps even the shortened life span of obese humans may arise, in part, from greater susceptibility to chemical and drug toxicity. It would be valuable if concepts established with the obese overfed rat were pursued in the clinical setting, where the uncertainty of animal model extrapolation would be obviated. The negative impact of obesity on human health and healthcare expenditures will continue to grow over the next decades. Because obesity is the second most common preventable human disease, the time is now to accelerate the pace of research into the bases for this disease and discover new means of reversing its progression and morbidities and preventing premature mortality.

ACKNOWLEDGMENTS The author wishes to acknowledge the valuable contribution made by his many colleagues and students, as well as generous support from the National Institutes of Health (NIH GM20852, NIH GM41564, NIH 2S07RR05454) and the Research Foundation of SUNY.

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Bray, G.A., The epidemic of obesity and changes in food intake: the ﬂuoride hypothesis, Physiol. Behav., 82, 115, 2004. [2] Sclafani, A., Animal models of obesity: classiﬁcation and characterization, Int. J. Obes., 8, 419, 1984. [3] Kahn, S.E., Sinman, B., Haffner, S.M., O’Neill, M.C., Kravitz, B.G. et al., Obesity is a major determinant of the association between C-reactive protein levels and the metabolic syndrome in type 2 diabetes, Diabetes, 55, 2357, 2006.

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Obesity: Epidemiology, Pathophysiology, and Prevention Grundy, S.M., Brewer, Jr., H.B., Cleeman, J.I., Smith, Jr., S.C., and L’Enfant, C., Deﬁnition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientiﬁc issues related to deﬁnition, Circulation, 109, 433, 2004. Bray, G.A., Nielsen, S.J., and Popkin, B.M., Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity, Am. J. Clin. Nutr., 79, 537, 2004. Wee, C.C., Phillips, R.S., Legedza, A.T.R., Davis, R.B., Soukup, J.R. et al., Health care expenditures associated with overweight and obesity among U.S. adults: importance of age and race, Am. J. Pub. Health, 95, 159, 2005. Anon., Obesity accounts for nearly 30 percent of health care spending increase since ’87, Hosp. Health Netw., 78, 58, 2004. NCHS, Health, United States, 2004 (with Chartbook on Trends in the Health of Americans), National Center for Health Statistics, Hyattsville, MD, 2004 (http://www.cdc.gov/nchs/data/hus/hus04.pdf). Olshansky, S.J., Passaro, D.J., Hershow, R.C., Layden, J., Barnes, B.A. et al., A potential decline in life expectancy in the United States in the 21st century, N. Engl. J. Med., 352, 1138, 2005. Build Study, Society of Actuaries and Association of Life Insurance Medical Directors, Chicago, 1979. Hubert, H.B., The importance of obesity in the development of coronary risk factors and disease: the epidemiologic evidence, Annu. Rev. Public Health, 7, 493, 1986. Kotalta, G., Obesity declared a disease, Science, 227, 1019, 1985. Andersen, T., Christoffersen, R., and Gluud, C., The liver in consecutive patients with morbid obesity: a clinical, morphological and biochemical study, Int. J. Obes., 8, 107, 1984. Calle, E.E., Rogriguez, C., Walker-Thurmond, K., and Thun, M.J., Overweight, obesity, and mortality from cancer in prospectively studied cohort of U.S. adults, N. Engl. J. Med., 348, 1625, 2003. Wanless, I.R. and Lentz, J.S., Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors, Hepatology, 12,1106, 1990. Miller, M.S., Gandolﬁ, A.J., Vaughan, R.W., and Bentley, J.B., Disposition of enﬂurane in obese patients, J. Pharmacol. Exp. Ther., 215, 292, 1980. Rice, S.A. and Fish, K.J., Anesthetic metabolism and renal function in obese and non-obese Fisher 344 rats following enﬂurane and isoﬂurane anesthesia, Anesthesiology, 65, 28, 1986. Samuelson, P.N., Berin, R.G., Taves, D.R., Freeman, R.B., Calimlim, J.F., and Kumazawa, T., Toxicity following methoxyﬂurane anaesthesia. IV. The role of obesity and the effect of low dose anesthesia on ﬂuoride metabolism and renal function, Can. Anesth. Soc., 23, 465, 1976. Abernethy, D.R. and Greenblatt, D.J., Drug disposition in obese humans: an update, Clin. Pharmacokin., 11, 199, 1986. McLean, A.J., Lalka, D., Corcoran, G.B., and Melander, A., Drug–nutrient interactions, Rec. Adv. Clin. Nutr., 2, 1, 1986. Abernethy, D.R., Divoll, M., Greenblatt, D.J., and Ameer, B., Obesity, sex, and acetaminophen disposition, Clin. Pharmacol. Ther., 31, 783, 1982. Abernethy, D.R. and Greenblatt, D.J., Drug disposition in obese humans: an update, Clin. Pharmacokinet., 11, 199, 1986. Caroll, L., Voisey, J., and Van Daal, A., Mouse models of obesity, Clin. Dermatol., 22, 245, 2004. Comuzzie, A.G., Williams, J.T., Martin, L.J., and Blangero, J., Searching for genes underlying normal variation in human adiposity, J. Mol. Med., 79, 57, 2001. Bouchard, C., Tremblay, A., Despres, J.P., Nadeau, A., Lupien, P.J. et al., The response to long-term overfeeding of identical twins, N. Engl. J. Med., 322, 1477, 1990. Stunkard, A.J., Sorensen, T.I., Hanis, C., Teasdale, T.W., Chakraborty, R. et al., An adoption study of human obesity, N. Engl. J. Med., 314, 193, 1986. Price, R.A. and Gottesman, I.I., Body fat in identical twins reared apart: roles for genes and environment, Behav. Genet., 21, 1, 1991. Rankinen, T., Zuberi, A., Chagnon, Y.C., Weisnagel, S.J., Argyropoulos, G. et al., The human obesity gene map: the 2005 update, Obesity 14, 529, 2006. Schemmel, R., Mickelson, O., and Gill, J.L., Body weight and body fat accretion in seven strains of rat, J. Nutr., 100, 1041, 1970. Chua, Jr., S.C., Cheung, W.K., Wu-Peng, X.S., Zhang, Y., Liu, S.-M. et al., Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor, Science, 271, 994, 1996.

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Part IV Novel Concept in Obesity Drug Development

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Drug Targets 15 Adipose for Obesity Treatment Olivier Boss, Lorenz Lehr, and Jean-Paul Giacobino CONTENTS Introduction ....................................................................................................................................177 Pivotal Role of Adipose Tissue ..............................................................................................177 General Criteria for Anti-Obesity Drug Development...........................................................178 Adipose Targets..............................................................................................................................178 Leptin ......................................................................................................................................179 Adiponectin .............................................................................................................................179 Peroxisome Proliferator-Activated Receptors ........................................................................180 Peroxisome Proliferator-Activated Receptor γ ................................................................180 Peroxisome Proliferator-Activated Receptor δ ...............................................................181 Dual PPAR Agonists........................................................................................................182 Potential Unwanted Side Effects of PPAR Ligand Treatments......................................182 Stearoyl-CoA Desaturase 1 ....................................................................................................182 Acyl CoA:Diacylglycerol Acyltransferase 1 ..........................................................................183 Protein Tyrosine Phosphatase 1B ...........................................................................................184 β3-Adrenergic Receptor ..........................................................................................................185 Other Target Candidates .........................................................................................................185 Adipose Tissue Remodeling Conversion of White to Brown-Like Adipocytes ...........................185 Conclusions ....................................................................................................................................188 Molecular Targets with Small-Molecule Leads or Drugs Successfully Developed (PPARs) .........................................................................188 Key Targets from the Lipid Synthesis Pathway (SCD1, DGAT1) ........................................189 New, High-Potential Molecular Target (PTP1B) ...................................................................189 Acknowledgment............................................................................................................................189 References ......................................................................................................................................189

INTRODUCTION PIVOTAL ROLE

OF

ADIPOSE TISSUE

It is well known that diet and exercise can be, in most individuals, effective means to treat obesity; however, the steadily increasing prevalence of obesity in most countries undoubtedly shows that knowing this is not sufﬁcient to avoid or cure this disease. Indeed, obesity is still in need of effective treatments that have a long-term impact on the course of the disease and its associated cardiovascular risk factors.

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In the last few years adipose tissue has been recognized as a very important endocrine organ that communicates with the brain and peripheral tissues to balance energy intake and expenditure with the level of energy stored in adipocytes. Recent studies have shown that during the development of obesity macrophages inﬁltrate the adipose tissue and generate an inﬂammation-like state [1]. Macrophages residing in adipose tissue, and possibly also enlarged adipocytes, then produce cytokines that are believed to play a role in the development of pathologies associated with obesity (i.e., insulin resistance, type 2 diabetes, dyslipidemia, and cardiovascular disease). Adipose tissue plays a key role in the regulation of energy metabolism, as a source of both fuel (fatty acids) and hormones (e.g., leptin), and in the metabolic adaptations to body weight or fat loss observed upon food restriction in both animals and humans [2–5]. At least two energy balance sensor systems would seem to exist: one that responds to acute changes in adipose mass and another that monitors longterm levels of fat stores. The former seems to involve leptin and the sympathetic nervous system as regulator of appetite and metabolic rate. The chronic “adipostat” system, on the other hand, likely plays a key role in the regain of fat stores after weight loss, and its mechanism remains obscure. Adipose tissue must be the source of factors informing other tissues of the status of fat stores [6].

GENERAL CRITERIA

FOR

ANTI-OBESITY DRUG DEVELOPMENT

The treatment of obesity requires induction, for a certain period of time, of a state of negative energy balance. This can be achieved through a decrease in the entry of energy (food intake), an increase in the output of energy (metabolic rate), or a combination of both. In most instances, a modiﬁcation of the activity of a single target with a drug will have to trigger additional effects in another part of the system controlling energy balance to result in a state of negative energy balance. For example, drug inhibition of an enzyme involved in triglyceride (fat) synthesis will have to cause a decrease in food intake and/or an increase in energy expenditure to have a therapeutic effect on obesity. This requirement might seem difﬁcult to meet unless several drugs are used simultaneously. The endocrinological nature of the control of energy balance implies that metabolic adaptations develop when one part of the system is altered. Some adaptations prevent long-term weight loss (such as the drop in metabolic rate appearing upon body weight loss with food restriction), whereas other adaptations aid weight loss. In fact, in the last few years, a number of genetic animal models have shown that inhibition of lipid synthesis by targeted disruption of a key enzyme in the lipogenic pathway (e.g., SCD1 or DGAT1) can lead to an increase in metabolic rate. These models thus provide biological validation of novel potential drug targets that are expressed in adipose tissue; however, we must keep in mind that disruption of the gene encoding a target will not necessarily predict the effects of inhibition of that target by a drug in adult animals, let alone in humans. Novel drugs to treat obesity should possess some key features [7]. They must be devoid of signiﬁcant side effects over the long term, as treatments will be of long duration. To improve appreciably on currently available medications, future treatments should aim to induce, and sustain, a weight loss of at least 10% of body weight. Finally, as life-long therapy will probably be necessary, the cost associated with therapy must be affordable. In this chapter, we discuss the potential of various adipose targets for the development of drugs to treat obesity and insulin resistance.

ADIPOSE TARGETS Two categories of adipose drug targets can be distinguished: targets that reside in adipocytes (e.g., cell-surface receptors, enzymes, nuclear receptors) and targets that are secreted by adipocytes (i.e., adipokines) that act on other tissues (e.g., brain, skeletal muscle, liver). Adipokines stand for any factors released by adipose tissue, including adipocytes and stromavascular cells [8,9]. In the past 10 years numerous adipokines have been discovered [8,10–15] that inﬂuence the regulation of body weight, insulin sensitivity, and glucose metabolism, as well as the cardiovascular system, but it is likely that additional adipokines that have an impact on energy metabolism remain to be uncovered

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[12,16,17]. Additional adipokines of importance in the development of insulin resistance, type 2 diabetes, dyslipidemia, and cardiovascular disease (e.g., RBP4, TNFα, resistin, visfatin, IL-1β, IL-6) will not be discussed here as they do not seem to represent direct drug target candidates for obesity treatment [18].

LEPTIN Most people add about a pound of fat per year in adulthood, which represents a less than 1% inequality in energy balance. This is an indication of the amazingly tight coupling between food intake and energy expenditure. An afferent signal secreted from the adipose tissue to the central nervous system (CNS) was discovered in leptin a decade ago [19]. The amount of leptin secreted into the circulation is usually proportional to the fat mass [20,21], and it is now well established that leptin plays a major role in coordinating the regulation of food intake and metabolic rate [22]. The effects seen in rodents led to great hopes for leptin as a means to treat obesity; unfortunately, the effects of leptin on food intake and body weight have not been found to be as strong in humans as in mice. A very strong response to leptin was seen in a few people with a mutation causing a lack of leptin [23]; however, in the majority of cases, it seems that obese patients exhibit resistance to the action of leptin, rather than a deﬁciency of leptin. Several clinical studies, however, have shown a signiﬁcant effect of leptin in obese patients [24,25]. The short half-life of leptin in humans (25 minutes) [26] and the route of administration (injection) present pharmacodynamic hurdles for the use of leptin as a therapeutic agent. To address this issue, some studies used a long-acting, polyethylene glycol-modiﬁed recombinant human leptin [25]. Results from human studies highlight a very similar role for leptin in humans and rodents; however, the prevalent leptin resistance seen in obese patients blunts the response to leptin, as observed in certain obese rodent models. The mostly disappointing clinical results together with the high cost of production of the recombinant protein and the inconvenient route of administration have broadly reduced the interest in leptin as a therapeutic agent [27]. Nevertheless, a few ongoing clinical trials are investigating the use of recombinant leptin as treatment for severe insulin resistance and lipodystrophy [28]. The clinical validation of the action of leptin does make the leptin system a very interesting target, and a longacting, orally available, small-molecule leptin receptor agonist would be of tremendous value. Developing a small molecule that mimics the activating effects of leptin (a protein) will be a daunting task, however. Part of the challenge is due to the fact that the leptin receptor is a cytokine receptor, a class of drug targets that has traditionally been very difﬁcult to activate with small molecules. On the other hand, reversing the resistance to the action of leptin on food intake and energy metabolism, which seems to develop with age [29], looks like a very promising strategy for treating obesity. Unfortunately, like insulin resistance, leptin resistance is not yet well understood. Interestingly, protein tyrosine phosphatase 1B (PTP1B) has been shown to be implicated in leptin resistance [30–32], even further increasing the biological validation of PTP1B, a pharmacologically very challenging target. Very recent results suggest that C-reactive protein (CRP), a blood plasma marker of inﬂammation present in higher levels in obese and insulin-resistant patients, could play a role in the leptin resistance seen in obese patients [33]. If this mechanism operates in most patients, then inhibitors of CRP binding to leptin might represent novel agents with clear potential to treat obesity and insulin resistance.

ADIPONECTIN Adiponectin (also known as adipocyte complement-related protein of 30 kDa [Acrp30], adipoQ, or adipose most abundant gene transcript [apM1]) was discovered a few years ago as a 30-kDa protein abundantly produced by adipocytes [34–36]. It is present in the circulation in two major oligomeric forms with molecular weights of about 180 kDa (hexamer) and 400 kDa (higher order structure); the respective levels of these two forms have been suggested to be key to the action of

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PPAR ligand

RXR

PPARα PPARγ PPARδ PGC-1α PPAR response element

Gene promoter

FIGURE 15.1 PPAR nuclear hormone receptor family. PPARs and PGC-1α play a key role in energy dissipation.

this adipokine [37]. Several studies found that circulating adiponectin levels in humans were positively correlated with the degree of insulin sensitivity [38]. In addition, increases in the expression of adiponectin in white adipose tissue, as well as in the plasma levels of adiponectin, have been shown after treatment with peroxisome proliferator-activated receptor γ (PPARγ) agonists, which could contribute to the insulin-sensitizing effects of PPARγ agonists [11,12,38–42]. Adiponectin knockout mice were shown by one group [43], but not another [44], to display severe diet-induced insulin resistance. This apparent discrepancy suggests that genetic background inﬂuences compensatory mechanisms with regard to the effect of adiponectin on insulin action [38]. Administration of adiponectin to mice was reported to increase fatty acid oxidation in muscle, decrease hepatic glucose production, and induce weight loss [45–48], suggesting that this hormone could represent a therapeutic agent to treat insulin resistance, type 2 diabetes, and obesity. In fact, a recombinant adiponectin fragment (Famoxin from Genset, now part of Serono) has been tested in early clinical trials in recent years, but the results of these investigations have not been published. Due to the apparent complexity of adiponectin biology (with multiple complexes having potentially different effects) and the cost and inconvenience associated with recombinant protein treatments, the development of small-molecule adiponectin mimetics seems preferable. For this purpose, knowledge of the receptors mediating the effects of adiponectin is essential. Recently, adiponectin cell-surface receptors (AdipoR1, AdipoR2, and T-cadherin) expressed in skeletal muscle and liver have been described [42,49,50], and signaling pathways downstream of adiponectin receptors have the potential to uncover novel molecular targets amenable to small-molecule drug development. Given the phenotype of the mouse genetic model and the effects of adiponectin treatment in mice, it seems that adiponectin and its signaling pathway represent potential therapeutic agent and drug targets for the treatment of insulin resistance/type 2 diabetes, dyslipidemia, and cardiovascular disease, rather than obesity per se [11].

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS Peroxisome proliferator-activated receptors are a family of three (α, β or δ, γ) nuclear receptors that affect the transcription and expression level of target genes. PPARs act in conjunction with the retinoid X receptor, their activity is controlled by the recruitment of coactivators and corepressors, and they can be modulated by ligands [12,51] (see Figure 15.1). Peroxisome Proliferator-Activated Receptor γ Peroxisome proliferator-activated receptor γ (PPARγ) is primarily expressed in adipose tissue (white and brown), and it plays an essential role in adipogenesis (i.e., adipocyte differentiation) [52]. Ligands that activate PPARγ improve insulin resistance in obese, insulin-resistant animals and

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Increase in mitochondriogenesis and fatty acid oxidation PPARα agonists PPARδ agonists

PPARα agonists

Decrease in adipogenesis PPARγ antagonists or modulators

PPARγ agonists

Dual, Janus-like action of PPARγ agonists; they improve insulin sensitivity and increase adipogenesis

FIGURE 15.2 PPAR ligands might improve insulin sensitivity and treat obesity.

humans. Thiazolidinediones (TZDs) are a class of PPARγ agonists currently on the market for the treatment of type 2 diabetes that include rosiglitazone (Avandia® from GlaxoSmithKline) and pioglitazone (Actos® from Takeda and Eli Lilly). Unfortunately, because full activation of PPARγ enhances adipocyte differentiation (and mildly increases metabolic efﬁciency), animals and humans treated with TZD tend to gain weight. It is now clear, however, that the beneﬁcial effects of PPARγ ligands on insulin sensitivity are not dependent on their effects on adipogenesis [53,54]; thus, it should be possible to develop agents that modulate the activity of PPARγ in such a way that the compounds improve insulin sensitivity but have no effects on adipogenesis (and metabolic efﬁciency). Several companies are currently trying to achieve this with new compounds that do not fully activate PPARγ but modulate its activity (selective PPAR modulators, or SPPARMs) [53]. Such agents should induce PPARγ to recruit a different set of coactivators and corepressors in the adipocytes than those induced by full PPARγ agonists, ultimately leading to improvement of insulin resistance without increasing adipogenesis and body weight [12,55,56]. In addition, mouse models where the PPARγ gene was disrupted (gene knockout mice) and studies with PPARγ antagonists show that inhibition of PPARγ can also improve insulin resistance and, contrary to what is observed with full activation of PPARγ, cause a decrease in fat mass [12,53,54,57–62] (see Figure 15.2). Peroxisome Proliferator-Activated Receptor δ Peroxisome proliferator-activated receptor δ (PPARδ; also called PPARβ) is the lesser known member of the PPAR family. This protein is abundantly expressed in most tissues, and it was recently shown to play a key role in mitochondriogenesis and fatty acid oxidation in adipose tissue and skeletal muscle in mice [14,52,55,63,64]. Overexpression of PPARδ in skeletal muscle was found to increase muscle mitochondrial content and oxidative capacity and to decrease diet-induced obesity and insulin resistance [65,66]. Also, overexpression of a constitutively active PPARδ in adipose tissue of mice was reported to enhance uncoupling protein 1 (UCP1) gene expression and fatty acid oxidation, and as a result it prevents the development of obesity induced by a high-fat diet [67]. PPARδ-deﬁcient mice, on the other hand, were found to be more prone to obesity [52,67].

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In addition, treatment of obese mice with the PPARδ agonist GW501516 induced a reduction in body fat, apparently by promoting fatty acid oxidation in skeletal muscle and adipose tissue and by increasing adaptive thermogenesis [12,63,66,68]. These results suggest that activation of PPARδ might represent a promising strategy for the treatment of obesity and insulin resistance [69–71] (see Figure 15.2). Dual PPAR Agonists An alternative to activating a single PPAR is to develop dual PPAR agonists or pan PPAR agonists, which activate both PPARα and PPARγ or all three PPARs, respectively, hoping that the PPARα or PPARδ part (which might both activate fatty acid oxidation) will balance out the adipogenic effects of PPARγ activation [14,55]. This strategy has the potential to produce agents that treat the metabolic syndrome as a whole (obesity, type 2 diabetes, dyslipidemia, atherosclerosis, and hypertension) and not only obesity. Potential Unwanted Side Effects of PPAR Ligand Treatments It is currently hoped that PPARδ agonists, SPPARMs, dual PPARα/PPARγ agonists, or pan PPAR agonists will develop into successful drugs to treat obesity and type 2 diabetes; however, prolonged treatment with reasonable doses (10 mg/kg) of the PPARδ agonist GW501516 was found to cause hepatomegaly in diet-induced obese C57BL/6J mice [68]. In fact, it is well known that pure PPARα agonists (e.g., ﬁbrates) induce peroxisome proliferation and hepatomegaly in rodents but appear well tolerated in humans, where peroxisome proliferation is not observed [52,72]. That some PPAR agonists can have hepatotoxic effects was demonstrated by the withdrawal of troglitazone, the ﬁrst PPARγ agonist of the TZD family that went to market, following cases of acute liver failure; however, more recent TZDs currently on the market for the treatment of type 2 diabetes (rosiglitazone and pioglitazone) have shown extremely rare (and reversible) signs of hepatotoxicity [73]. PPARγ agonists have been reported to promote the growth of colon cancer tumors in mice, although the effects on human colon cancer cell lines showed conﬂicting results [52]. Similarly, the PPARδ agonist GW501516 was shown to accelerate the growth of small intestine polyp in cancer-prone mice [52]. Recent phase III clinical studies with the dual PPARα/PPARγ agonist muraglitazar showed encouraging therapeutic efﬁcacy but also revealed a dose-related higher incidence of weight gain, edema, and congestive heart failure. In summary, the potential toxicity on liver, heart, and skeletal muscle and the carcinogenicity of PPAR agonists will have to be carefully investigated in the evaluation of drug candidates for chronic treatments. The U.S. Food and Drug Administration (FDA) now requires the completion of 2-year carcinogenicity studies before clinical studies of more than 6-months’ duration with PPAR agonists can be initiated [56,72].

STEAROYL-COA DESATURASE 1 Stearoyl-CoA desaturase 1 (SCD1) is an essential enzyme for the desaturation of long-chain fatty acids to generate monounsaturated fatty acids, mainly oleic acid (C18:1). This fatty acid desaturation seems to be key for triglyceride synthesis and body fat accumulation [74,75]. Indeed, lines of mice with either a targeted disruption of the Scd1 gene (Scd1 knockout) or a natural inactivating mutation in the Scd1 gene (asebia) show a decrease in high-fat-diet-induced obesity and insulin resistance, apparently as a consequence of an elevated metabolic rate as compared to wild-type mice. In addition, treatment of mice with antisense oligonucleotides (ASOs) repressing the expression of Scd1 in liver and adipose tissue resulted in prevention of high-fat-diet-induced obesity, hepatic steatosis, and insulin resistance without affecting food intake [76]. In this latter study, SCD1 ASO also reduced de novo fatty acid synthesis, decreased the expression of lipogenic enzymes, and increased the expression of genes potentially promoting energy dissipation in liver and adipose

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Inhibitor of DGAT1

Glucose Glycerol phosphate Dietary fats

Fatty acids

DGAT1

C18:1 Oleic acid Inhibitor of SCD1

SCD1Re-esterification Triglycerides C18 Stearic acid Lipolysis Fatty acid

Fuel for tissues

FIGURE 15.3 Inhibitors of triglyceride synthesis that might help treat obesity. DGAT1, acyl CoA:diacylglycerol acyltransferase 1; SCD1, stearoyl-CoA desaturase 1.

tissue. Interestingly, SCD1 has been shown to be a major effector of leptin action on fatty acid metabolism in liver [77–79], and it could play a similar role in adipose tissue and skeletal muscle. These results strongly support, from a biological point of view, SCD1 being a high-potential target for treating obesity. In addition, the fact that SCD1 is an enzyme that would have to be inhibited by therapeutic drugs represents a very attractive avenue from a drug development point of view. Mice that completely lack Scd1 (homozygous knockout) have abnormal skin, eyelid, and hair due to deﬁciencies in triglycerides and cholesterol ester synthesis; however, mice lacking only one allele of the Scd1 gene (heterozygous knockout) [75] or treated with an SCD1 ASO [76] showed no such abnormalities despite a 50 to 75% reduction in Scd1 expression and SCD activity. These results suggest that partial inhibition of SCD1 might have beneﬁcial metabolic effects without signiﬁcant repercussions on skin, eyelid, and hair development [79]. This last point is very encouraging for the development of SCD1 inhibitors for the treatment of obesity and insulin resistance. Importantly, inhibition of other enzymes also involved in triglyceride synthesis (i.e., ACC2 and DGAT1) is also associated with enhanced energy expenditure and resistance to the development of obesity in mice, suggesting that triglyceride synthesis is a promising target pathway for the development of anti-obesity drugs [79] (see Figure 15.3).

ACYL COA:DIACYLGLYCEROL ACYLTRANSFERASE 1 Acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) is a microsomal enzyme that catalyzes the ﬁnal and committed step in the glycerol phosphate pathway. Targeted disruption of the DGAT1 gene produced mice that are resistant to high-fat-diet-induced obesity and hepatic steatosis [80], apparently as a consequence of an increase in energy expenditure and physical activity [81]. DGAT1-deﬁcient mice also highlighted enhanced insulin and leptin sensitivity [82]. Intriguingly, the protection against obesity and insulin resistance was not seen in ob/ob (leptin-deﬁcient) mice (crossed with DGAT1 knockout mice), possibly due to an increase in DGAT2 expression in the white adipose tissue of this animal model [83]. These data support the value of DGAT1 as a molecular target for the development of anti-obesity drugs. A total lack of DGAT1 was reported to cause alopecia and to impair the development of the mammary gland, abnormalities that were not seen in animals with only partial DGAT1 deﬁciency [80]. Importantly, obesity resistance and

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enhanced insulin sensitivity were also observed in wild-type mice transplanted with white fat pads from DGAT1 knockout mice, suggesting that adipose tissue lacking DGAT1 secretes a factor that can decrease fat stores and enhance glucose disposal [16,83]. Thus, partial inhibition of the enzyme seems sufﬁcient to produce desired effects on adiposity, suggesting that pharmacological inhibition of the enzyme should be a productive therapeutic strategy for human obesity and type 2 diabetes (Figure 15.3). Furthermore, identiﬁcation of the putative factor secreted by adipose tissue lacking DGAT1 that improves blood glucose homeostatis could provide additional target candidates for drug development.

PROTEIN TYROSINE PHOSPHATASE 1B Protein tyrosine phosphatase 1B (PTP1B) is a protein tyrosine phosphatase expressed in most tissues that can interrupt insulin signaling by dephosphorylating Tyr residues on the insulin receptor and possibly also on the insulin receptor substrate 1 (IRS1) [84]. PTP1B has also been shown to dephosphorylate Janus kinase 2 (JAK2) and interrupt leptin signaling in hypothalamus [30–32]. Thus, inhibition of PTP1B has the potential to reverse the resistance to the action of both insulin (type 2 diabetes) and leptin (obesity) [85]. With the exception of the β3-AR, no other adipose target has been as strongly validated (in animals) as PTP1B in the ﬁeld of obesity and insulin resistance. Mice that lack the PTP1B gene were found to be resistant to high-fat-diet-induced obesity and insulin resistance through an increase in skeletal muscle and possibly liver, insulin sensitivity, and an increase in resting and total daily metabolic rate (expressed per gram of body weight) [86,87]. The phenotype of these mice suggested that PTP1B plays a critical role in the action of insulin on glucose metabolism in muscle and liver. Recent studies using RNA inhibition technology to repress the normal expression of PTP1B in mice suggest that PTP1B also plays a signiﬁcant role in adipose tissue [88,89]. In fact, the PTP1B antisense oligonucleotides that, in mice, reached the adipose tissue and liver, where they strongly decreased the expression of PTP1B but did not reach the skeletal muscle or the brain [89–91], induced improvements in glucose metabolism and insulin sensitivity, as well as a decrease in body weight in obese, insulin-resistant ob/ob and db/db mice [88–91]. These studies suggested that inhibition of PTP1B expression in adipose tissue and liver can lead to improvements in glucose metabolism and insulin sensitivity and a decrease in body weight in obese, insulin-resistant ob/ob and db/db mice [88–91]. At this point, it is not yet clear what the main target tissues for PTP1B inhibition are. Results from the gene knockout mice suggest that skeletal muscle and liver, but not adipose tissue, are responsible for the enhanced action of insulin (anti-insulin resistance), whereas the mechanism underlying lower body fat and weight (anti-obesity) is uncertain [87]. The results from the PTP1B antisense oligonucleotides studies, on the other hand, suggest that adipose tissue and liver play a key role in increased insulin sensitivity, as inhibition of PTP1B expression in only these two tissues was sufﬁcient to improve insulin resistance [89–91]. The lack of PTP1B in parts of the brain involved in the control of body weight and glucose metabolism might play an important role in the phenotype of PTP1B knockout mice [30,32]. Investigation of the impact of brain-speciﬁc disruption of the PTP1B gene might clarify the role of central PTP1B on energy metabolism. The development of PTP1B inhibitors that are active in vivo (animals) turned out to be a major challenge, in part because the protein tyrosine phosphatase family represents a new, largely unexplored class of drug targets and because it seems that compounds that bind to the enzymatic active site are highly charged and do not readily permeate the cell membrane or show poor oral bioavailability [85]. Nonetheless, some reports have recently described remarkable effects of small-molecule PTP1B inhibitors (e.g., IDD-3, PTP-3848, KR61639) in obese, insulin-resistant ob/ob, db/db, KKAy, and C57BL mice [92–98]. In fact, these effects were quite similar to those observed with antisense oligonucleotides repressing the expression of PTP1B. Interestingly, the inhibitor IDD-3 was shown to improve insulin sensitivity and glucose homeostasis after only 3 days of treatment

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in ob/ob mice and after a single dose in high-fat-fed, insulin-resistant Wistar rats [99]. This pharmacodynamic proﬁle suggests that, if the mechanism of action is similar in humans, proof-ofconcept early clinical studies could be performed quite rapidly and give valuable indications regarding the validity of PTP1B as a drug target in human obesity and type 2 diabetes. In summary, inhibition of PTP1B is one of the most promising approaches for treating obesity and insulin resistance, and we will soon know whether the challenges met by many companies in their efforts to develop small-molecule inhibitors for this enzyme can be overcome.

β3-ADRENERGIC RECEPTOR The pharmacological effects of β3-adrenergic receptor (β3-AR) agonists developed so far represent a classical example of the risks of extrapolating the effects observed in rodent models to clinical effects in humans. Rodent adipose tissues (brown and white) express high levels of β3-AR, and β3AR agonists are well known to be effective in these animals in terms of reducing body weight and fat stores and improving insulin resistance and blood glucose homeostasis. Human adipose tissue, however, has been shown to express very low levels of β3-AR [100–102], possibly because humans live at thermoneutrality and, unlike rodents kept at room temperature, do not need to rely on nonshivering thermogenesis to maintain their body temperature. Because of this low expression level, it is hardly surprising that β3-AR agonists have very weak effects on energy metabolism in humans [103,104]. The possibility remains that the expression of β3-AR in human adipose tissue could be upregulated by future treatment strategies; however, there is currently no clear target candidate to achieve this effect [104,105]. A different but related approach would be to induce the conversion of white to brown-like adipocytes with signiﬁcant levels of expression of β3-AR in human adipose tissue.

OTHER TARGET CANDIDATES Thyroid hormones have been used to treat obesity in the past, but their use showed unacceptable adverse effects on the heart function and skeletal muscle mass; however, recent data suggest that selective activation of thyroid hormone receptor β (TRβ) can induce an increase in metabolic rate and a decrease in body weight in rodents and nonhuman primates without adverse effects on the heart function [106,107]. Thus, new TRβ-selective agonists, or possibly TRβ modulators, represent a new class of therapeutic candidates against obesity [108]. The realization that the activity of nuclear receptors (e.g., PPARs) can be modiﬁed in different ways (and not only by full activation or inhibition) opens up new avenues in drug discovery for thyroid hormone receptors.

ADIPOSE TISSUE REMODELING: CONVERSION OF WHITE TO BROWN-LIKE ADIPOCYTES The main effector of cold- and diet-induced thermogenesis in rodents is brown adipose tissue (BAT). Thermogenesis in this tissue is mainly regulated by the sympathetic nervous system. Sympathetic activation leads to the local release of catecholamines by the sympathetic nerve terminals. Catecholamines then mediate their effects through α- and β-adrenergic receptors (ARs). The β-AR family consists of β1/β2/β3-AR subtypes, and the three β-subtypes coexist in the BAT. In contrast to rodents maintained at room temperature (i.e., below their thermoneutrality temperature), adult humans do not possess signiﬁcant amounts of BAT. Induction of brown adipocyte differentiation with drugs might be possible, although no druggable molecular target has yet been identiﬁed to achieve this in humans [7,104,109]. Various studies have shown that the white and brown preadipocytes differentiate in vitro in characteristic white and brown adipocytes, respectively [110–112]. Multilocular fat cells, expressing UCP1 and rich in mitochondria, have been observed for the ﬁrst time in a white adipose tissue

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A

B

FIGURE 15.4 (A) Cold-exposure recruitment in the mouse white adipose tissue (WAT) of brown adipocytelike multilocular cells expressing UCP1. (B) Thermogenic cells act as a Trojan horse to transform the lipidstoring WAT into an energy dissipating tissue. (From Jimenez, M. et al., Eur. J. Biochem., 270, 699–705, 2003. With permission.)

(WAT) depot by Young et al. [113]. The emergence of these so-called ectopic brown adipocytes in the WAT was found to be induced by cold acclimation in rats [114,115] and mice [116–118] (see Figure 15.4). This phenomenon is generally called recruitment. The new cells were found to be sympathetically innervated [119] and to remain present as long as a sympathetic stimulation persisted [117]. Several reports showed that in mice the administration of selective β3-AR agonists such as CL 316243 induced the emergence of brown adipocytes in WAT depots [118,120–122] and that this phenomenon was strongly dependent on the mouse genetic background [118,121,123]. It was, however, recently shown that transgenic overexpression of the human β1-AR in the WAT of mice also induced the appearance of abundant brown adipocytes in this tissue [124]. These results suggested that the β3-AR might not be the only β-subtype controlling the emergence of brown adipocytes in the WAT; however, administration of β1-AR agonists would not be appropriate for the treatment of obesity due to the well-known effects of these agents on the heart. Cells expressing UCP1 should, by dissipating energy, provide heat and therefore contribute with the BAT to maintain body temperature and energy balance. Administration of the β3-AR agonist CL 316243 was found to induce the recruitment of brown adipocytes in WAT depots and at the same time to reduce adiposity in the Zucker fa/fa rat [122]. Important information on the physiological importance of brown adipocyte recruitment in the WAT was obtained by comparing obesity-prone and obesity-resistant strains of mice. Chronic treatment with CL 316243 prevented obesity induced by a high-fat diet in the obesity-resistant A/J but not in the obesity-prone C57BL/6J mice. As CL 316243 also induced a marked UCP1 expression in the WAT depots of the A/J but not of the C57BL/6J mice, it could be postulated that the ability of the β3-AR agonist to prevent diet-induced obesity depended on the recruitment phenomenon [121]. A strong correlation was found, in response to cold exposure or CL 316243 treatment in various mouse strains, between body weight loss and UCP1 levels in the retroperitoneal WAT [118]. Transgenic mice ectopically expressing UCP1 in their WAT displayed an increase in the oxygen consumption of this tissue and were protected from genetic and dietary obesity [125]. Surprisingly, their BAT was atrophied and the animals were cold sensitive [126]. On the other hand, mice with a genetic ablation of their BAT were cold sensitive and obese [127]. This raises the possibility of distinct functions for brown adipocytes depending on their presence in BAT or in WAT depots. BAT brown adipocytes would impart both cold and obesity resistance, whereas WAT brown adipocytes would be associated only with obesity resistance. However, the phenotype of the UCP1

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knockout mice, which are cold sensitive but not obese [128,129], does not support a role for UCP1 in obesity resistance. The origin and the real nature of the multilocular cells rich in mitochondria and expressing UCP1 that appear in WAT upon cold acclimation or β3-AR stimulation have yet to be determined. The presence of brown adipocyte progenitors in the WAT has been suggested by studies showing that 10 to 15% of the precursor cells isolated from mouse WAT differentiate into brown adipocytes in culture [130] and that brown adipocyte progenitors are present in human WAT depots [131]. Another hypothesis suggests that a few unilocular white adipocytes are indeed “masked“ brown adipocytes that can recover a brown phenotype in response to sympathetic nervous system stimulation such as that induced by cold exposure. Himms-Hagen et al. [132], studying the effect of CL 316243 in rats, suggested that the multilocular cells expressing UCP1 that appeared in the WAT were different from the classical brown adipocytes and postulated that they might derive, at least in part, from preexisting unilocular adipocytes. Orci et al. [133] showed that hyperleptinemia in rats induces the transformation of white adipocytes into so-called post adipocytes (or fat-oxidizing machines) which have the phenotype of brown adipocytes. Gene expression studies have shown different responses to various stimuli of WAT vs. BAT brown adipocytes. In the BAT of β3-AR knockout mice, it was observed that UCP1 expression levels were normal at 24°C as well as after 10 days of cold exposure, whereas in the WAT of β3-AR knockout mice UCP1 expression levels and the density of multilocular cells were strongly depressed at 24°C and after a 10-day cold exposure as compared to wild-type mice [134]. These results conﬁrm that β3-ARs play a major role in the appearance of brown adipocytes in WAT and suggest that the multilocular cells recruited in the WAT differ from genuine brown adipocytes. Recently, Coulter et al. [135] evaluated whether the quantitative trait loci controlling UCP1 expression also modulate PPARγ coactivator-1α (PGC-1α) expression levels, by analysis of backcross progeny from the A/J and C57BL/6J mouse strains. They found, comparing mice on a low- or high-fat diet, allelic variations modulating the expression of UCP1 and PGC-1α in brown adipocytes in the WAT but not in the BAT. These results suggested fundamentally different regulatory mechanisms for the control of UCP1 expression in WAT vs. BAT. Several studies using transgenic animals have demonstrated the strong implication of various genes in the occurrence of ectopic brown adipocytes in the WAT. Among them, we have selected a few possible early target candidates for anti-obesity drugs. 4E-BP1 was found to play an important inhibitory role on the recruitment of brown adipocytes in the WAT. Indeed, in 4E-BP1 knockout mice, a robust recruitment of ectopic brown adipocytes was observed in the inguinal and retroperitoneal WAT, PGC-1α and UCP1 expression levels were increased in WAT, and body fat mass was decreased [136]. Thus, a speciﬁc inhibitor of 4E-BP1 in the WAT could stimulate the resurgence of brown adipocytes in this tissue. Forkhead box protein C2 (FOXC2), a member of the FOX family of transcription factors, has been shown to have an effect on the switch between WAT and BAT in rodents. Its expression in mice is restricted to adipose tissues, and mice with adipose-tissue-targeted overexpression of FOXC2 displayed an atrophy of the WAT and a hypertrophy of the BAT [137]. Those mice also exhibited an increase in insulin sensitivity and a more efﬁcient signaling though β-adrenergic receptors. Further analysis showed that the overexpression of FOXC2 prevented diet-induced insulin resistance and intracellular lipid accumulation in the skeletal muscle [138]. It was therefore postulated that FOXC2 could be a novel therapeutic target for the treatment of obesity and insulin resistance. Yet another approach would be to induce the conversion of white adipocytes to brown-like adipocytes, which are cells rich in mitochondria with multilocular lipid droplets, not necessarily expressing UCP1 [109,132,139]. Induction of mitochondriogenesis in white adipose tissue, assuming that it would trigger an elevation of adipocyte metabolic rate through partial uncoupling of oxidative phosphorylation and an increase in thermogenesis, should favor fatty acid oxidation (possibly also glucose utilization), as well as decrease fat deposition and promote weight loss [140]. The nuclear hormone receptor coactivators PGC-1α and PGC-1β have been shown to increase mitochondriogenesis

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when overexpressed in cells or in mice [141–147]. The resulting increase in cellular or tissue oxidative capacity was accompanied, in most cases, by an increase in metabolic rate. Direct activation of PGC-1α (a coactivator) is hardly a possibility with a small-molecule drug, and it might not be a fruitful strategy to treat obesity and insulin resistance as this would probably enhance PGC-1αmediated hepatic glucose production [148]. A possible avenue to activate PGC-1α in adipose tissue would be to interfere with a tissue-speciﬁc factor that inhibits PGC-1α. An inhibitor of PGC-1α activity, p160MBP, was recently described [149,150], and this factor could represent an interesting drug target to activate PGC-1α as long as it does not affect the activity of PGC-1α on hepatic gluconeogenesis. In addition, the nuclear receptor estrogen-related receptor α (ERRα) and possibly ERRγ have been shown to play a key role in the effects of PGC-1α on mitochondriogenesis [151–154]. Thus, ERRα and ERRγ could represent novel drug targets for the treatment of obesity and insulin resistance. These nuclear receptors, as yet orphan, would be a priori more amenable to drug development [155,156] than a coactivator such as PGC-1α, even though the active conformation of ERRα (but not ERRγ) was shown to possess a very small ligand-binding pocket [155]. Activation of lipolysis, if it enhances metabolic rate (e.g., by increasing fatty acid cycling), could represent a strategy to induce weight loss [157]. Alternatively, activation of lipolysis could, through a locally increased efﬂux of fatty acids possibly providing ligands to nuclear receptors involved in mitochondriogenesis, trigger a remodeling of white adipocytes into brown-like adipocytes. This effect has recently been reported after a few days of treatment with the selective β3-AR agonist CL 316243 in mice [102] and shown to be mediated by PPARα [102,158]. This suggests that PPARα agonists (e.g., ﬁbrates) could have direct anti-obesity properties in addition to their well-known effects on dyslipidemia. Alternatively, PPARα modulators (rather than full agonists) might recapitulate some of the effects seen with β3-AR agonists in rodent white adipose tissue. Interestingly, a PPARα agonist (K-111, formerly BM 17.0744) was shown to produce, in addition to improvements of dyslipidemia and insulin resistance, body weight loss in nonhuman primates [159,160].

CONCLUSIONS Obesity and insulin resistance or type 2 diabetes are pathologies with rapidly growing prevalence in most of the world and with dire, unmet medical needs. Novel, effective long-term treatments of these medical conditions are urgently needed to help decrease patient suffering as well as contain the rapidly increasing cost of health care. Fortunately, remarkable progress in the understanding of the mechanisms controlling energy balance has been achieved in the last decade. Much remains to be learned until we have an complete understanding of these complex systems, but we are very optimistic that the near future will bring efﬁcacious treatments of obesity for most patients. It is unlikely, however, that a single drug against obesity will be effective in most patients; rather, an assortment of drugs will probably be necessary to treat a large proportion of patients who almost certainly present heterogeneous mechanistic etiologies of obesity. In this regard, a better characterization of obese patient subcategories could help stratify patient populations for clinical trials and therapeutic strategies.

MOLECULAR TARGETS WITH SMALL-MOLECULE LEADS OR DRUGS SUCCESSFULLY DEVELOPED (PPARS) A few molecular targets offer the most hope for anti-obesity therapeutics. These targets have been quite well validated biologically (in animals) and are known to be reachable with small molecules as drugs already exist that act on targets from the same family. PPARs and possibly other nuclear hormone receptors are part of this category. For PPARs, the key for success will be to ﬁnd the optimal combination of PPAR subtype activation or inhibition to obtain the desired effect on body fat stores and glucose metabolism. PPARα is the target for the ﬁbrate family compounds used for

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years to treat dyslipidemia linked to cardiovascular disease. Fibrates activate PPARα in the liver and adipose tissue, but they do not usually have a strong impact on body weight, fat mass, or blood glucose levels. PPARδ agonists have shown interesting effects on body fat stores in mice, and these agents could represent a new generation of anti-obesity drugs. Modulation (partial activation or inhibition) of PPARγ, rather than full activation, has a promising future, as does the dual activation of PPARγ and PPARα (or PPARδ). Modulation of the activity of nuclear receptors (e.g., PPARs, thyroid hormone receptors, orphan nuclear receptors) by affecting the recruitment of their coactivators or corepressors represents a new avenue for future drug development to treat obesity and type 2 diabetes. Potential safety issues of PPAR ligands with regard to organ toxicity and carcinogenicity will have to be carefully monitored.

KEY TARGETS

FROM THE

LIPID SYNTHESIS PATHWAY (SCD1, DGAT1)

Promising targets for anti-obesity drugs include SCD1 as well as other enzymes playing a critical role in triglyceride synthesis. Even though it might appear odd that inhibiting an enzyme necessary to store excess energy as fat would help in the treatment of obesity without causing metabolic problems, rodent models show that lacking these key enzymes can induce an adaptive increase in metabolic rate that dissipates the excess energy instead of storing it as fat.

NEW, HIGH-POTENTIAL MOLECULAR TARGET (PTP1B) Protein tyrosine phosphatase 1B is a molecular target with very high potential for the development of drugs that could be very effective in the treatment of obesity and diabetes. PTP1B inhibitors would represent an important innovation in drug discovery, as no drugs exist today that act on protein tyrosine phosphatases. Hence, PTP1B inhibitors would establish a precedent for this new class of drug targets. In summary, PTP1B is a high-risk but very high-potential drug target that could generate unmatched gratiﬁcation to the successful creators of an orally active inhibitor. Adipocytes have provided several novel potential targets for the development of therapeutic drugs against obesity and diabetes in recent years. Research and development efforts are still needed for these recent target candidates to be validated and drugs to be developed. In addition, novel adipose factors having an impact on energy metabolism will almost certainly be identiﬁed in the near future and will provide additional opportunities for the development of anti-obesity drugs.

ACKNOWLEDGMENT We thank Nils Bergenhem for his contribution to a recent review article containing information that was used when writing this chapter.

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Obesity: Epidemiology, Pathophysiology, and Prevention Spiegelman, B.M., Puigserver, P., and Wu, Z., Regulation of adipogenesis and energy balance by PPARgamma and PGC-1, Int. J. Obes. Relat. Metab. Disord., 24, S8–S10, 2000. Lin, J., Wu, H., Tarr, P.T., Zhang, C.Y., Wu, Z. et al., Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle ﬁbres, Nature, 418, 797–801, 2002. Kamei, Y., Ohizumi, H., Fujitani, Y., Nemoto, T., Tanaka, T. et al., PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand whose expression induces a high-energy expenditure and antagonizes obesity, Proc. Natl. Acad. Sci. USA, 100, 12378–12383, 2003. Meirhaeghe, A., Crowley, V., Lenaghan, C., Lelliott, C., Green, K. et al., Characterization of the human, mouse and rat PGC1 beta (peroxisome-proliferator-activated receptor-gamma co-activator 1 beta) gene in vitro and in vivo, Biochem. J., 373, 155–165, 2003. St.-Pierre, J., Lin, J., Krauss, S., Tarr, P.T., Yang, R. et al., Bioenergetic analysis of peroxisome proliferator-activated receptor gamma coactivators 1alpha and 1beta (PGC-1alpha and PGC-1beta) in muscle cells, J. Biol. Chem., 278, 26597–26603, 2003. Lin, J., Handschin, C., and Spiegelman, B.M., Metabolic control through the PGC-1 family of transcription coactivators, Cell. Metab., 1, 361–370, 2005. Yoon, J.C., Puigserver, P., Chen, G., Donovan, J., Wu, Z. et al., Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1, Nature, 413, 131–138, 2001. Knutti, D., Kressler, D., and Kralli, A., Regulation of the transcriptional coactivator PGC-1 via MAPKsensitive interaction with a repressor, Proc. Natl. Acad. Sci. USA, 98, 9713–9718, 2001. Fan, M., Rhee, J., St.-Pierre, J., Handschin, C., Puigserver, P. et al., Suppression of mitochondrial respiration through recruitment of p160 Myb binding protein to PGC-1alpha: modulation by p38 MAPK, Genes Dev., 18, 278–289, 2004. Schreiber, S.N., Knutti, D., Brogli, K., Uhlmann, T., and Kralli, A., The transcriptional coactivator PGC-1 regulates the expression and activity of the orphan nuclear receptor estrogen-related receptor alpha (ERRalpha), J. Biol. Chem., 278, 9013–9018, 2003. Mootha, V.K., Handschin, C., Arlow, D., Xie, X., St. Pierre, J. et al., ERRalpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle, Proc. Natl. Acad. Sci. USA, 101, 6570–6578, 2004. Schreiber, S.N., Emter, R., Hock, M.B., Knutti, D., Cardenas, J. et al., The estrogen-related receptor alpha (ERRalpha) functions in PPARgamma coactivator 1alpha (PGC-1alpha)-induced mitochondrial biogenesis, Proc. Natl. Acad. Sci. USA, 101, 6472–6477, 2004. Willy, P.J., Murray, I.R., Qian, J., Busch, B.B., Stevens, Jr., W.C. et al., Regulation of PPARgamma coactivator 1alpha (PGC-1alpha) signaling by an estrogen-related receptor alpha (ERRalpha) ligand, Proc. Natl. Acad. Sci. USA, 101, 8912–8917, 2004. Kallen, J., Schlaeppi, J.M., Bitsch, F., Filipuzzi, I., Schilb, A. et al., Evidence for ligand-independent transcriptional activation of the human estrogen-related receptor alpha (ERRalpha): crystal structure of ERRalpha ligand binding domain in complex with peroxisome proliferator-activated receptor coactivator-1alpha, J. Biol. Chem., 279, 49330–49337, 2004. Schulman, I.G. and Heyman, R.A., The ﬂip side: identifying small molecule regulators of nuclear receptors, Chem. Biol., 11, 639–646, 2004. Langin, D., Lucas, S., and Lafontan, M., Millennium fat-cell lipolysis reveals unsuspected novel tracks, Horm. Metab. Res., 32, 443–452, 2000. Li, P., Zhu, Z., Lu, Y., and Granneman, J.G., Metabolic and cellular plasticity in white adipose tissue. II. Role of peroxisome proliferator-activated receptor-alpha, Am. J. Physiol. Endocrinol. Metab., 289, E617–E26, 2005. Bodkin, N.L., Pill, J., Meyer, K., and Hansen, B.C., The effects of K-111, a new insulin-sensitizer, on metabolic syndrome in obese prediabetic rhesus monkeys, Horm. Metab. Res., 35, 617–624, 2003. Schafer, S.A., Hansen, B.C., Volkl, A., Fahimi, H.D., and Pill, J., Biochemical and morphological effects of K-111, a peroxisome proliferator-activated receptor (PPAR)alpha activator, in non-human primates, Biochem. Pharmacol., 68, 239–251, 2004.

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Part V Safety of Obesity Drugs

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16 Safety of Obesity Drugs Alok K. Gupta and Frank L. Greenway CONTENTS Background ....................................................................................................................................199 Obesity Drugs: A Historical Prescriptive ......................................................................................200 Thyroid Hormone ...................................................................................................................200 Dinitrophenol ..........................................................................................................................200 Amphetamines ........................................................................................................................201 Rainbow Pills ..........................................................................................................................201 Aminorex Fumarate ................................................................................................................202 Fenﬂuramine and Dexfenﬂuramine ........................................................................................202 Phenylpropanolamine..............................................................................................................202 Ephedra ...................................................................................................................................203 Obesity Drugs Currently Available................................................................................................203 Amphetamine Derivatives.......................................................................................................203 Benzphetamine.................................................................................................................204 Phendimetrazine...............................................................................................................204 Diethylpropion .................................................................................................................204 Phentermine .....................................................................................................................204 Sibutramine .............................................................................................................................205 Orlistat.....................................................................................................................................205 Rimonabant .............................................................................................................................206 Drugs Approved for Other Reasons Associated with Weight Loss ..............................................206 Bupropion................................................................................................................................206 Exenatide.................................................................................................................................207 Fluoxetine and Sertraline........................................................................................................207 Metformin ...............................................................................................................................208 Pramlintide ..............................................................................................................................208 Somatostatin............................................................................................................................209 Topiramate...............................................................................................................................209 Zonisamide..............................................................................................................................210 Potential for Using Herbs to Develop New Obesity Drugs..........................................................210 Discussion and Conclusions ..........................................................................................................211 References ......................................................................................................................................212

BACKGROUND During the early development of mankind, acquisition of food for sustenance was a major physical endeavor. It was also a difﬁcult task due to the paucity of food. Humans have thus evolved by adapting to famine more than plenty [1]. An increased availability of food without the need for physical activity to acquire it is thought to have resulted in obesity, due to a mismatch between

199

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energy intake (easy availability of energy dense foods) and energy expenditure (increasingly sedentary lifestyle). This trend for overweight and obese began growing dramatically around 1980 in the United States [2] and is being observed worldwide today [3,4], affecting both adults [5] and adolescents [5]. Which environmental changes explain the increased prevalence of obesity is not clear, but genetic mutations are too slow to be responsible. Obesity predisposes to cardiovascular disease, diabetes, and other medical problems [6], which have both medical and economic consequences. Obesity alone has been estimated to cost the United States $100 billion per year and is clearly a major public health problem [7,8]. Only since the National Institutes of Health (NIH) consensus conference of 1985 [9] classiﬁed obesity as a chronic disease have drugs been approved for long-term obesity treatment. It was the discovery of leptin in 1994, however, that spurred scientiﬁc inquiry into the mechanisms of obesity. Despite the new scientiﬁc interest in obesity, we are at the same place with obesity drugs today that we were with hypertension drugs in the 1950s. In the 1950s, we had thiazide diuretics that caused a loss of sodium in the urine and centrally acting drugs, such as reserpine, with side effects related to their upstream mechanisms. Only two obesity drugs are approved for long-term use: orlistat and sibutramine. Orlistat, by causing a loss of fat in the stool, can be likened to thiazides causing urinary sodium loss for the treatment of hypertension. Sibutramine suppresses central noradrenergic neuronal reuptake which prevents improvement in hypertension and causes stimulation associated with its upstream target. Since 1994, obesity mechanisms have been actively investigated, and potential drug targets now ﬁll the developmental pipeline. Just as hypertension drugs now act upon peripheral blood vessel targets with minimal side effects [10], it is likely that a similar evolution will be seen in the development of obesity drugs by targeting peripheral mechanisms associated with improved safety. Because the scientiﬁc tools available for drug development are more advanced today than in the 1950s, it is reasonable to believe that the search for safer and more effective obesity drugs will be quicker and more efﬁcient. Not only does obesity represent a public health concern, but it is also a stigmatized condition, especially for women in Western societies [11]. Because the stigma may induce some to take unwarranted risks to lose weight, the safety of obesity drugs takes on a particular concern. In this chapter, we review the safety of obesity drugs from a historical perspective, pointing out that their history is littered with safety disasters [12]. We also review the safety of currently available drugs for the treatment of obesity and of rimonabant, an obesity drug that has received an approvable letter from the U.S. Food and Drug Administration (FDA). We then discuss the safety of drugs available for other indications that also result in weight loss, and we touch on the potential of herbs as safe and effective obesity drugs.

OBESITY DRUGS: A HISTORICAL PRESCRIPTIVE THYROID HORMONE As early as 1893, thyroid hormone was used to induce weight loss [13]. Thyroxine at 150 µg/d increases weight loss, but 75% of this occurs from loss of the lean tissue rather than from the loss of fat [13]. A loss of lean tissue increases mortality, but a loss of fat decreases mortality [14]. Thyroid hormone stimulates cardiac muscular inotropy and chronotropy and leads to cardiac muscular hypertrophy. Because obesity by itself increases the cardiac work load, thyroid hormone adds to that burden. Thyroid hormone, appropriately, is no longer used as a treatment for obesity.

DINITROPHENOL In World War I, French munitions workers who handled a mixture of dinitrophenol and trinitirophenol were noted to have toxic symptoms and even death from hyperthermia [15]. Animal studies demonstrated a stimulation of respiration and rise in body temperature due to dinitrophenol [16,17].

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Dinitrophenol is a weak acid that binds to protons. It can cross membranes protonated and return as an anion to repeat the cycle. It thus increases the basal proton conductance of the mitochondria, uncouples oxidative phosphorylation from adenosine triphosphate (ATP) generation, and increases the loss of calories as heat. In the 1930s, a series of controlled studies of dinitrophenol were undertaken at Stanford University. A dinitrophenol dose–response relationship was demonstrated in which an 11% increase in resting metabolic rate was observed with every dose increase of 100 mg. Patients taking dinitrophenol experienced warmth and sweating but tolerated dosages of 500 mg to 1 g a day when attention was given to the individualization of dosing based on the increase in metabolic rate. Dosages of dinitrophenol between 300 and 500 mg/d induced a 40% increase in resting metabolic rate, and this increase was sustained over 10 weeks. Unlike thyroid hormone, which was being used for weight loss at that time, dinitrophenol did not increase nitrogen excretion [18], suggesting that weight loss resulted from the loss of fat and not from lean tissue. Dinitrophenol caused edema in some people, offsetting some of the weight loss. This edema resolved and the weight loss became apparent after stopping the drug. Dinitrophenol did not increase blood pressure but instead lowered blood pressure and improved glucose metabolism with continued treatment. It was released to an enthusiastic populace (100,000 people took dinitrophenol in 1934) [19] as a weight-loss drug without the need for diet modiﬁcation. Dinitrophenol was sold directly to the public in patent medicines, resulting in accidental and intentional overdoses leading to deaths due to hyperthermia. Rashes, loss of the ability to taste sweet or salt, and cataracts were reported. In addition, a small number of cases of agranulocytosis was reported. In 1938, the FDA acquired new powers to regulate drug manufacturers. The sales of dinitrophenol were halted due to threats of prosecution by the FDA.

AMPHETAMINES Amphetamine was ﬁrst synthesized in 1887; however, the psychopharmacological properties of amphetamine were not described until 1927. Amphetamine was found to induce euphoria, increase energy, increase wakefulness, increase alertness, and decrease fatigue. During clinical testing in 1937, weight loss was reported [20,21]. Amphetamines and related compounds cause weight loss by inhibiting food intake through the release of norepinephrine in nerve terminals centrally. Alphamethyl-para-tyrosine (AMPT), an inhibitor of noradrenaline synthesis, increased feeding when injected into the perifornical area of the hypothalamus [22]. In 1938, weight loss was reported in response to amphetamine in both obese adults and children [23]. Amphetamine has stimulatory effects on blood pressure and pulse rate and causes the release of free fatty acids through its adrenergic mechanism. It also has a potential for addiction and abuse. Amphetamine is a Drug Enforcement Administration (DEA) Schedule II drug, as are dextroamphetamine and methamphetamine. Amphetamines, therefore, are rarely used today for the treatment of obesity.

RAINBOW PILLS Diet pills containing thyroid hormone, digitalis, diuretics, laxatives, and amphetamine became popular in the 1960s. Because different colors were to be taken at different times of the day, they were called rainbow pills. The potential for drug interactions and toxicity should be obvious from the composition of this approach. Hyperthyroidism, digitalis toxicity, and hypokalemia were all reported and were even responsible for the deaths of patients taking this polypharmaceutical combination [24,25]. Although case reports suggested toxicity [25], controlled trials by Asher et al. [26,27] were less troubling. Subjects in these trials lost 20 to 40 lb, the all-cause mortality rate in the diet pill group was 77% of that seen in the general population, and the cardiac mortality rate was equal to the general population. Nevertheless, safety concerns resulted in discontinuation of the use of rainbow pills. Because digitalis produces anorexia only at toxic dosages and diuretics and laxatives do not reduce fat, the use of these drugs to treat obesity was deemed to be both unsafe and inappropriate.

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AMINOREX FUMARATE A chemical relative of amphetamine, aminorex fumarate was sold over the counter for the treatment of obesity [28] in Austria, Switzerland, and West Germany in 1965. The mechanism of action for weight loss was through the release of noradrenaline in the central nervous system [29]. The prevalence of primary pulmonary hypertension rose 20-fold from 0.87% (1955–1966) to 15.4% (1967–1968), but declined to baseline levels by 1972 [30,31]. Aminorex fumarate was withdrawn from the market in 1968 due to its association with primary pulmonary hypertension. The symptoms of primary pulmonary hypertension lagged by 6 to 12 months after starting the drug and consisted of dyspnea on exertion, syncope, and chest pain [28]. These symptoms regressed in about 50% of the cases, but the other half of the exposed individuals were dead by 1980. This experience sensitized the obesity research community to the potential association of obesity drugs with primary pulmonary hypertension.

FENFLURAMINE

AND

DEXFENFLURAMINE

In 1973, fenﬂuramine was approved for the treatment of obesity. It did not become popular, however, until 1992, when it was combined with phentermine and a study using full dosages of both drugs was published [33]. The efﬁcacy of the two compounds was additive, while the side effects tended to cancel each other, fenﬂuramine being a depressant and phentermine being a stimulant [32,33]. Although fenﬂuramine was approved for 12 weeks of therapy, long-term use became prevalent when it was combined with phentermine. In 1996, more then 18 million prescriptions were written for this combination. In 1997, dexfenﬂuramine was approved for long-term use and was sometimes substituted for fenﬂuramine in the combination. Primary pulmonary hypertension surfaced as the ﬁrst safety concern associated with fenﬂuramine in 1996. The risk, however, was judged to be so small that the beneﬁts of treatment outweighed the risks by 20:1 [34,35]. Heart-valve abnormalities in 24 women with previously normal hearts were reported in 1997 by Connolly et al. [36]. These women had been treated with fenﬂuramine and phentermine for an average of 1 year and presented with cardiac symptoms and murmurs. Pulmonary hypertension was also present in eight of these women, the heart valves of whom, at surgery, exhibited the characteristics of right-sided heart valve lesions associated with the carcinoid syndrome [37]. The study by Ryan et al. [38] was the only prospective study of fenﬂuramine and dexfenﬂuramine performed in subjects who had baseline echocardiograms. In that series, 16.5% subjects with previously normal heart valves developed abnormalities taking fenﬂuramine or dexfenﬂuramine, and the lesions occurred at or after 6 months of treatment. The mechanism for fenﬂuramine-induced weight loss is through increased levels of serotonin in the central nervous system. The cardiac valvular abnormalities, however, were found to be due to binding of a major metabolite of fenﬂuramine, nordexfenﬂuramine, which has a higher afﬁnity than serotonin for the serotonin receptors on the heart valves [39]. The valvular pathology was reversible over 6 months, depending on the severity of the cardiac valvular lesions, as was pulmonary hypertension (in one subject). Fenﬂuramine and dexfenﬂuramine were voluntarily withdrawn from the market in 1997 due to these safety concerns.

PHENYLPROPANOLAMINE Phenylpropanolamine, a nonmethylated form of ephedrine, was synthesized in 1910. It was used as an intravenous agent for postoperative hypotension in the 1930s. It was noted to be a decongestant with a low propensity for stimulation of the central nervous system or for the elevation of pulse and blood pressure. Although its effectiveness as an appetite suppressant was observed in 1939, it was not approved by the FDA as an over-the-counter nasal decongestant until 1976 or as an overthe-counter appetite suppressant until 1979 [40]. It was a well-tolerated medication, with efﬁcacy similar to the prescription drugs available for obesity at the time [41]. Although the dose for obesity

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was limited to 75 mg/d (half of the nasal decongestant dosage of 150 mg/d), it was reported to increase the incidence of hemorrhagic stroke in women taking it for obesity but not in men or women using cough and cold preparations containing phenylpropanolamine. The phenylpropanolamine subjects in this case–control study had a statistically higher prevalence of a family history of hemorrhagic stroke, a personal history of hypertension, and a greater use of alcohol, tobacco, and cocaine compared to the control group. Nevertheless, after publication of the case–control study by Kernan et al. [42], in 2000 phenylpropanolamine was withdrawn from the market both as an agent for obesity and as a nasal decongestant.

EPHEDRA Ephedra has been used in China for over 2000 years. A sympathomimetic herb, ephedrine is the most active of the four isomers of ephedra. Ephedrine was introduced into the United States in 1930 by Chen [43], who described its pharmacology and therapeutic uses. It has been used as an agent for the treatment of asthma in combination with methylxanthines since the 1930s. In the 1970s, a Danish physician noted weight loss in patients he treated for asthma with ephedrine and caffeine. A combination pill containing 200 mg caffeine and 20 mg ephedrine, taken three times a day for weight loss, was eventually approved for prescription use to treat obesity in Denmark. It was well tolerated and captured 80% of the market share, even when fenﬂuramine was available [44]. In 1994, the Dietary Supplement Health and Education Act was passed in the United States, and it classiﬁed herbs as foods. This was landmark legislation in relation to dietary herbal supplements. Not only did it add impetus to the entire ﬁeld, but it also gave rise to the widespread use of ephedra in dietary herbal supplements for weight loss. Widespread, nonregulated use of ephedra in the treatment of obesity resulted in reports of cardiovascular and neuropsychiatric adverse events. Of these adverse events, 10 resulted in death and 13 in permanent disability [46]. An extensive review of the controlled trials of ephedrine and ephedra with and without caffeine demonstrated a 2.2- to 3.6-fold increase in cardiovascular and neuropsychiatric adverse events compared to placebo; however, no increase in serious adverse events was observed in controlled clinical trials. Based on the adverse event reports, the FDA declared ephedra as an adulterant [45]. Because the FDA is required to prove that a food is unsafe and adverse event reports cannot prove cause and effect, the decision to remove ephedra from the market was reversed in court. The legal climate relative to ephedra has made liability insurance coverage almost impossible to obtain by manufacturers of ephedra products, which makes the return of their widespread use for the treatment of obesity unlikely.

OBESITY DRUGS CURRENTLY AVAILABLE AMPHETAMINE DERIVATIVES The amphetamine derivatives benzphetamine and phendimetrazine in DEA Schedule III and diethylpropion and phentermine in DEA Schedule IV are currently available in the United States for the treatment of obesity. They have less abuse and addiction potential than amphetamine itself. Abuse of these drugs during treatment of obesity has rarely been a problem, but these drugs have been sold and abused on the street for recreational purposes. Although benzphetamine and phendimetrazine are rarely used today, phentermine is the most commonly prescribed obesity medication [47]. These drugs were approved when obesity was still considered to be the result of bad habits, and these drugs were approved for continuous use for periods up to 12 weeks. The mechanism by which amphetamine-related drugs reduce weight is through the release of noradrenaline in the central nervous system (CNS) which has the potential for CNS stimulation [48]. The potential for addiction is related to the potential for these drugs to also release dopamine in the CNS. As might be expected from their mechanism of action, these drugs can increase pulse rate, increase blood pressure, and stimulate lipolysis.

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Benzphetamine Benzphetamine was ﬁrst used in 1960, is available as 25-mg tablets, and has similar but less frequent side effects than amphetamine. Benzphetamine is contraindicated in the presence of hyperthyroidism, advanced arteriosclerotic vascular disease (ASCVD), moderate to severe hypertension (HTN), symptomatic cardiovascular disease, agitated states, a history of drug abuse, glaucoma, pregnancy (due to the association with fetal toxicity), lactation, within 14 days of monoamine oxidase inhibitor (MAOI) drug use, and known sensitivity to sympathetic amines. Benzphetamine should be used with caution during the operation of hazardous machinery, as it could impair mental alertness and coordination. It should also be used with caution in the presence of mild to moderate hypertension or in people younger than 12 years of age, and its potential for addiction must be kept in mind. Phendimetrazine Phendimetrazine is available as 35-mg tablets with side effects similar to benzphetamine. Contraindications to the use of phendimetrazine include hyperthyroidism, advanced ASCVD, moderate to severe HTN, symptomatic cardiovascular disease, concomitant use of CNS stimulants, agitated states, a history of drug abuse, glaucoma, pregnancy, lactation, within 14 days of MAOI drug use, and known sensitivity to sympathetic amines. Phendimetrazine should be used with caution during the operation of hazardous machinery, as it could impair mental alertness and coordination. It should also be used with caution in the face of mild hypertension or in people younger than 12 years of age, and its potential for addiction must be kept in mind. Abnormal heart valves and primary pulmonary hypertension have been reported with phendimetrazine, and it should not be used with other anorectics. Diethylpropion Diethylpropion is available as 25-mg, immediate-release and 75-mg, sustained-release tablets. The potential for CNS stimulation and rise in blood pressure is minimal due to keto substitution on the β-carbon of the phenethylamine side chain. Diethylpropion is contraindicated in the presence of hyperthyroidism, advanced ASCVD, severe HTN, agitated states, a history of drug abuse, glaucoma, pregnancy, lactation, within 14 days of MAOI drug use, and known sensitivity to sympathetic amines. Diethylpropion should be used with caution during the operation of hazardous machinery, as its use could impair mental alertness and coordination. Caution should also be exercised in the presence of hypertension or cardiovascular disease, including arrhythmias, in people younger than 12 years of age and in people with epilepsy, as it has initiated seizures in epileptic patients. Phentermine Phentermine is available as a resin in 15- and 30-mg tablets, and it is also available in 37.5-mg tablets. Phentermine has an α-methyl substitution on the phenethylamine side chain, resulting in a lower CNS stimulation potential. It can, however, increase blood pressure and pulse rate, in addition to causing insomnia and dry mouth. Phentermine is the most prescribed obesity drug in the United States, and treatment on alternate months has been shown to be as efﬁcacious as continuous treatment. Alternate-month treatment allows the drug to be used for prolonged periods of time while staying within the constraints of the package insert, which limits the drug to no more than 12 weeks of continuous use [49]. Phentermine is contraindicated in the presence of hyperthyroidism, advanced ASCVD, moderate to severe HTN, symptomatic cardiovascular disease, agitated states, a history of drug abuse, glaucoma, pregnancy, lactation, within 14 days of MAOI drug use, and known sensitivity to sympathetic amines. Phentermine should be used with caution during the operation of hazardous machinery, as it could impair mental alertness and coordination. Phentermine should also be used with caution in the presence of hypertension or in people less than 16 years

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of age, and its addiction potential should be kept in mind. Phentermine should not be used with selective serotonin reuptake inhibitors (SSRIs), and administration of the drug should be stopped for symptoms of primary pulmonary hypertension or valvulopathy. These symptoms include dyspnea, angina, syncope, ankle edema, and a deterioration in exercise tolerance.

SIBUTRAMINE Sibutramine is a noradrenaline and serotonin (5-HT) reuptake inhibitor that was approved for the long-term treatment of obesity in 1997. Because sibutramine causes an increase in the concentration of noradrenaline and serotonin in the intraneuronal cleft in response to food intake, it increases satiety. Sibutramine increases thermogenesis to a lesser degree [50]. Like most other obesity drugs, sibutramine-associated weight loss occurs over 6 months of treatment and plateaus after 6 months, as observed in registration studies lasting up to 2 years [51,52]. Sibutramine reduces serum triglycerides, increases high-density lipoprotein (HDL) cholesterol [53], and improves glucose control in patients with diabetes [54,55]. Sibutramine does not produce the decrease in blood pressure and heart rate expected with weight loss, and it is contraindicated in patients with uncontrolled hypertension, coronary heart disease, cardiac dysrhythmias, congestive heart failure, or stroke [56]. It is distributed as capsules of 5, 10, or 15 mg and is taken once a day, typically starting at 10 mg/d. The dose can be adjusted up to 15 mg/d or down to 5 mg/d depending on response while monitoring the blood pressure and pulse. The rise in blood pressure is modest and is usually offset by the decrease in weight. Sibutramine is associated with dry mouth, insomnia, constipation, headache, and dizziness. These symptoms are similar to some of those seen with amphetamine derivatives, as both medications increase noradrenergic activity. Although no evidence of abuse has been found, sibutramine is a DEA Schedule IV drug due to its structural similarities with amphetamine [57] Sibutramine is contraindicated in patients receiving MAOIs or patients who have a hypersensitivity to sibutramine or any of the inactive ingredients and should not be used in the presence of a major eating disorder (anorexia nervosa or bulimia nervosa) or in patients taking other centrally acting weight-loss drugs. Sibutramine should be used with caution in patients with a history of hypertension, coronary artery disease, congestive heart failure, arrhythmias, stroke, narrow-angle glaucoma, or pulmonary hypertension. The use of sibutramine comes with a warning relative to blood pressure and pulse, as sibutramine substantially increases blood pressure or pulse rate in some patients. Blood pressure and pulse should be measured prior to starting therapy and should be monitored at regular intervals thereafter. For patients who experience a sustained increase in blood pressure or pulse rate, either dose reduction or discontinuation should be considered. Sibutramine should not be given to patients with uncontrolled or poorly controlled hypertension.

ORLISTAT Orlistat is a reversible gastrointestinal lipase inhibitor (both gastric and pancreatic) that impairs the absorption of dietary fat from the intestinal lumen. It is approved for long-term use and acts entirely within the gastrointestinal tract. Orlistat treatment results in signiﬁcant and sustained weight reduction in clinical trials lasting 2 years [58]. Orlistat improves low-density lipoprotein (LDL) cholesterol more than expected from the weight loss it induces, possibly due to enforcing a lowfat diet [59,60]. Other lipid parameters improve in the expected manner with weight loss. Orlistat improves glucose metabolism in obese patients with and without diabetes [61,62] and reduces high blood pressure in proportion to the weight loss it induces [63,64]. It is supplied as 120-mg capsules to be taken three times a day with meals. It is recommended that the drug be used with a 30% fat diet. Orlistat use can result in adverse gastrointestinal events, including ﬂatus with discharge, fatty stools, oily stools, oily spotting, oily evacuation, fecal urgency, fecal incontinence, increased defecation, and abdominal pain. These symptoms usually occur early in the course of treatment, are exaggerated in patients who eat a high-fat diet, and rarely were severe enough to cause

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discontinuation in clinical trials. A nightly multivitamin supplementation is recommended to compensate for impaired absorption of fat-soluble vitamins (A, D, E, and K). Despite the demonstrated beneﬁts of orlistat, its use in clinical practice has been disappointing. This lack of use may be due to the fear of side effects resulting from FDA-mandated warnings in direct-to-consumer advertising and the potential for fecal incontinence becoming fodder for late-night television comedians. An over-the-counter preparation of orlistat with a reduced dosage of 60 mg three times a day may be available as early as late 2006. Orlistat is contraindicated in patients with chronic malabsorption syndrome or cholestasis and in patients with known a known hypersensitivity to orlistat.

RIMONABANT Rimonabant is a selective antagonist of the cannabinoid-1 (CB1) receptor. These receptors are present in the white adipose tissue, gastrointestinal tract, lateral hypothalamus, and limbic system. The location of the receptors is consistent with the side effects and the beneﬁts associated with its use [65–68]. Marijuana contains ∆9-tetrahydrocannabinol (THC), a CB1 receptor agonist, and smokers experience relaxation, euphoria, and an increased intake of sweet and fat food [69]. Rimonabant was studied in phase III clinical trials with over 6000 patients, including those with dislipidemia, and has received an approvable letter from the FDA for the treatment of obesity [70]. Published trials have shown a reduction in triglycerides, an increase in HDL cholesterol, a decrease in small dense LDL particles, and a decrease in the number of patients meeting the criteria for the metabolic syndrome, which was in excess of that expected for the amount of weight loss induced by the drug [71]. Rimonabant at 20 mg a day has a weight loss efﬁcacy similar to sibutramine. Nausea and diarrhea are prominent side effects and consistent with CB1 receptors being present in the gastrointestinal tract. Anxiety, insomnia, dizziness, and depression are also seen and might be expected, as they are opposite of the sensations associated with marijuana smoking.

DRUGS APPROVED FOR OTHER REASONS ASSOCIATED WITH WEIGHT LOSS BUPROPION Bupropion is a norepinephrine and dopamine reuptake inhibitor that is approved for the treatment of depression and smoking cessation. It has been used in weight-loss studies ranging from 8 to 48 weeks in doses of 300 to 400 mg a day. The largest trials included subjects with depressive symptoms [72] and subjects with uncomplicated obesity [73] enrolled across multiple centers. Among those who completed the trial, weight loss in subjects with depressed symptoms treated with 300 to 400 mg of bupropion per day over a 6-month period was 6.0% in the bupropion group compared to 2.8% in the placebo group [72]. Weight loss in subjects with uncomplicated obesity was 5%, 7.2%, and 10.1% of initial body weight in subjects on placebo, 300 mg bupropion, and 400 mg bupropion, respectively [73]. Dropout rates for the two trials were 45% and 30% at 6 months in subjects with depressive symptoms and the uncomplicated obese subjects, respectively. Bupropion can induce epilepsy (0.1% at doses up to 300 mg/d and 0.4% at a dose of 400 mg/d) and is contraindicated in patients with a seizure disorder. Patients with bulimia or anorexia nervosa have a higher incidence of seizures, and the use of bupropion in this patient group is contraindicated. Due to its association with epilepsy, bupropion should be administered with extreme caution in patients with a lowered seizure threshold (alcohol or drug withdrawal, history of head trauma, or the use of drugs such as theophylline). Due to its adrenergic mechanism, bupropion can be associated with hypertension and is contraindicated for use with MAOIs. Allergic reactions, agitation, tinnitus, pharangitis, insomnia, psychosis, confusion, mania, neuropsychiatric phenomenon, and an increased risk for suicide in depressed patients have also been associated with bupropion use. Caution is advised if bupropion is used in subjects with hepatic or renal insufﬁciency.

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EXENATIDE Glucagon-like peptide 1 (GLP-1), or enteroglucagon, is a protein derived from proglucagon and secreted by L-cells in the terminal ileum in response to a meal. GLP-1 decreases food intake and has been postulated to be responsible for the superior weight loss and superior improvement in diabetes seen with obesity bypass surgery [74,75]. Increased GLP-1 inhibits glucagon secretion, stimulates insulin secretion, and stimulates glycogenogenesis along with delaying gastric emptying [76]. GLP-1 is rapidly degraded by dipeptidyl peptidase 4 (DPP-4), an enzyme that is elevated in the obese. Gastric bypass operations for obesity increase GLP-1 but do not change the levels of DPP-4 [77]. Exendin-4 is a 39-amino-acid peptide that is produced in the salivary gland of the Gila monster lizard. It has 53% homology with GLP-1 and has a much longer half-life. Exendin-4 induces satiety and weight loss in Zucker rats with peripheral administration and crosses the blood–brain barrier to act in the central nervous system [78,79]. It decreases food intake and body weight gain while lowering HgbA1c [80]. It also increases β-cell mass to a greater extent than would be expected for the degree of insulin resistance [81]. In humans, exendin-4 reduces fasting and postprandial glucose levels, slows gastric emptying, and decreases food intake by 19% [82]. It was tested in a placebo-controlled trial where 377 type 2 diabetic subjects who were failing maximal sulfonylurea therapy were given 10 µg subcutaneously per day for 30 weeks. Their HgbA1c levels fell 0.74% more than for placebo, fasting glucose decreased, and a progressive weight loss of 1.6 kg was observed [83]. The side effects include headache, nausea, and vomiting, which can be lessened by gradual dose escalation [84]. Thus, exendin-4 shows promise of being an effective treatment for diabetes with a favorable weight-loss proﬁle. Exenatide, however, is contraindicated in patients with known hypersensitivity to this product or any of its components. Exenatide should be used with caution in subjects with severe gastrointestinal disease, as exenatide can cause nausea, vomiting, and diarrhea.

FLUOXETINE

AND

SERTRALINE

Fluoxetine and sertraline are both selective serotonin reuptake inhibitors approved for the treatment of depression. Fluoxetine at a dose of 60 mg/d has been used in the treatment of obesity. Goldstein et al. [85] reviewed several trials: a 36-week trial in type 2 diabetic subjects, a 52-week trial in subjects with uncomplicated obesity, and two 60-week trials in subjects with dyslipidemia, diabetes, or both. A total of 1441 subjects were involved in these trials, and approximately 70% completed 6 months of treatment. (Comment: This dropout rate is not unusual for weight loss trials.) Weight loss in the ﬂuoxetine and placebo groups at 6 months and 1 year was a modest 4.8, 2.2 and 2.4, 1.8 kg, respectively. The regain of 50% of the lost weight during the second 6 months of treatment on ﬂuoxetine made it inappropriate for the treatment of obesity, which requires chronic treatment. Sertraline has resulted in an average weight loss of 0.45 to 0.91 kg in clinical trials lasting 8 to 16 weeks for depression. Fluoxetine and sertraline may be preferred over tricyclic antidepressants for the treatment of depression in the obese, as tricyclic antidepressants are associated with signiﬁcant weight gain; however, ﬂuoxetine and sertraline are not, by themselves, good drugs for the treatment of obesity. Fluoxetine is contraindicated in patients known to be hypersensitive to it. Thioridazine and MAOIs are contraindicated with its use. The neuroleptic malignant syndrome, a serious and sometimes fatal reaction, can occur with its use, and the same has been reported with sertraline. Sertraline is contraindicated with the concomitant use of MAOIs. Sertraline has been associated with inappropriate antidiuretic hormone secretion and altered platelet function. When these drugs are used for the treatment of depression, clinical worsening and an increased suicide risk can occur with both medications. Fluoxetine should be used with caution in subjects with chest pain or chills or who have attempted suicide. Sertraline use has been associated with impotence, palpitations, chest pain, and sexual dysfunction.

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METFORMIN Metformin is a biguanide that is approved for the treatment of diabetes mellitus. This drug reduces hepatic glucose production, decreases intestinal absorption from the gastrointestinal tract, and enhances insulin sensitivity. In clinical trials where metformin was compared with a sulfonylurea, it produced weight loss [86]. The best trial of metformin in terms of evaluating weight loss effects is the Diabetes Prevention Program (DPP) study of individuals with impaired glucose tolerance. This study included three treatment arms to which participants were randomly assigned; subjects were over 25 years of age, had a body mass index (BMI) above 24 kg/m2 (except Asian-Americans, who only needed a BMI ≥ 22 kg/m2), and had impaired glucose tolerance. The three primary arms included lifestyle (N = 1079 participants), metformin (N = 1073), and placebo (N = 1082). At the end of 2.8 years, on average, the Data Safety Monitoring Board terminated the trial because the advantages of lifestyle and metformin were clearly superior to placebo. During this time, subjects in the metformin-treated group lost 2.5% of their body weight (p < 0.001 compared to placebo), and the conversion from impaired glucose tolerance to diabetes was reduced by 31% compared to placebo. In the DPP trial, metformin was more effective in reducing the development of diabetes in the subgroup who were most overweight and in the younger members of the cohort [87]. Although metformin does not produce enough weight loss (5%) to qualify as a weight-loss drug using the FDA criteria, it would appear to be a very useful choice for overweight individuals newly diagnosed with diabetes. Metformin has also found use in the treatment of women with the polycystic ovarian syndrome, where the modest weight loss may contribute to increased fertility and a reduction in insulin resistance [88]. Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function; thus, patients with serum creatinine levels above the upper limit of normal for their age should not use metformin. Renal function should be monitored during metformin treatment, and metformin should be stopped prior to surgical procedures or procedures using x-ray contrast material. Because alcohol potentiates the effect of metformin on lactic acid metabolism, excessive alcohol intake should be avoided. Metformin should be used with caution in patients with congestive heart failure, hepatic insufﬁciency, hypoxic conditions, or acidosis. Metformin is also associated with a decline in vitamin B12 levels.

PRAMLINTIDE Beta-cells in the pancreas secrete amylin in a ﬁxed ratio to insulin. In type 1 diabetes mellitus, immunologically damaged β-cells are deﬁcient in amylin. Pramlintide, a synthetic amylin analog, was recently approved by the FDA for the treatment of insulin-requiring diabetes. Unlike insulin and many other diabetes medications, pramlintide is associated with weight loss. Maggs et al. [89] analyzed the data from two 1-year studies in insulin-treated type 2 diabetic subjects randomized to pramlintide 120 µg twice a day or 150 µg three times a day. Weight decreased by 2.6 kg and hemoglobin A1C decreased 0.5%. When weight loss was then analyzed by ethnic group, AfricanAmericans lost 4 kg, Caucasians lost 2.4 kg, and Hispanics lost 2.3 kg. The improvement in diabetes correlated with the weight loss obtained, suggesting that pramlintide is effective in the ethnic group with the greatest obesity burden. The most common adverse event was nausea, which was usually mild and conﬁned to the ﬁrst 4 weeks of therapy. Pramlintide treatment in insulin-treated type 2 diabetes mellitus may offer an added beneﬁt of weight loss in subjects with preexisting obesity. Pramlintide is contraindicated in patients with a known hypersensitivity to pramlintide or any of its components, including metacresol. Because pramlintide delays gastric emptying, it should not be used in subjects with a conﬁrmed diagnosis of gastroparesis or hypoglycemia unawareness. Pramlintide and insulin should always be administered as separate injections. Pramlintide should be used with caution in subjects with moderate or severe renal impairment, local allergy, hepatic impairment, coughing, or pharangitis.

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SOMATOSTATIN Insulin hypersecretion accompanies hypothalamic obesity [90]. Treatment with octreotide, an analog of somatostatin, resulted in weight loss in children with hypothalamic damage, and their weight loss correlated with reduced insulin secretion on glucose tolerance tests [91]. This open-label trial was followed by a randomized controlled trial of octreotide treatment in children with hypothalamic obesity. The subjects received 5 to 15 µg/kg/d octreotide or placebo for 6 months. The children on octreotide gained 1.6 kg compared to a 9.1-kg gain for those in the placebo group [92]. A trial of 44 subjects, a subset of obese subjects with insulin hypersecretion by an oral glucose tolerance test, was undertaken. A dose of 40 mg/month octreotide LAR was given for 6 months. These subjects lost weight, reduced food intake, and reduced their carbohydrate intake. Weight loss was greatest in those with insulin hypersecretion, and the amount of weight loss was correlated with the reduction in insulin hypersecretion [93]. Because a larger prospective study of 172 insulinhypersensitive subjects randomized to 40 or 60 mg of long-acting octreotide vs. placebo lost a maximum of 3.8% of initial body weight in the high-dose group, it does not appear that octreotide will meet with the criteria for approval as a weight-loss drug by the FDA [94]. Octreotide has been shown to decrease gastric emptying [95]. Octreotide treatment of patients with the Prader–Willi syndrome who have elevated ghrelin levels does not cause weight loss but ghrelin levels are normalized. The reason for the lack of weight loss has been postulated to be the reduction of PYY, a satiating gastrointestinal hormone that also decreased [96]. Octreotide is contraindicated in the face of sensitivity to it or any of its components. It causes gallbladder stasis and is associated with gallstones, gallbladder sludge, and biliary duct dilatation. Octreotide alters the glucose counterregulatory hormones and can be associated with hypoglycemia, hyperglycemia, and hypothyroidism. Cardiac conduction abnormalities have developed in patients on octreotide, and cases of pancreatitis have been reported. Octreotide can alter absorption of dietary fat and depress vitamin B12 levels.

TOPIRAMATE Topiramate is an antiepileptic drug that was observed to give weight loss in the clinical trials for epilepsy. Weight losses of 3.9% of initial weight were seen at 3 months, and losses of 7.3% of initial weight were seen at 1 year [97]. Bray et al. [98] reported a 6-month, placebo-controlled, dose-ranging study. In this study, 385 obese subjects were randomized to placebo or topiramate at 64, 96, 192, or 384 mg/d. These doses were gradually reached by a tapering increase and were reduced in a similar manner at the end of the trial. Weight loss from baseline to 24 weeks was 2.6, 5, 4.8, 6.3, and 6.3% in the placebo, 64 mg, 96 mg, 192 mg, and 384 mg groups, respectively. The most frequent adverse events were paresthesia, somnolence, and difﬁculty with concentration, memory, and attention. This trial was followed by two large multicenter trials extending for 1 year [99,100]. Despite impressive weight losses of 7 to 16.5% of initial body weight, a signiﬁcant improvement in blood pressure, and improvement in glucose tolerance, the sponsor terminated further study to pursue a time-released formulation of the drug. Although topiramate is still available as an antiepileptic drug, the development program to pursue an indication for obesity was terminated by the sponsor in December 2004 due to associated adverse events. Topiramate has been evaluated in the treatment of binge eating disorder [101]. Sixty-one subjects were randomized to 25 to 600 mg/d of topiramate or placebo in a 1:1 ratio. The topiramate group had improvement in binge eating symptoms and lost 5.9 kg at an average topiramate dose of 212 mg/d [102,103]. It has also been used to treat patients with the Prader–Willi syndrome [104–106] and patients with the nocturnal eating syndrome (a sleep-related eating disorder) [107]. Topiramate is a carbonic anhydrase inhibitor associated with kidney stones (1.5%) and metabolic acidosis. Topiramate has been associated with the syndrome of acute myopia and secondary angle closure glaucoma. Topiramate can decrease sweating and increase the risk of hyperthermia.

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Central nervous system adverse events associated with topiramate include psychomotor slowing, difﬁculty in concentration, speech difﬁculties, language problems, word-ﬁnding difﬁculties, somnolence, fatigue, irritability, and depression. Peripheral nervous system adverse events consist of paresthesias. Dosage adjustment of topiramate is necessary in renal and hepatic failure.

ZONISAMIDE Zonisamide is an antiseizure drug that has been evaluated for the treatment of obesity. It has serotonergic and dopaminergic activity in addition to blocking neuronal sodium and calcium channels. In a 16-week trial of 60 subjects (92% women) who were administered a hypocaloric diet, 400 to 600 mg/d zonisamide was shown to result in greater weight loss compared with placebo, with few adverse effects [108]. Because zonisamide is a sulfonamide anticonvulsant, it can cause hypersensitivity reactions in those allergic to sulfa. Zonisamide can reduce sweating and increase the risk of hyperthermia, and rare but serious cases of aplastic anemia have been reported. The possible CNS effects of zonisamide include depression, psychosis, psychomotor slowing, difﬁculty with concentration, word-ﬁnding difﬁculties, somnolence, and fatigue. Zonisamide is also associated with asthenia, vomiting, tremor, abnormal gait, hyperesthesia, and incoordination. Because zonisamide inhibits carbonic anhydrase, it is associated with the formation of renal calculi. A decrease in glomerular ﬁltration rate that is also associated with zonisamide can cause an increase in the blood urea nitrogen. Rare reports of creatine phosphokinase elevation and pancreatitis have been reported with zonisamide. Zonisamide can also cause birth defects and should not be used in women with the potential for pregnancy unless the beneﬁts are felt to outweigh this risk.

POTENTIAL FOR USING HERBS TO DEVELOP NEW OBESITY DRUGS The traditional method of discovering new drugs for obesity, or for other purposes, is to screen novel compounds for activity in assays measuring a mechanism of the disease in question. Activity in a screening assay leads to further in vitro testing and eventually to testing in humans. Most candidate compounds with activity in screening assays fall out of the development process due to safety considerations. As we have already noted, safety is of particular concern in the treatment of obesity; thus, we have adopted a slightly different strategy for obesity drug development by selecting an assay that relates to a mechanism of obesity and screening herbs with a history of safe use in folk medicine with the belief that they may be active in treating obesity. We will outline an example of one project that, although unsuccessful, demonstrates the potential for herbs to form the basis of future obesity medications. Wei Kai-Yuan developed an herbal decoction, which he called “NT,” to treat obesity; it was derived empirically using herbs with a history of safety and long-term usage and by applying the principles of traditional Chinese medicine. He tested this combination using Western scientiﬁc methods, patented his work in China and the United States, and licensed this intellectual property. The herbal mixture consisted of a combination of 40% rhubarb root and stem (radix et rhizoma rhei), 13.3% astragulus root (radix astragali), 13.3% red sage root (radix salviae miltiorrhizae), 26 to 27% turmeric (rhizoma curcumae longae), and 6 to 7% dried ginger (rhizoma zingiberis ofﬁcinalis). This mixture was extracted in water, and 0.5 g of solids was produced from 10 mL of liquid. This herbal extract was tested in groups of young, growing, male Wistar rats (mean 220 g), which were placed on an obesity-inducing diet. The groups of rats was given one of three doses of NT, fenﬂuramine, or saline by gavage daily for 90 days. These animals gained 420, 400, 360, 400, and 450, respectively, and the herbal extract was well tolerated [109]. A pilot study using a subtherapeutic dose of the herbal extract was performed in 24 overweight or obese human females. As expected from the low dose, there was no signiﬁcant weight loss, but the herbal extract increased the frequency of bowel movements from 1 per day to 3 per day. Further

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testing of the herbal extract revealed the presence of sennosides, which are known to be herbal laxatives. Because it was obvious that therapeutic levels of the herbal extract would result in intolerable gastrointestinal symptoms, an attempt was made to use one of its active ingredients [109]. Inhibition of angiogenesis has been shown to reverse animal models of obesity [110]. Brown et al. [111] described a human placental vein angiogenesis model that uses disks of human placental vein implanted in a ﬁbrin matrix to evaluate angiogenesis. Gulec and Woltering [112] adapted this assay to the study of human tumor and other tissue fragments. By maintaining the tissue architecture in which the blood vessels grow faster than the tissue stroma, one can differentially evaluate the vascular and tissue compartments. We have adapted this assay to human fat tissue, which has angiogenic properties different from those of placental tissue [113]. By using the placental assay and serially fractionating an herbal extract, gallic acid was isolated as an angiogenic inhibitor. The potential of gallic acid to completely inhibit angiogenesis at 10–3 M and partially inhibit angiogenesis at 10–4 M was conﬁrmed using the fat tissue assay [114]. Gallic acid has been shown to inhibit food intake in rats when given orally [115] or parenterally [116]. Because gallic acid is derived from gall nuts and is on the list of Generally Recognized as Safe (GRAS) ingredients by the FDA, gallic acid (80%) and the herbal extract (20%) were mixed and tested for the treatment of obesity [117]. Despite the weight loss efﬁcacy in rodents, the herbal extract and gallic acid mixture did not result in weight loss in humans. When oral pharmacokinetic studies were performed, 40% of a 50-mg dose of gallic acid was absorbed, but only 6% of an 800-mg dose was absorbed. Thus, the blood levels with the dose used in the trial never exceeded 10–6 M, suggesting a saturated transport system that prevents a therapeutic level of gallic acid from ever being reached [117]. Although gallic acid does not fulﬁll the criteria of effective oral dosing necessary to become a dietary herbal supplement or an obesity drug that will be well accepted, it was well tolerated in both humans and rodents. We have also been exploring the mechanisms of lipolysis and 11 β-hydroxysteroid dehydrogenase inhibition, in addition to angiogenesis inhibition, to identify potential dietary herbal supplements for the treatment of obesity. By screening herbs for which folklore suggests efﬁcacy in treating obesity, we feel that the potential for a safe therapeutic agent will be greater, as the longterm use in food and folk medicine already suggests safety. Our assays allow us to isolate the active chemical compounds, which can be developed as ethical pharmaceutical agents for the treatment of obesity while a standardized dietary herbal supplement ﬁlls the therapeutic gap created by the lengthy drug development process. We believe this strategy has the potential for much greater safety than might be possible developing drugs from novel chemical entities.

DISCUSSION AND CONCLUSIONS Obesity drugs have a very poor track record of safety. Obese individuals, especially women, experience discrimination in our society [11]. This discrimination encourages some women to take unreasonable risks to lose weight. This makes drug safety all the more important for the treatment of obesity. The drugs available today for the treatment of obesity have limited efﬁcacy and work on upstream targets. The situation with obesity drugs today can be compared to the situation with hypertension drugs in the 1950s. At that time, we had thiazide diuretics that caused the loss of salt in the urine and drugs working at the level of the brain, such as reserpine that had side effects on mood. Orlistat, which leads to the loss of calories in the stool, has parallels with diuretics for the treatment of obesity. Sibutramine and the older obesity medications derived from the basic amphetamine chemical structure provide CNS stimulation and have parallels with the antihypertensive drugs of the 1950s, such as reserpine, that produced such CNS side effects as depression. The pipeline of new obesity drug candidates is rich, and the technology available to the pharmaceutical industry is much more advanced compared to what existed in the 1950s; thus, the future is bright for a much more rapid development of safe obesity drugs that act on downstream targets. Drugs acting on downstream targets have less potential for side effects than drugs acting

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upstream in the CNS. We now have drugs such as angiotensin receptor blockers that act in the periphery and treat hypertension with few side effects. As we develop new drugs for obesity that act on downstream targets, we should see a similar advance in the safety of pharmacological obesity treatment. Using herbs as a platform for the development of obesity drugs offers an additional strategy that may increase the safety of future obesity drugs and serves to emphasize why a chapter on obesity drug safety is germane to a book on phytopharamceuticals and the therapy of obesity.

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Part VI Natural, Nutritional, and Physical Approaches to Weight Management

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Fundamental Role 17 The of Physical Activity and Exercise in Weight Management Dawn Blatt and Cheri L. Gostic CONTENTS The Growing Obesity Epidemic ....................................................................................................219 Initiatives to Combat Obesity ........................................................................................................220 The Fundamental Role of Exercise in Weight Management ........................................................221 Exercise Prescription......................................................................................................................221 Exercise Options ............................................................................................................................222 The Role of Daily Physical Activity in Weight Management ......................................................223 Considerations for Special Populations.........................................................................................224 Pediatrics .................................................................................................................................224 Daily Activity Level and Exercise ..................................................................................224 School-Based Intervention...............................................................................................225 Geriatrics .................................................................................................................................226 Bariatric Surgery.....................................................................................................................226 Considerations for Speciﬁc Medical Conditions (Diabetes, Hypertension, Osteoarthritis) .........227 Information Available Online ........................................................................................................228 Summary ........................................................................................................................................228 Thoughts on Prevention .................................................................................................................228 References ......................................................................................................................................229

THE GROWING OBESITY EPIDEMIC Obesity has grown into one of the most troubling public health epidemics in the United States over the past two decades. The prevalence of obesity has doubled in adults, while the incidence of overweight children and adolescents has tripled since 1980 [1]. Data from the National Health and Nutrition Examination Survey (NHANES) obtained from 2003 to 2004 reveal that 66.3% of adults are overweight and 32.2% of those meet the criteria for obesity [2]. In the United States, obesity is ranked second only to the use of tobacco as the leading preventable cause of death [3]. Body mass index (BMI), deﬁned as body weight (kg) divided by height squared (m2), has become the most commonly used indicator of obesity in recent years. Whereas a BMI equal to or greater than 30 kg/m2 signiﬁes obesity, the National Center for Health Statistics reports that health risks actually begin to increase at a BMI greater than 27 kg/m2. Children are at risk of being overweight if their BMI falls between the 85th and 95th percentile for their sex and age, and they are deemed obese at or above the 95th percentile. 219

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Children and adolescents who are overweight are at risk of developing type 2 diabetes, sleep apnea, and poor self-esteem and have to deal with the social consequences of being overweight [4]. They are six times more likely to have at least one cardiovascular risk factor as compared to children of healthy weight and are at increased risk for various chronic diseases as adults [5]. In adults, the health risks associated with obesity are well established. Obesity increases the risks of cardiovascular disease, stroke, diabetes, arthritis, gallbladder disease, certain cancers, and lung pathologies [6]. Abdominal or central obesity and insulin resistance are also considered the primary risk factors associated with metabolic syndrome, a cluster of conditions that appear to directly promote the development of atherosclerotic cardiovascular disease [7]. Research by Shen et al. [8] suggests that measurement of waist circumference has a stronger correlation to health risks associated with metabolic syndrome than BMI or percent body fat measured by dual-energy x-ray absorptiometry (DEXA) and is an important adjunct in the clinical assessment of obesity. Based on recent research, Bray [9] has proposed that men with a waist circumference between 100 and 120 cm are at high risk and above 120 cm at very high risk for cardiovascular disease. His new proposed risk classiﬁcation categorizes women with a waist circumference between 90 and 109 cm at high risk and those above 110 cm at very high risk. The problem of overweight and obesity results from an imbalance involving elevated caloric intake relative to energy expenditure and is inﬂuenced by genetic, behavioral, metabolic, and socioeconomic factors. The World Health Organization Consultation on Obesity (2002) determined that physical inactivity and overindulgence in food are primarily responsible for the obesity epidemic in the United States. Americans’ devotion to television and computers, labor-saving devices, and contracted household services has contributed greatly to a more sedentary culture. Research has revealed a strong relationship between the amount of television an individual watches and the prevalence of obesity and diabetes [10]. The U.S. Department of Health and Human Services reports that 40% of adults in the United States engage in no leisure-time physical activity, and 80% of overweight adults are completely sedentary. A review of the literature by Blair and Brodney [11] demonstrated that regular physical activity attenuates many of the health risks associated with obesity. They found that overweight or obese individuals who are physically ﬁt and active have remarkably lower morbidity and mortality than individuals of normal weight who are sedentary. Research by Hu et al. [12] concluded that a sedentary lifestyle as well as increased adiposity were strong and independent predictors of death which together accounted for 31% of all premature deaths among the nonsmoking women involved in their study. It is clear that regular exercise and physical activity result in improved ﬁtness and health and should be foundational elements in combating obesity in this country. Despite national initiatives to reverse the growing problem of obesity in the United States, research shows that only 42% of adults who are obese are advised to lose weight by their healthcare providers [13,14]. It is obvious that physicians and other healthcare professionals need to more consistently educate patients regarding the beneﬁts of physical activity and weight loss if we are to deal effectively with this growing crisis.

INITIATIVES TO COMBAT OBESITY Based on a systematic review of the literature from 1980 to 1997, the National Heart, Lung, and Blood Institute (NHLBI) released clinical guidelines in 1998 on the identiﬁcation, evaluation, and treatment of overweight and obese adults. Recommendations included a call for all health professionals to address risk factor reduction and weight management strategies with patients who are obese. The NHLBI also advocated the establishment of a modest target weight loss of 10% of body weight, at a rate of 1 to 2 pounds per week. Studies have demonstrated that even modest weight loss results in improvement or prevention of hypertension, diabetes, and hyperlipidemia [15]. Goals related to weight management should focus on achieving and maintaining clinically meaningful weight loss and on reducing the risk of obesity-related pathologies. The promotion of long-term

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lifestyle changes in diet and physical activity in conjunction with the establishment of modest weight-loss goals offers a realistic chance of success in combating the obesity epidemic. An approach to weight loss that combines an increase in physical activity, restriction of calories, and behavior modiﬁcation has been shown to be the most effective regimen for weight loss, weight maintenance, and improved quality of life [15]. Realistic goal setting, stimulus control, problemsolving strategies, and contingency planning are all components of an effective behavioral therapy program. Self-monitoring of exercise and diet using a journal and enlisting the support of family and friends can be useful in reinforcing positive behavioral change.

THE FUNDAMENTAL ROLE OF EXERCISE IN WEIGHT MANAGEMENT Exercise is a critical adjunct to diet and behavioral modiﬁcation in a comprehensive weight-loss program. Exercise not only increases energy expenditure, but it has also been shown to diminish the loss of lean body mass and associated decline in resting metabolic rate characteristic of dieting alone [16]. Exercise improves the body’s ability to burn fat, thus enhancing the loss of adipose tissue [17]. In addition, it has been shown to improve dietary adherence while reducing anxiety, stress, and depression, which can trigger overeating [18]. Research conﬁrms that the combination of diet and exercise results in greater weight loss than diet or exercise alone [19]. Extreme caloric restriction alone can produce a signiﬁcant decrease in metabolic rate that can persist after the dieting period ends, often leading to rapid weight regain. Research has repeatedly demonstrated that daily physical activity and exercise adherence are the greatest determinants of weight maintenance following weight loss [20–22].

EXERCISE PRESCRIPTION Prior to the initiation of an exercise program, the patient’s risk factors, medical history, and medications should be assessed and, when indicated, medical clearance obtained from a physician. The Physical Activity Readiness Questionnaire (PAR-Q) has been recommended by the American College of Sports Medicine (ACSM) as a minimal standard for participation in a moderate-intensity exercise program [23]. The ACSM has developed risk stratiﬁcation guidelines based on age, health status, coronary artery disease risk factors, and symptoms that can be utilized to determine the need for a medical exam and exercise testing prior to the initiation of an exercise program [24]. Heart-rate parameters derived from an exercise stress test should be included in the exercise prescription. Individuals at low risk can be counseled and provided with patient-education literature to guide them in developing an exercise program that can be incorporated into their lives. It is recommended that healthcare professionals follow these individuals’ progress on a regular basis to improve compliance. Information regarding an individual’s previous level of activity, exercise preferences, physical impairments, and time constraints should be ascertained. Exercise should be pain free, convenient, and enjoyable to the participant to facilitate long-term compliance [24,25]. Whereas exercise classes or group settings may provide valuable support and social beneﬁts for some, home-based exercise programs may improve compliance for others. An exercise prescription should include a warm-up, training, and cool-down program, as well as guidelines for progression of the intensity, duration, and frequency of exercise. The warm-up and cool-down portions should be designed to address impairments that may contribute to functional limitations while also serving to prevent injuries and sudden changes in heart rate and blood pressure. Warm-up and cool-down exercises can include ﬂexibility, resistive, or balance exercises tailored to address any impairments an individual may have. Flexibility exercises can improve posture, enhance function, and provide greater freedom of movement. Resistance exercises can be

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TABLE 17.1 Indicators of Moderate-Intensity Exercise 55–69% maximum heart ratea 12–14 Borg Ratings of Perceived Exertion Scale (“somewhat hard”)b 3–6 METsc a b c

Data from Pollock, M.L. et al., Med. Sci. Sports Exer., 30, 975, 1998. Data from Borg, G.A., Med. Sci. Sports Exer., 14, 377, 1982. Data from Pate, R.R. et al., JAMA, 273, 402, 1995.

useful in improving function. An increase in strength that results in an improved level of mobility can facilitate an increase in daily physical activity. Resistance exercises should target weak muscle groups involved in functional tasks. Balance exercises can be a valuable component of a warm-up or cool-down program, as they reduce the risk of falls, enhance function during gait, and promote a more active lifestyle. Physical therapists can play an integral role in prescribing an appropriate exercise program for patients who are overweight or obese. Individuals should be encouraged to gradually increase the intensity of their exercise from low to moderate over time. Parameters that can be utilized to deﬁne moderate-intensity exercise are listed in Table 17.1. A gradual increase in duration and frequency of exercise should be implemented as well, based on the individual’s tolerance and prior activity level. The cumulative effect of exercise over time is substantial, and research has demonstrated a clear dose–response relationship between the amount of weekly exercise performed and the amount of weight lost in individuals who are overweight [26]. The most successful exercise programs for individuals who are obese are of moderate intensity, of long duration, and performed frequently [27–29]. Individuals should be counseled to strive for a long-term goal of 60 minutes of moderate-intensity physical activity over the course of a day. An example of an exercise prescription is provided in Table 17.2.

EXERCISE OPTIONS Aerobic exercise is the preferred type of exercise for individuals initiating a weight-loss program due to its well-established cardiovascular beneﬁts and volume of calories burned. Aerobic exercise options include walking or the use of treadmills, upper-body exercise cycles, stationary or recumbent cycles, swimming, exercise videos, and exercise classes. The selection of an appropriate mode of aerobic exercise should be made by individuals based on preferences, access to equipment, time constraints, and physical impairments. In a randomized controlled trial involving women who were overweight, having access to exercise equipment at home was associated with better exercise adherence and weight loss at 18 months when compared with women without home exercise equipment [30]. Walking can be accomplished indoors at a local mall or on a treadmill or outdoors around a neighborhood or at a local track. Pedometers can be useful to monitor activity levels and to improve compliance. Based on available evidence in the literature, it has been proposed that healthy individuals need to accrue 10,000 or more steps a day to be classiﬁed as “active” [31]. The America on the Move (AOM) Foundation is a nonproﬁt organization that has established a free pedometer-based program on the Internet as a national initiative to improve health and the quality of life. Members establish a baseline step count and aim to increase their daily steps by 2000 per day toward a long-term goal of 10,000 or more. The website allows members to map their progress weekly and offers information, support, and dietary tips to enhance success. Home cycle units are a relatively inexpensive and convenient aerobic option and impart minimal stress to the joints. Recumbent cycles are more expensive but provide a comfortable alternative to upright cycles. Swimming or aquatic therapy is an excellent alternative for individuals with arthritis.

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TABLE 17.2 Example of an Aerobic Exercise Prescription for Weight Loss Phase Initial Improvement Maintenance

Weeks

Duration (Minutes)

Frequency (Times/Week)

Intensity (% of Maximum Heart Rate)

Time (Optional)

1–4 5–24 25+

15–30 30–40 30–60

3–4 4–5 5–7

40–55 50–69 60–69

5- to 10-minute bouts 15- to 20-minute bouts Continuous

Indoor pools can be found by contacting local YMCAs, school districts, health clubs, or hotels for information about pool membership and class availability. Exercise classes (e.g., yoga, aquatic, aerobic, t’ai chi) provide a social and structured environment that may improve compliance for some. Videotapes (e.g., yoga, low-impact aerobics, dance, t’ai chi) are a convenient and inexpensive choice for those who prefer to exercise at home. Health clubs are an option, but individuals who are obese must be aware that exercise equipment such as treadmills, cycles, and elliptical trainers manufactured for the general public tend to have weight limits of 300 to 350 lb. Individuals who are severely obese may require specialized equipment to facilitate an increase in physical activity. Bariatric gait training systems, lift-and-transfer devices, tilt tables, walkers, and wheelchairs are available to meet the needs of these individuals.

THE ROLE OF DAILY PHYSICAL ACTIVITY IN WEIGHT MANAGEMENT Daily physical activity plays a fundamental role in energy balance, weight control, and overall health. New guidelines were issued by the National Academies Institute of Medicine in 2002 on exercise and nutrition that recommended that children and adults get a minimum of 1 hour of physical activity daily, twice the previous public health recommendation [32]. The new guidelines reﬂect the need for 1 hour of moderate-intensity physical activity to maintain a healthy weight and acknowledge that this activity can be accumulated in short bouts. This recommendation is derived from normative data of total daily energy expenditure in healthy adults with normal BMIs. Research indicates that, although signiﬁcant health beneﬁts can be obtained through participation in at least 2.5 hours of moderate-intensity physical activity or exercise per week, a gradual progression to 3.3 to 5 hours per week facilitates long-term maintenance of weight loss [27]. Individuals should establish realistic goals that allow adequate time to steadily progress to this recommended level of daily physical activity. The incorporation of “lifestyle” activity in a weight-loss regime can be an effective adjunct or alternative to more structured, continuous forms of exercise. Research demonstrates that intermittent, moderate-intensity physical activity is an appropriate means to achieve the recommended quantity of daily physical activity. A weight-loss program of diet with moderate-intensity lifestyle activity seems to offer similar health and weight-loss beneﬁts as a program of diet in conjunction with a structured aerobic exercise program [11,20,28]. Participation in a program of intermittent exercise or activity may appeal to individuals with time constraints or to those that dislike continuous exercise. A comparison of the effects of performing multiple 10-minute bouts of exercise throughout the day with a single, longer session in overweight subjects revealed greater adherence among those exercising in short bouts and no negative impact on long-term weight loss or ﬁtness [30,33]. Participation in moderate-intensity physical activities, such as those listed in Table 17.3, for at least 1 hour per day satisﬁes the National Academies Institute of Medicine guidelines. Individuals should be instructed to park in distant parking spaces, climb stairs whenever possible, get off the bus or subway a stop early and walk the remaining distance, walk during lunch breaks, perform

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TABLE 17.3 Examples of Moderate-Intensity Physical Activity Activity Swimming (leisurely) General health-club exercise Golf (pulling cart or carrying clubs) Mowing lawn (power mower) Home repair (painting) Mopping ﬂoors or washing windows Gardening (weeding and cultivating) Raking the lawn Brisk walking (3 to 4 mph) Cycling (<10 mph) Fishing (standing, casting) Yoga, t’ai chi, stretching Water aerobics Canoeing (leisurely) Childcare (bathing, feeding, dressing) Housecleaning

METs 6.0 5.5 5.0 4.5 4.5 4.5 4.5 4.0 4.0 4.0 4.0 4.0 4.0 3.5 3.5 3.5

Source: Data from Ainsworth, B.E. et al., Med. Sci. Sports Exerc., 25, 71, 1993.

more of their own household chores, and participate in more active leisure-time activities on a daily basis. Yardwork or housework, playing with children, or dancing can meet the Institute of Medicine’s recommendations if performed at an adequate intensity. The accumulation of physical activity in intermittent, short bouts has been shown to be an effective means to achieving an adequate activity level. The literature suggests that the accumulated amount of activity is far more important than the manner in which the activity is performed [28].

CONSIDERATIONS FOR SPECIAL POPULATIONS PEDIATRICS Obesity in children is growing at an alarming rate. Because overweight children are two times as likely to become obese adults, it is of the utmost importance to treat and prevent obesity in childhood [34]. The goal of intervention in this population is to promote good nutritional habits and increase daily physical activity and exercise to improve physical ﬁtness and increase energy expenditure. For children, the school system affords an additional means to provide education and institute programs to address the problem of obesity. Daily Activity Level and Exercise The U.S. Department of Health and Human Services recommends that children accumulate at least 60 minutes of moderate physical activity on most days of the week [35]. This is a goal that sedentary children can build up to gradually by incorporating small bouts of activity throughout the course of the day. Children who are overweight or obese need to strive toward a long-term goal of more than 60 minutes of physical activity most days of the week to facilitate or maintain weight loss. Children should progress to a level of intensity where they are working up a sweat. If questions arise regarding

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the structure of a program for a particular child, referral to an intervention program or physical therapist may be warranted. Children can participate in structured activities such as team sports, dance, martial arts, or swimming. If preferred, health-club memberships are options for older children (many clubs offer membership for children 12 and older), and some health clubs are developing programs targeted at children under 12 as a need and interest have been identiﬁed. Children should wait until adolescence to pursue resistance training as a mode of exercise. Resistance training should be limited to a maximum of two times per week and should target 8 to 10 major muscle groups. Children should limit sets of each exercise to 10 to 15 repetitions and strive for a perceived exertion rating of 12 to 14 (“somewhat hard”) [36]. The key is to choose an activity that the child enjoys and one that will allow them to feel good about themselves while participating. They should be cultivating interests that will allow them to maintain an improved level of ﬁtness into adulthood. It has been suggested that obese children are less active over the course of a day in moderate and vigorous activities when compared with nonobese children [37]. Television has been identiﬁed as a common sedentary activity that consumes hours of time each day for the average child. According to data collected during the NHANES 2003–2004 survey, the average time spent watching television for adolescents ages 12 to 17 is 4 hours a day; for children ages 6 to 11, it is 2 hours, 13 minutes a day [38]. A report by the Kaiser Foundation in 2004 indicated that other factors may be related to children’s media use that contribute to weight gain. Not only are children seated in front of the screen, but they also tend to snack while watching television. It was found that advertising related to food choices (e.g., candy, fast food, soda) has an additional inﬂuence beyond the sedentary act of watching television [39]. The American Academy of Pediatrics recommends limiting total screen time (which includes television, videotapes, video games, and computer games) to 1 to 2 hours a day [40]. Parents play a critical role in setting limits for children, as well as encouraging children to participate in activities that are not sedentary. Parents should provide active choices to their children such as going to a park or riding a bike, instead of choices that include sedentary activities. Parents can inﬂuence an overweight or obese child to increase overall energy expenditure by decreasing sedentary activities and enhancing accessibility to physically active alternatives. Parents must consider alternatives for their children as they look to change a child’s preferences. During a 2-year study of a family-based behavioral weight program, it was found that promoting a reduction in sedentary behaviors was as effective as targeting physical activity [41]. Physical activity can be made appealing to children in an endless number of ways. It is common for some children to participate in organized sports, but this must be an enjoyable option for them. If not, they can choose activities such as jumping rope, dancing, or general outdoor play. For the child who enjoys video games, physical activity can be incorporated into this pastime as well. Interactive dance mats are a great option; they plug into common game systems and allow children to set the level of difﬁculty, time, and mode of play. In addition, stationary cycles are available that plug into video game systems; these cycles allow interactive play, and physical activity is required to participate in the game. A child can play alone or compete against another player with either of these options. The American Physical Therapy Association has a list of tips for avoiding the obesity trap available online [42]. They suggest that parents set an example for their children by participating in physical activities with the child and becoming the child’s “exercise buddy.” Parents should plan active family activities, instead of simply trying to ﬁt exercise in when time allows. School-Based Intervention The school setting provides an additional opportunity to inﬂuence children’s daily activity. The percentage of public schools that provide daily physical education (PE) programs ranges from 17 to 22% at the elementary level; 22% of public schools offer PE only one day per week, and 43% of ﬁrst-grade classes and 34% of ﬁfth- and sixth-grade PE classes were found to be 30 minutes

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or less in duration [43]. The 2006 Youth Risk Behavior Surveillance Report by the Centers for Disease Control and Prevention (CDC) found that, as children reach high school, only 54.2% are enrolled in PE, and, of those participating in PE, only 20% are active for 20 minutes or longer [44]. The school system has the ability to engage students in more vigorous activities and provide additional exposure to activities that may be of interest. Healthy People 2010, an initiative by the CDC and President’s Council on Physical Fitness, includes a goal to increase the proportion of public and private schools requiring daily PE for all students to 50% [45]. The CDC publishes a pamphlet titled “Making a Difference at Your School” that offers 10 strategies for schools to utilize to aid in the battle against obesity in children and adolescents [46]. Recess is another prime opportunity for schools to offer activities that get children moving. Health education curricula in the schools can promote healthy lifestyles and instill health-conscious values in children at younger ages.

GERIATRICS The lack of physical activity is more common in the geriatric population than in any other age group and contributes to a loss of independence in later years of life [47]. The reduction in endurance and strength often attributed to aging is partly the result of reduced physical activity. Research has demonstrated that diet and exercise training improve physical function and ameliorate frailty in older adults who are obese [48]. It is recommended that exercise programs be instituted under the supervision of a qualiﬁed healthcare professional for elderly patients who are obese and have concomitant medical problems, with the long-term goal of a self-monitored, independent exercise regimen. Physical therapists are experts in developing appropriate exercise programs to address impairments and functional limitations in patients with cardiovascular, neurological, or musculoskeletal disorders. An assessment of strength, range of motion, function, balance, and endurance should be performed and an exercise program designed to address the deﬁcits found. Appropriately designed exercise programs can reduce the risk of falls and facilitate a more active lifestyle through improved mobility and function. Strength training is beneﬁcial for seniors as it prevents loss of bone mass and sarcopenia frequently observed in the elderly. Extension exercises are particularly important to consider for older adults to improve ﬂexibility due to their tendency to develop ﬂexed postures and tightness in hip ﬂexors, hamstrings, abdominal, and cervical muscles. To promote compliance and minimize the risk of medical complications, exercise intensity should start low and progress gradually to a moderate level based on tolerance and heart-rate parameters. It is recommended that a maximum heart rate be derived from a stress test when prescribing exercise intensity in this population due to the variability in peak heart rate seen in the elderly and their increased risk of underlying coronary artery disease [36]. It is also important to take into consideration the medications that older adults are taking when prescribing and monitoring an exercise program.

BARIATRIC SURGERY Bariatric surgery rates are increasing, especially since surgery was recognized as a weight-loss intervention by the National Institutes of Health for individuals who are morbidly obese (BMI of 40 or above) and have failed medical management [49]. Between 1990 and 1997, bariatric surgery rates more than doubled from 2.7 to 6.3 per 100,000 adults in the United States [50]. Little in the way of exercise guidelines can be found in the literature for pre- or postoperative intervention. Individuals who are morbidly obese generally have multiple comorbidities that may affect their ability to exercise. A study by Elkins et al. [51] that examined noncompliance after bariatric surgery found that 40% and 41% of the 100 subjects at 6 and 12 months, respectively, were not exercising. A New York State report, Focus on Overcoming Obesity, recommends participation in a preoperative exercise program for a few months prior to bariatric surgery [52]. The preoperative

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program at Northwest Kaiser Permanente includes the establishment of a 60- to 90-minute daily home exercise program to improve physical ﬁtness and prepare patients for the postoperative weight-loss program. They recommend walking for those who are able and water aerobics or “water walking” as a viable alternative. A bigger picture goal of the preoperative program strives for patients to ﬁnd activities they can sustain following surgery [53]. Immediately postop, patients are at risk for blood clots and pneumonia and should be encouraged to perform ankle pumps, deep breathing exercises, and ambulation as tolerated. In reviewing discharge instructions from various surgical programs, lifting objects greater than 15 to 20 lb is generally prohibited for 6 weeks following invasive surgery and 3 weeks following laparoscopic surgery. Upon discharge from the hospital, general recommendations include walking with a gradually increase in the time and distance walked. Speciﬁc recommendations vary greatly, with little attention being paid to the intensity of the exercise. Generally, patients need to ﬁnd an activity that they enjoy, one that is well tolerated and that they will engage in on a regular basis at a moderate intensity. No speciﬁc contraindications for exercise have been noted in the literature, except that individuals who undergo adjustable gastric banding should avoid the use of resisted trunk ﬂexion exercise equipment due to a report that a port connection had become dislodged in one patient following this type of exercise [54].

CONSIDERATIONS FOR SPECIFIC MEDICAL CONDITIONS (DIABETES, HYPERTENSION, OSTEOARTHRITIS) Initiating an exercise program can attenuate some of the health risks associated with diabetes, hypertension, and osteoarthritis. Due to the common comorbidities associated with obesity, however, some precautions should be considered when prescribing exercise. For the person with diabetes who is obese, exercise is contraindicated when blood glucose is over 300 mg/dL or greater than 240 mg/dL with urinary ketone bodies. At the initiation of an exercise program, blood glucose should be monitored before, during, and after activity if insulin or oral medications have been prescribed. Exercise has an insulin-like effect and may lead to exercise-induced hypoglycemia. A carbohydrate snack may be needed either before or during exercise. It is important to review the signs of hypoglycemia (dizziness, light-headedness, confusion, anxiety) with the individual. Exercise-induced hypoglycemia can occur up to 4 to 6 hours after the cessation of exercise. Exercise should be planned for early to midday, avoiding the evening due to an increased risk of nocturnal hypoglycemia. As the exercise program progresses, insulin needs may change; therefore, close monitoring and followup with a physician are important. People with diabetes are at risk for autonomic neuropathies associated with silent heart ischemia or a blunted heart-rate response to exercise. It is important that heart rate monitoring be performed in conjunction with a rating of perceived exertion scale to determine a safe exercise program intensity level [55]. Hypertension is another common comorbidity. Exercise is contraindicated if resting systolic blood pressure is greater than 200 mmHg or diastolic is greater than 115 mmHg. For persons on alpha-1, alpha-2, or calcium channel blockers or vasodilators, the risk of post-exertion hypotension exists, and the cool-down phase of the exercise program must be strictly adhered to [55]. A third common comorbidity is lower-extremity osteoarthritis. Public health records from 1971 and 2002 reveal an increase from 3% to 18% in the incidence of arthritis due to obesity in the baby boomer population [56]. Non-weight-bearing exercises may be best tolerated by this group. Stationary exercise cycles and water walking or water aerobics are alternatives that place less stress on hips, knees, and ankles. If exercise produces pain, compliance will be diminished. A recent study found that children who were overweight had a higher incidence of bone fractures, joint and muscle pain, and abnormal knee-joint alignment [57]. This may contribute to an increase in sedentary behaviors, requiring a recommendation for non-weight-bearing exercise and physical activity to counteract this potential.

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INFORMATION AVAILABLE ONLINE A multitude of information is available to consumers with online access. Below is a list and summary of Internet sites that individuals can refer to for education and to pick up tips, strategies, and structure to improve their activity levels, overall ﬁtness, and nutrition: •

•

• •

•

• • • •

www.shapeup.org — The mission of this not-for-proﬁt organization is to increase awareness of obesity as a health issue by providing evidence-based information. They offer a 10-step program for weight loss and strategies to increase daily activity. They advocate 10,000 steps/day. www.americaonthemove.org — America on the Move is a national initiative dedicated to improving health and quality of life through healthy eating and increased activity. Participation can be on an individual basis or as part of a larger group afﬁliation. www.americanheart.org — The American Heart Association provides tips for parents and activities for children. www.mypyramid.gov — The U.S. Department of Agriculture promotes the newest food pyramid as a guide for healthy eating and includes sections for children and health professionals. www.nichd.nih.gov/msy — Media Smart Youth is a health promotion program instituted by the NIH to help children 11 to 13 years old recognize how media inﬂuences nutrition and activity choices. www.nhlbi.nih.gov/health/public/heart/obesity/wecan — The NIH’s We Can! site provides practical tools for parents of children 8 to 13 years old to assist in healthy weight management. www.cdc.gov/nccdphp/dnpa/physical/recommendations/older_adults.htm — The CDC offers recommendations for physical activity for older adults. www.niapublications.org/engagepages/exercise.asp — Provides access to the free pamphlet Exercise: Getting Fit for Life from the National Institute on Aging. www.nia.nih.gov/HealthInformation/Publications/ExerciseGuide/ — The National Institute on Aging provides free access to their comprehensive book, Exercise: A Guide from the National Institute on Aging.

SUMMARY Exercise and physical activity are fundamental components of a comprehensive weight-loss program. The most successful exercise programs are those of low to moderate intensity and long duration that are performed frequently. The cumulative effect of exercise over time is substantial, and research has demonstrated a clear dose–response relationship between the amount of weekly exercise performed and the amount of weight lost in overweight individuals [26]. Emphasizing long-term lifestyle changes in diet and physical activity and establishing modest weight-loss goals are key factors in successful weight-loss programs. Adherence to daily physical activity and exercise are the greatest determinants in weight maintenance following weight loss. Healthcare professionals need to be aware of the unique challenges posed by pediatric, geriatric, and post-bariatric surgery patients and medically complex individuals when counseling for weight management.

THOUGHTS ON PREVENTION Research indicates that a relatively small percentage of people who lose weight are successful in maintaining their weight loss. It is important to implement strategies to prevent obesity in children and adults who are overweight. It is essential that healthcare professionals consistently intervene when dealing with overweight individuals to prevent weight progression to the level of obesity. Successful long-term weight control requires that overweight or obese individuals value physical

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activity and exercise as components of a healthy lifestyle. To effectively address the obesity epidemic in the United States, it will be necessary to institute public policy that promotes education, prevention, and wellness.

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and Dietary 18 Nutritional Approaches for Weight Management: An Overview Sanjiv Agarwal CONTENTS Introduction ....................................................................................................................................233 Factors Contributing to Obesity.....................................................................................................233 Hunger, Satiety, and Food Intake ..................................................................................................234 Food Factors Related to Satiety.....................................................................................................234 Novel Satiety Ingredients and Functional Foods ..........................................................................235 Functional Foods Affecting Energy Metabolism ..........................................................................235 Botanicals and Dietary Supplements for Weight Management ....................................................235 Conclusion......................................................................................................................................236 References ......................................................................................................................................236

INTRODUCTION Obesity is a condition of excess body fat. It is one of the most rapidly evolving public health issues in the recent years. According to the Centers for Disease Control and Prevention (CDC) [1,2] over two thirds of Americans are overweight, one third of Americans are obese, and one sixth of American children and adolescents are considered overweight or obese. The reported prevalence of obesity among adolescents has nearly tripled in the past two decades [1,2]. Obesity is not only a cosmetic issue but is also associated with several comorbidities and comortalities, including cardiovascular disease, type 2 diabetes, many forms of cancer, gallbladder disease, and osteoarthritis [3,4]. It is estimated that ≈400,000 deaths each year in the United States are associated with obesity [5].

FACTORS CONTRIBUTING TO OBESITY Obesity is a multifactorial health problem arising from biological, behavioral, and environmental sources [6–8]. Demographic factors (i.e., family history, race or ethnicity. and gender) are, to some extent, determinant of individual’s susceptibility to obesity [6–8]. However, the preponderance of data indicates that behavioral and environmental inﬂuences play a key role in obesity [6–8]. It is believed that today environmental factors, such as the availability, convenience, and nature of food and behaviors such as decreased physical activity and increased sedentary lifestyle, have contributed to this issue. Indeed, the energy imbalance involving increased energy intake (eating too many calories), decreased energy expenditure (not enough physical activity), or a combination of both leads to weight gain and obesity [9]. This chapter describes some of the nutritional and dietary factors, metabolically active agents, and functional food ingredients that are related to addressing the energy imbalance issue.

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TABLE 18.1 Common Hormone/Peptide Signals That Control Satiety and Hunger Satiety Signals

Stimulus

Cholecystokinin (CCK) Glucagon-like-peptide 1 (GLP-1) Peptide YY (PYY)

Fat or protein Carbohydrate or protein Meal

Ghrelin Leptin

Fasting —

Site of Production Duodenum Ileum Gut endocrine cells Gut Adipocytes

Effects Decreases food intake by controlling the meal size Decreases food intake, affects mobility of nutrients from stomach to intestine, and stimulates insulin secretion Decreases food intake, inhibits gut motility and gastric emptying Increases food intake Decreases food intake only during energy imbalance

HUNGER, SATIETY, AND FOOD INTAKE Food consumption in humans is a complex process regulated by a number of factors including environmental cues, sensory stimulus, social pressures, appetite, and feelings of hunger. Physiologically, the regulation of food intake depends on direct and feedback signals from gut and adipose tissue to the hypothalamus in the brain containing the hunger and satiety centers [10,11]. Food intake is generally in distinct bouts or episodes (i.e., meals and snacks). The meals are eaten until full (satiated) and then the next meal is not eaten for a certain time (satiety). The gastrointestinal tract, in response to meals, generates a variety of biochemical peptide signals or satiety factors that accumulate during eating and contribute to meal termination. These signals are transmitted to the central nervous system and are manifested as a behavioral modiﬁcation of feeding [11–14]. Some peptide signals (anorexigenic signals) decrease food intake as they promote satiety, whereas other peptides signals (orexigenic signals) increase food intake as they induce appetite. Table 18.1 lists various peptide- and hormone-related signals that are generated in the gut and inﬂuence feelings of satiety and hunger.

FOOD FACTORS RELATED TO SATIETY Physical characteristics as well as the macronutrient composition of a meal are important determinants of its satiating effects. Studies have shown that increasing the volume of a food (by adding water or air) can improve satiety and signiﬁcantly reduce the calorie intake at the next meal [15,16]. The energy density (ED) of a diet or caloric value of a food per unit weight or volume also plays a key role in satiety. Dietary ED depends mainly on the water content of the foods eaten. As a rule, high-ED foods are more palatable but less satiating, whereas low-ED foods are more satiating but less palatable [17]. Lowering the energy density of a diet may also increase the ﬁber content of the diet, especially if ﬁber-rich fruits and vegetables or whole grains are added. Studies have demonstrated that eating low-energy-dense foods (such as fruits, vegetables, and soups) maintains satiety while reducing energy intake [18]. Some data suggest that solid diets are more satiating than semisolid or liquid diets, and more viscous liquid foods are more satiating than less viscous foods [19]. The macronutrient composition of foods also appears to be a determinant of satiety [20]. Traditionally, fats are considered to be most satiating; however, fats are most energy dense. In isocaloric preload studies, where subjects are provided with a fat-, protein-, or carbohydratebased preload food and subsequently tracked for satiety over a period of time, fat was found to be the least satiating macronutrient [21]. A strong body of evidence suggests that on a relative scale proteins and ﬁber are more satiating than carbohydrates and fat [22–26].

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NOVEL SATIETY INGREDIENTS AND FUNCTIONAL FOODS Several functional food ingredients are metabolically active and help improve satiety. Many of these novel ingredients have been known to function by activating the cholecystokinin (CCK) mechanism. Satíse® (Kemin Industries, Inc.) is a protein extract from vegetables called “P12” and is claimed to stimulate CCK [27]. Similarly, Satietrol® (Paciﬁc Health Laboratories, Inc.) is a milkderived peptide (glycomacropeptide) and is also claimed to stimulate CCK and thus improve satiety [28]. Satietrol also contains potato and guar ﬁbers, as well as alfalfa, to help maintain the higher levels of CCK longer. Olibra™ is a novel fat emulsion containing fractionated palm oil and fractionated oat oil in water; it has been shown to have satiating effects via a fat-induced ileal brake mechanism [29].

FUNCTIONAL FOODS AFFECTING ENERGY METABOLISM Many functional foods have been shown to alter energy metabolism or fat partitioning by inﬂuencing the substrate utilization or thermogenesis [30,31]. These may not inﬂuence the absorption of the nutrients, but they act post-absorptively and increase the oxidation rate: •

•

•

•

Tea — Tea is a widely consumed beverage made from the leaves and buds of the plant Camellia sinensis. The three types of tea are nonfermented green tea, semifermented oolong tea, and fermented black tea. Tea contains high amounts of antioxidant polyphenols (catechins, theaﬂavins, and thearubigins) [32]. Green tea and oolong tea are particularly rich in catechins and have been shown to increase fat oxidation in clinical and animal studies. A catechin (EGCG) and the caffeine found in tea are implicated in the thermogenic effects of tea [33,34]. Medium-chain triglycerides (MCTs) — These are naturally occurring or commercially prepared dietary fats containing 6- to 12-carbon fatty acid chains. Like long-chain triglycerides (LCTs), MCTs are also digested to their medium-chain fatty acids (MCFs) and absorbed in the gastrointestinal tract; however, they are not repackaged as MCTs in chylomicrons for transportation through peripheral circulation like the LCTs are. Medium-chain fatty acids from MCTs are directly transported via the portal system to the liver for oxidation. MCTs therefore bypass the adipose tissue and do not get deposited into adipose tissue store [35,36]. Diacylglycerols (DAGs) — These are naturally occurring as minor components (1 to 10%) of oils. DAGs are glycerides in which the glycerol molecule is esteriﬁed to only two fatty-acid chains. Similar to triacylglycerol (TAG), DAGs are also absorbed in the gastrointestinal tract; however, they are transported via the portal system to the liver for oxidation and they bypass the adipose tissue. A few human clinical studies have shown that the replacement of TAG by DAG leads to signiﬁcant weight reduction [37–39]. Conjugated linoleic acid (CLA) — CLA is a group of naturally occurring trans-isomers of linoleic acid. The main dietary sources are dairy products and beef. In animal studies, CLA has been found to reduce body fat, possibly through increased fat oxidation and decreased fat deposition in adipose tissue [40]; however, the human data available to support the efﬁcacy of CLA in weight management are inconsistent [40–42].

BOTANICALS AND DIETARY SUPPLEMENTS FOR WEIGHT MANAGEMENT Several dietary supplements and herbal products are currently being promoted for weight management [43–46]. The potential biological mechanisms include increased energy expenditure, increased fat oxidation, decreased fat absorption, and increased satiety (Table 18.2). Concerns have been

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TABLE 18.2 List of Dietary Supplements Commonly Used for Weight Management and Their Proposed Mechanisms Dietary Supplement or Herbal

Proposed Mechanism

Ephedra, yerba maté, caffeine Psyllium, guar gum, hoodia, pinnothin (pine extract) Chitosan Green tea, Garcinia cambogia (hydroxycitric acid) Chromium picolinate, ginseng

Increase energy expenditure Increase satiety Inhibit fat absorption Increase fat oxidation Inﬂuence carbohydrate metabolism

Source: Data from Pittler and Ernst [43], Heber [45], and Lenz and Hamilton [46].

raised, however, regarding the efﬁcacy and safety of herbal products and dietary supplements promoted for weight management. The U.S. Food and Drug Administration (FDA) has taken regulatory actions against a number of dietary supplements. The scientiﬁc evidence is insufﬁcient or conﬂicting, and clinical data are necessary to ensure their safety and efﬁcacy.

CONCLUSION Obesity has become an important health issue in the recent years. Energy imbalance is an important etiological factor, and dietary and nutritional factors, functional food ingredients, and dietary supplements may help address this issue. Readers are advised, however, to be sure of the safety and efﬁcacy of functional food ingredients and dietary supplements before using them.

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Druce, M.R., Small, C.J., and Bloom, S.R., Minireview: gut peptides in regulating satiety, Endocrinology, 145, 2660–2665, 2004. Woods, S.C., Gastrointestinal satiety signals. 1. An overview of gastrointestinal signals that inﬂuence food intake, Am. J. Gastrointest. Liver Physiol., 286, G7–G13, 2004. Rolls, B.J., Bell, E.A., and Waugh, B.A., Increasing the volume of a food by incorporating air affects satiety in men, Am. J. Clin. Nutr., 72, 361–368, 2000. Rolls, B.J., Castellanos, V.H., Halford, J.C., Kilara, A., Panyam, D. et al., Volume of food consumed affects satiety in men, Am. J. Clin. Nutr., 67, 1170–1177, 1998. Drewnowski, A., Energy density, palatability, and satiety: implications for weight control, Nutr. Rev., 56, 347–353, 1998. Ello-Martin, J.A., Ledikwe, J.H., and Rolls, B.J., The inﬂuence of food portion size and energy density on energy intake: implications for weight management, Am. J. Clin. Nutr., 82, 236S–241S, 2005. Hulshof, T., De Graaf, C., and Weststrate, J.A., The effects of preloads varying in physical state and fat content on satiety and energy intake, Appetite, 21, 273–286, 1993. Kundrat, S., Satiety: why we feel full, Inform, 17, 200–202, 2006. Rolls, B.J., Carbohydrates, fats, and satiety, Am. J. Clin. Nutr., 61, 960S–967S, 1995. Pereira, M.A. and Ludwig, D.S., Dietary ﬁber and body-weight regulation: observations and mechanisms, Pediatr. Clin. North Am., 48, 969–980, 2001. Blundell, J.E. and MacDiarmid, J.I., Fat as a risk factor for overconsumption: satiation, satiety, and patterns of eating, J. Am. Diet. Assoc., 97, S63–S69, 1997. Howarth, N.C., Saltzman, E., and Roberts, S.B., Dietary ﬁber and weight regulation, Nutr. Rev., 59, 129–139, 2001. Anderson, G.H. and Moore, S.E., Dietary proteins in the regulation of food intake and body weight in humans, J. Nutr., 134, 974S–979S, 2004. Halton, T.L. and Hu, F.B., The effects of high protein diets on thermogenesis, satiety and weight loss: a critical review, J. Am. Coll. Nutr., 23, 373–385, 2004. What Is Satíse®?, Kemin Industries, Inc., http://www.satise.ca/whatis. Satietrol®: The Appetite Control Protein, Paciﬁc Health Laboratories, Inc., http://www.satietrol.com/ pages/appetite_control.html. Burns, A.A., Livingstone, M.B., Welch, R.W., Dunne, A., and Rowland, I.R., Dose–response effects of a novel fat emulsion (Olibra) on energy and macronutrient intakes up to 36 h post-consumption, Eur. J. Clin. Nutr., 56, 368–377, 2002. St.-Onge, M.P., Dietary fats, teas, dairy, and nuts: potential functional foods for weight control?, Am. J. Clin. Nutr., 81, 7–15, 2005. Kovacs, E.M. and Mela, D.J., Metabolically active functional food ingredients for weight control, Obes. Rev., 7, 59–78, 2006. McKay, D.L. and Blumberg, J.B., The role of tea in human health: an update, J. Am. Coll. Nutr., 21, 1–13, 2002. Rumpler, W., Seale, J., Clevidence, B., Judd, J., Wiley, E. et al., Oolong tea increases metabolic rate and fat oxidation in men, J. Nutr., 131, 2848–2852, 2001. Dulloo, A.G., Duret, C., Rohrer, D., Girardier, L., Mensi, N. et al., Efﬁcacy of a green tea extract rich in catechin polyphenols and caffeine in increasing 24-h energy expenditure and fat oxidation in humans, Am. J. Clin. Nutr., 70, 1040–1045, 1999. Babayan, V.K., Medium-chain triglycerides and structured lipids, Lipids, 22, 417–420, 1997. St.-Onge, M.P., Ross, R., Parsons, W.D., and Jones, P.J., Medium-chain triglycerides increase energy expenditure and decrease adiposity in overweight men, Obes. Res., 11, 395–402, 2003. Katsuragi, Y., Yasukawa, T., Matsuo, N., Flickinger, B.D., Tokimitsu, I., and Matlock, M.G., Eds., Diacylglycerol Oil, AOCS Press, Champaign, IL, 2004. Nagao, T., Watanabe, H., Goto, N., Onizawa, K., Taguchi, H. et al., Dietary diacylglycerol suppresses accumulation of body fat compared to triacylglycerol in men in a double-blind controlled trial, J. Nutr., 130, 792–797, 2000. Rudkowska, I., Roynette, C.E., Demonty, I., Vanstone, C.A., Jew, S., and Jones, P.J., Diacylglycerol: efﬁcacy and mechanism of action of an anti-obesity agent, Obes. Res., 13, 1864–1876, 2005. DeLany, J.P. and West, D.B., Changes in body composition with conjugated linoleic acid, J. Am. Coll. Nutr., 19, 487S–493S, 2000.

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Differences 19 Gender in Body Fat Utilization During Weight Gain, Loss, or Maintenance Gabriel Keith Harris and David J. Baer CONTENTS Introduction ....................................................................................................................................239 Fat Distribution ..............................................................................................................................240 Metabolic Rate ...............................................................................................................................240 Food Intake.....................................................................................................................................240 Exercise Effects..............................................................................................................................241 Conclusions ....................................................................................................................................242 References ......................................................................................................................................243

INTRODUCTION During the late nineteenth and throughout the twentieth century, numerous experiments were conducted to determine the effects of diet on health in humans. Notable examples include the work of Goldberg [2], who studied the effects of diet on pellagra in prisoners, and of Keys [1], who examined the effects of starvation and refeeding on conscientious objectors during the Second World War. Without delving into the ethical dilemmas associated with those studies, one thing is clear: The majority of these early studies were conducted on men, but the results were often extrapolated to both men and women. Now, at the beginning of the twenty-ﬁrst century, it is becoming increasingly apparent that men and women differ considerably in their response to diet, physical activity, and other factors that may affect changes in body fat. The increasing prevalence of obesity throughout the world is often referred to as an “obesity epidemic” [3]. One example of this increase in obesity can be found in the 1999–2000 National Health and Nutrition Examination Survey (NHANES), which reported that an estimated 30.5% of U.S. citizens were obese, as deﬁned by excessive weight for a given height, compared to 22.9% from the 1988–1994 survey [4]. Regardless of the source of the data, it appears that an increasing proportion of the world’s population is now overweight and overfat. The primary concern is not obesity itself but the increased disease risk associated with it. Although the problem of obesity seems to be an exceedingly simple one to solve (do not consume more calories than necessary for proper development or weight maintenance), controlling obesity has proven to be exceedingly difﬁcult. One facet of this problem that has received little attention is the role that gender plays in obesity and fat gain or loss. The purpose of this chapter is to outline the known differences in fat gain, loss, and maintenance between men and women and, perhaps more importantly, highlight how little is known about the subject. To this end, we discuss the reported effects of gender differences on body fat distribution, fat use as an energy source, and exercise-related fat loss. 239

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FAT DISTRIBUTION One of the most obvious distinctions between men and women is the difference in body fat distribution. Although there is an equally obvious continuum of fat distribution among the genders, men tend to store fat in the abdominal region to a greater degree than women. Conversely, women tend to store fat in the gluteal and femoral (thigh) areas. Less obvious is that men have a greater tendency to store visceral (internal, organ-associated, abdominal) fat, whereas women tend to store fat in subcutaneous tissues (between skin and muscle). In both genders, visceral fat as a percentage of total body fat tends to increase with age, but this effect is especially apparent in men [5]. Gender-based differences in fat distribution appear to be due, at least partially, to the tendency to store fat in or recruit stored fat from distinct areas; for example, men tend to recruit more free fatty acids from the thigh region than women during weight loss and exercise. Under the same conditions, total body fat mobilization from upper body stores appears to be similar between genders, although men tend to recruit a larger percentage of that fat from subcutaneous tissue [6]. The net result is a protection of subcutaneous lower body fat in women. This effect is clearly evident in male and female bodybuilders, where body fat loss is essential to display maximum muscularity. Male competitors tend to display an equal degree of upper and lower body leanness, but female competitors tend to retain more lower body fat [7]. A study comparing lipolysis (conversion of stored triglycerides to glycerol and fatty acids) rates in the subcutaneous abdominal fat of morbidly obese men and women undergoing bariatric surgery found that lipolysis rates were only elevated in women. This ﬁnding may indicate that women have an increased resistance to the accumulation of abdominal fat relative to men, even in cases of extreme obesity [8]. In summary, gender-speciﬁc differences in body fat storage and mobilization tend to favor the preservation of lower body and subcutaneous fat in women and of abdominal and visceral fat in men.

METABOLIC RATE In addition to differences in fat distribution, men and women also differ with respect to basal metabolic rate and the use of macronutrients as energy sources. Basal metabolic rate is primarily inﬂuenced by fat free mass [9]. Because men tend to possess more muscle mass both in absolute terms and as a percentage of body weight, they also tend to burn more calories at rest than women. Women appear to use stored body fat differently than men, both at rest and during exercise. At rest and in a fed state, women tend to use a smaller percentage of fat as an energy source than men. Conversely, during exercise, women have been reported to use twice as much fat as a fuel source than men [10,11]. In the fasted state, men and women use fat similarly, although women appear to switch more quickly from the use of glucose to fat as an energy source [12]. Because energy burned at rest (basal metabolic rate) represents the majority of total daily energy expenditure in Western societies, the overall effect of these gender differences on metabolic rate and macronutrient usage appears to be a tendency toward body fat conservation in women [9]. With that said, the fact that the “obesity epidemic” is not restricted to women indicates that a great number of both men and women in many countries around the world are consuming an excess of energy, not exercising enough, or both.

FOOD INTAKE In addition to gender differences in the use of stored body fat as an energy source, men and women have also been reported to differ with regard to responses to food consumption in general. Not surprisingly, food intake tends to reduce the use of stored fat as an energy source in both genders. This feeding effect is more pronounced in women than in men, because men continue to use small amounts of stored fat as an energy source even in a fed state. The result of this gender difference is a greater tendency to maintain established fat stores in women [13]. In keeping with previously

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mentioned differences in body fat distribution, men tend to store a higher percentage of dietary fatty acids in visceral tissue after meals, whereas women tend to store relatively larger percentages of dietary fat in subcutaneous tissues [6]. Overconsumption of food would thus appear to favor greater total body fat gains in women, primarily in subcutaneous tissues, and a greater degree of visceral fat gain in men than in women. With regard to the effects of speciﬁc macronutrients, a recent study reported that the ratios of dietary carbohydrate and fat have been reported to be related to body fat levels in women, but not men. In women, carbohydrate intake was reported to be negatively associated with percent body fat, while fat intake was reported to have a positive association with body fat percentage. The reasons for the association between fatty food consumption and higher percent body fat in women are not entirely clear. One reason suggested for this is the high-energy density of fatty foods, making overindulgence a stronger possibility [14]. In a separate study, carbohydrate intake was found to induce higher peak glucose levels and higher insulin responses in women [15]. The signiﬁcance of this ﬁnding with regard to body fat stores is unclear, although one role of insulin is to facilitate fat storage. Although the data are limited, they appear to suggest that gender-speciﬁc differences in body fat storage and utilization is a function not only of total calories consumed but also of macronutrient ratios.

EXERCISE EFFECTS Traditional wisdom would say that the best way to effect changes in body fat is a combination of calorie control or restriction combined with exercise, regardless of gender. In theory, exercise should generate a energy deﬁcit and result in weight and fat loss, but, in fact, the association between physical activity and body fat is not as straightforward as one might expect. For men, increased physical activity alone does appear to be an effective means of weight loss or maintenance [14,16]. Exercise alone appears to be less effective as a means of fat reduction for women than it does for men. At least three studies have examined the role of gender on fat loss in men and women. One study reported no effect of physical activity on body fat percent in women [14]. A second study found that exercise produced signiﬁcant fat losses in men, but not women [17]. A third study found that exercise was effective for body fat maintenance, but not fat loss, in women [18]. This apparent gender difference in the effectiveness of exercise as a tool for fat loss is one of the more robust ﬁndings in this body of literature, reﬂecting the lack of data on gender effects on fat loss [19]. It should be pointed out that exercise has many beneﬁts aside from weight loss or maintenance and that both men and women beneﬁt from regular exercise. At least two proposed mechanisms could account for the observed lack of effect of exercise on body fat stores in women. The ﬁrst is a compensatory increase in calorie intake in response to increased energy expenditure in women, but not in men [20,21]. The only study that measured actual food intake did not ﬁnd any compensation effect in women, however [14]. In this study, total energy expenditure (resting energy expenditure combined with energy expended during physical activity) was positively associated with body fat in women. The same study reported that physical activity was negatively associated with body fat in men only. Taken together, these studies raise several interesting questions. If women do not compensate for energy used during exercise, why does it appear to be less effective as a fat loss tool? Perhaps it is because voluntary exercise represents a relatively small fraction of total energy expenditure relative to basal metabolic rate. Second, why might total energy expenditure be positively associated with body fat in women? Is this counterintuitive ﬁnding simply reﬂective of the increased energy expenditure associated with weight gain? The current literature provides no obvious answers to these questions. Further studies are needed to determine the role of exercise on fat loss in women. A second proposed mechanism for gender differences in fat use and storage is the differential activation of adrenergic receptors in men vs. women. Exercise causes the release of the catecholamines epinephrine and norepinephrine, which interact with adrenergic receptors. In women, only beta-adrenergic receptors, which promote fat mobilization, are activated. In contrast, both

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Re

st

Fat

Re

st

Food Intake

Food Intake

Ex

se

ci er

Ex

er

Storage

cis

e

FIGURE 19.1 Gender-speciﬁc effects of activity level and food intake on fat storage and utilization. The left side of the ﬁgure illustrates the predominating effects in men, and the right side shows the predominating effects in women under the same conditions. The arrows indicates the movement of fat into or out of storage, and their size approximates the magnitude of the effect.

the pro-lipolysis beta receptors and the anti-lipolysis alpha-adrenergic receptors are activated in men [11,22]. These gender differences appear to be due to the relative amounts of epinephrine and norepinephrine released during exercise. Exercise-induced epinephrine (which has a greater afﬁnity for the anti-lipolytic alpha-adrenergic receptors) levels are twice as high in men as in women. This difference may be one reason why women, more so than men, use fat as an energy source during exercise. Even if exercise was deﬁnitively shown to be without effect for body fat loss in women, this would not negate the fact that achieving a negative energy balance will result in body weight or fat loss for both genders. It does indicate that weight loss may be more difﬁcult for women, even when energy expenditure is increased through exercise, via as yet to be deﬁned mechanisms.

CONCLUSIONS It is important to emphasize that the ﬁndings presented in this chapter are based on limited data and, as such, require further study. Figure 19.1 provides an overview of the gender-speciﬁc differences in fat utilization under various physical conditions. There are many unanswered questions with regard to the effects of gender on fat metabolism. These include the interaction of gender with long-term fat loss and with weight cycling. The majority of fat and weight loss studies are short term in nature (less than 1 year in duration). This fact raises the possibility that the health effects observed are a result of the process of weight loss and are not reﬂective of the effects of long-term weight loss itself [8]. The effects of weight cycling (repeated gain and loss of body weight and or body fat) on body fat percentage are unclear and are complicated by the fact that weight cycling in men is often related to “making weight” in athletics, but in women it is most often a result of repetitive dieting related to self-esteem and body image [23,24]. Some studies have reported a decreased basal metabolic rate across genders as a result of weight cycling, but this result is by no means an established fact. Based on the existing body of literature, the following conclusions may be drawn with regard to differences in body fat changes between men and women: • • •

Women have lower basal metabolic rates than men due to a lower fat free mass. Women preferentially store subcutaneous fat; men preferentially store visceral fat. Visceral fat is more easily gained or lost in men than in women.

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During fat loss, women preferentially retain lower body fat; men mobilize upper and lower body fat more equally but tend to retain abdominal fat. Women more readily use fat as an energy source during exercise; men more readily use fat as an energy source at rest. Exercise appears to be more effective for weight loss and maintenance in men than in women, for reasons that are not clear.

REFERENCES [1] [2] [3] [4] [5] [6] [7]

[8]

[9]

[10]

[11] [12] [13] [14] [15]

[16] [17] [18]

[19] [20]

Kalm, L.M. and Semba, R.D., They starved so that others be better fed: remembering Ancel Keys and the Minnesota experiment, J. Nutr., 135, 1347, 2005. Spies, T.D., Observations on the treatment of pellagra, J. Clin. Invest., 13, 807, 1934. James, P.T. et al., The worldwide obesity epidemic, Obes. Res., 9(Suppl. 4), 228S, 2001. Flegal, K.M. et al., Prevalence and trends in obesity among U.S. adults, 1999–2000. JAMA, 288, 1723, 2002. Bouchard, C., Despres, J.P., and Mauriege, P., Genetic and nongenetic determinants of regional fat distribution, Endocr. Rev., 14, 72, 1993. Blaak, E., Gender differences in fat metabolism, Curr. Opin. Clin. Nutr. Metab. Care, 4, 499, 2001. Sandoval, W.M., Heyward, V.H., and Lyons, T.M., Comparison of body composition, exercise and nutritional proﬁles of female and male body builders at competition, J. Sports Med. Phys. Fitness, 29, 63, 1989. Lofgren, P. et al., Major gender differences in the lipolytic capacity of abdominal subcutaneous fat cells in obesity observed before and after long-term weight reduction, J. Clin. Endocrinol. Metab., 87, 764, 2002. Johnstone, A.M. et al., Factors inﬂuencing variation in basal metabolic rate include fat-free mass, fat mass, age, and circulating thyroxine but not sex, circulating leptin, or triiodothyronine, Am. J. Clin. Nutr., 82, 941, 2005. Mittendorfer, B., Horowitz, J.F., and Klein, S., Effect of gender on lipid kinetics during endurance exercise of moderate intensity in untrained subjects, Am. J. Physiol. Endocrinol. Metab., 283, E58, 2002. Hellstrom, L., Blaak, E., and Hagstrom-Toft, E., Gender differences in adrenergic regulation of lipid mobilization during exercise, Int. J. Sports Med., 17, 439, 1996. Mittendorfer, B., Horowitz, J.F., and Klein, S., Gender differences in lipid and glucose kinetics during short-term fasting, Am. J. Physiol. Endocrinol. Metab., 281, E1333, 2001. Jensen, M.D., Gender differences in regional fatty acid metabolism before and after meal ingestion, J. Clin. Invest., 96, 2297, 1995. Paul, D.R., Novotny, J.A., and Rumpler, W.V., Effects of the interaction of sex and food intake on the relation between energy expenditure and body composition, Am. J. Clin. Nutr., 79, 385, 2004. Robertson, M.D., Livesey, G., and Mathers, J.C., Quantitative kinetics of glucose appearance and disposal following a 13C-labelled starch-rich meal: comparison of male and female subjects, Br. J. Nutr., 87, 569, 2002. Westerterp, K.R. and Goran, M.I., Relationship between physical activity related energy expenditure and body composition: a gender difference, Int. J. Obes. Relat. Metab. Disord., 21, 184, 1997. Westerterp, K.R. et al., Long-term effect of physical activity on energy balance and body composition, Br. J. Nutr., 68, 21, 1992. Donnelly, J.E. et al., Effects of a 16-month randomized controlled exercise trial on body weight and composition in young, overweight men and women: the midwest exercise trial, Arch. Intern. Med., 163, 1343, 2003. Donnelly, J.E. and Smith, B.K., Is exercise effective for weight loss with ad libitum diet? Energy balance, compensation, and gender differences, Exerc. Sport Sci. Rev., 33, 169, 2005. Stubbs, R.J. et al., The effect of graded levels of exercise on energy intake and balance in free-living women, Int. J. Obes. Relat. Metab. Disord., 26, 866, 2002.

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Stubbs, R.J. et al., The effect of graded levels of exercise on energy intake and balance in free-living men, consuming their normal diet, Eur. J. Clin. Nutr., 56, 129, 2002. [22] Lafontan, M., Berlan, M., and Villeneuve, A., Preponderance of alpha 2- over beta 1-adrenergic receptor sites in human fat cells is not predictive of the lipolytic effect of physiological catecholamines, J. Lipid Res., 24, 429, 1983. [23] Saarni, S.E. et al., Weight cycling of athletes and subsequent weight gain in middleage, Int. J. Obes. (Lond.), March 28, 2006 (Epub ahead of print). [24] Devlin, M.J. et al., Metabolic abnormalities in bulimia nervosa, Arch. Gen. Psychiatry, 47, 144, 1990.

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Body Weight, 20 Appetite, Health Implications of a Low-Glycemic-Load Diet Stacey J. Bell, Wendy Van Ausdal, and Greg Grochoski CONTENTS Introduction ....................................................................................................................................245 Deﬁnition of Terms ........................................................................................................................246 Glycemic Index.......................................................................................................................246 Glycemic Load........................................................................................................................248 Glycemic Load and the American Diet..................................................................................248 Physiological Effects of a Low-Glycemic-Load Diet ...................................................................249 Early Postprandial Period .......................................................................................................249 Middle Postprandial Period ....................................................................................................249 Late Postprandial Period.........................................................................................................249 Effect of Glycemic Load on Hunger.............................................................................................250 Glycemic Load and Weight Loss ..................................................................................................251 Favorable Studies....................................................................................................................251 Unfavorable Studies................................................................................................................253 Glycemic Load and Disease ..........................................................................................................254 Meta-Analyses ........................................................................................................................254 Cardiovascular Disease ...........................................................................................................255 Epidemiological Data ......................................................................................................255 Short-Term Studies ..........................................................................................................255 Type 2 Diabetes ......................................................................................................................256 Epidemiological Data ......................................................................................................257 Short-Term Study.............................................................................................................258 Other Conditions.....................................................................................................................258 How to Eat a Low-Glycemic-Load Diet .......................................................................................259 References ......................................................................................................................................260

INTRODUCTION Overweight and obesity pose a major public health concern in terms of increased mortality and morbidity, which is associated with increased risk of cardiovascular disease (CVD), type 2 diabetes mellitus, and osteoarthritis. Compared to normal-weight individuals, obesity (body mass index [BMI] ≥ 30 kg/m2) was associated with over 110,000 excess deaths per year [22]. Inspection of telomere length as a marker of aging showed that obesity corresponded to 8.8 years of aging; this was similar to smoking a pack of cigarettes a day for 40 years (7.4 years of aging) [64]. It has been postulated that only about a 10-calorie energy gap per day is the cause of obesity, so it would 245

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seem that it could be readily treated [8]; however, few strategies for losing weight have been effective, and new ones are welcome [3,46]. In contrast, strategies to get individuals to quit smoking have been more successful, showing that behaviors can be changed to improve health. Of the numerous strategies that exist for helping individuals lose weight, the most invasive — bariatric surgery — is still the most effective at producing weight loss (about 61% per patient) [9]. Pharmacological agents have met with mixed results. One of the most promising nonsurgical, nonpharmacological strategies to promote weight loss was ephedra, because it induced weight loss without its users actually having to consciously reduce calorie intake [13]; however, in 2004, the Food and Drug Administration (FDA) banned it from being sold, citing signiﬁcant side effects, including death. An equally promising weight-loss strategy has been the so-called low-carbohydrate diets popularized by the late Dr. Atkins [24,56]. It seemed that everyone in America knew someone who had lost weight on the Atkins diet; however, two major clinical studies evaluating the Atkins diet showed that, although weight loss after 6 months was greater compared to the conventional hearthealthy, low-fat diet, the difference disappeared by 1 year [24]. Soon after the publication of these articles, the appeal of the low-carb phenomenon waned. A lesser known weight-loss program is the low-glycemic-load (low-GL) or low-glycemic-index (low-GI) diet [17,38]. Of the seven leading drivers of health in the Western diet, a diet high in glycemic load was identiﬁed as that having the greatest impact [14]. The low-GL diet is gaining popularity among clinicians, researchers, and overweight and obese patients because it has been shown to promote satiety, to have a sound physiological basis behind how it works, and to contain all the essential nutrients. In addition, following a low-GL diet for both the short and long term has been shown to promote weight loss without hunger and to reduce the risk of many chronic diseases of aging including obesity, CVD, and type 2 diabetes. This chapter serves as a review on the subject of the glycemic load of the diet. Beginning with deﬁnitions of terms (e.g., GL, GI), the chapter also explores the physiological effects of glycemic load, including its effects on satiety, as well as the health implications of following a high-GI or high-GL diet. Finally, practical information is given on how to follow a low-GI or low-GL diet.

DEFINITION OF TERMS The GL and GI are rating systems for evaluating the change in postprandial blood glucose levels after consuming carbohydrate-containing foods (Table 20.1). Each is deﬁned below.

GLYCEMIC INDEX The concept of postprandial glucose levels was originally deemed important in the early 1980s, when it was thought that setting limits would lead to better daily glucose management in patients with diabetes [66,69]. The GI relates to the rate at which recently ingested carbohydrates appear in the blood as glucose. The GI is expressed as a percentage: Integrated increase in blood glucose level during a 2-hour period after a known quantitty of carbohydrates is ingested (usually 50 0 g of available carbohydrate) × 100 Integrated increase in blood glucose level during a 2-hour period after a known quantity of a reference food is ingested (usually 50 g of available carbohydrate) × 100 The values for GIs of foods typically range from 20 to 100; however, some foods that are highly processed may exceed this upper value (e.g., cornﬂakes have a GI of 120). Conceptually, a low-GL diet involves limiting the intake of foods that have the greatest impact on postprandial blood glucose concentrations; for example, foods that are composed of mainly protein and fat have virtually no impact on GI or GL. These include all meats, dairy products, and fats and oils; however, too much protein produces an undesirable insulinemic effect that may

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TABLE 20.1 Glycemic Index and Glycemic Load of Commonly Consumed Food Categories (Expressed as Approximate Values) Food Category Dairy (milk, cheese, yogurt) Fruits Vegetables (nonstarchy) Vegetables (starchy) Legumes, nuts Nonsweetened and sweetened bakery products, cereals, pasta, grainsa Carbonated beverages (e.g., colas) Juices Snack foods a

Glycemic Index (Compared to Glucose)

Glycemic Load

20–40 20–40 Insigniﬁcant 60–90 25–45 50–80

<10 <10 Insigniﬁcant 10–25 <5–15 10–20

63 40–60 >50

16 15–25 10–25+

White and whole-wheat products differ only slightly.

Source: Based on data from Foster-Powell, K. et al., Am. J. Clin. Nutr., 76, 5–56, 2002.

promote weight gain and increased hunger [44]. Protein from either a bar (29 g) or from a shake (15 g) had 2-hour area under the curve (AUC) insulin responses of 90% and 88%, respectively, compared to 50 g of glucose; thus, to manage both postprandial glucose and insulin, protein and carbohydrate intake should be controlled on a low-GL diet. The procedures for obtaining measurements of GI are described elsewhere [66,69]. The GI of carbohydrate-containing foods varies widely and cannot be predicted based on chemical analysis of the carbohydrates (i.e., simple vs. complex). In fact, large differences in GIs even exist within foods found in the same food group; for example, whole meal bread was found to have a GI of 72, and whole meal spaghetti has a GI of only 42. Similarly, among tubers and root vegetables, parsnips have a GI of 97, and sweet potatoes have a GI of 48. Ironically, the ﬁber content of foods has been found to have very little effect on GI. Other oddities occur. For example, the GI of sucrose (glucose and fructose), thought to be diabetogenic, is not among one of the highest foods measured, because the GI of fructose is much lower than glucose [10]. In addition to all of the other variables, cooking can affect the GI of a food. Precooked Russet potatoes elicited lower AUC glucose responses than those consumed the same day they were cooked [21]; however, this same effect was not seen in boiled white potatoes. All of these variables underscore the importance of measuring the GI of individual foods to determine the true effect that food has on postprandial blood glucose levels. With so many factors affecting the GI of individual foods, it is not surprising that the concept of GI has been criticized [48]. In response, an international group of researchers recently validated it. Seven different research groups from around the world measured the GIs of four foods: instant potato, rice, spaghetti, and barley [67]. Locally obtained white bread served as the control. All laboratories followed the protocol established by the Food and Agriculture Organization (FAO)/ World Health Organization (WHO) to measure the GIs. The GIs of these foods did not vary signiﬁcantly in the different centers, nor was a center and food interaction identiﬁed. The mean between-laboratory standard deviation was small (approximately nine), and the measurements were closer to nine when capillary, rather than venous, blood was sampled. The size of the standard deviation conﬁrmed the validity of the GI measurements, because most foods have GIs ranging from 20 to 120, and a standard deviation of nine indicates the tightness of the data. Moreover, the ease of using capillary blood compared to venous blood conﬁrmed that this test can easily be conducted at many facilities around the world.

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GLYCEMIC LOAD Ultimately, over 1200 GI measurements of individual carbohydrate-containing foods were conducted [23]. Each was measured using the requisite 50 g of available carbohydrate (total carbohydrate minus ﬁber) in the food; however, these portion sizes do not always match up with actual serving sizes, making the GI of limited use in meal planning. This limitation led to the development of a methodology, called glycemic load, which takes this portion size into account. The GL is representative of the GI of a food but is reﬂective of a usual serving size of a carbohydrate-containing food [20,33,55]. The GL can be calculated as: Glycemic load = (Glycemic index of a food × grams of carbohydrate in a serving of that food)/100 The GL values of foods typically range from 2 to 30 (Table 20.1). Each unit of the GL represents the equivalent of 1 g of carbohydrate from white bread [39]. White bread is often used as the standard (i.e., equal to a GI of 100). Of the carbohydrate-containing foods, nonstarchy vegetables and legumes have the lowest GLs (<5). Fruit and dairy foods are next (around 10), followed by unsweetened, grain-based foods (10–20), and then sweetened, grain-based foods, candy, and carbonated beverages (>15). Foods that have GLs in excess of 10 are typically considered to have high GLs. Most grain-based snack foods — both salty and sweet — have GLs at or above this value. Such foods only started creeping into the food supply within the past 100 years. The GLs from all of the foods ingested in a single day can be summed and used to compare dietary regimens among different populations. For example, the sum of all of the GLs for a day when a low-GL diet has been followed is about 50 to 70 [4]. In contrast, consuming a highcarbohydrate, heart-healthy, low-fat diet such as that outlined in the U.S. Department of Agriculture’s Food Guide Pyramid yields a total dietary GL for the day of at least 80, but it could be as high as 120. In addition, the typical American diet, which includes numerous servings of sweetened carbonated beverages, salty snacks, candy, and baked goods, could have a dietary GL of over 200. The GL and GI often trend in the same direction, but not always; for example, carrots have a high GI (71) but a low GL (4) [4]. The difference comes from the fact that the 50 g of carbohydrate used to compute the GI of carrots is more than a typical single serving of vegetables. To get 50 g of the available carbohydrate in carrots, you would have to consume about four cups of carrots at a sitting. Carrots are high in ﬁber and water, which take up space and weight, and a typical serving does not have an appreciable effect on blood glucose concentrations. Other nonstarchy vegetables and some fruits (e.g., berries) have this unique phenomenon, which explains their low GL. These examples demonstrate that the GL is a better tool than the GI for meal planning, because single servings of nonstarchy vegetables and selected fruits have minimal impact on blood glucose levels, which drive the GI. The GL methodology was recently validated [6]. In this two-part study, ten healthy subjects consumed foods that were thought to have the same GL to conﬁrm that they evoked similar effects on blood glucose levels. In the second part, another group of ten healthy subjects consumed different foods that were thought to produce a stepwise increase in GL. Both studies yielded predictable results. This was the ﬁrst report conﬁrming that the GL of foods has the physiologic validity to predict glycemic response.

GLYCEMIC LOAD

AND THE

AMERICAN DIET

One of the reasons why the low-GL diet concept is gaining in popularity is that the rising obesity rates are coincident with the consumption of foods with extremely high GLs. Never before in our evolution have foods been consumed that have such very high GIs (>100) or GLs (>10) [23]. As more individuals eat an appreciable amount of calories from snacks, it is easy to understand why

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the GL of the diet has increased. The GL of the diet of women 34 to 59 years of age rose 22% between 1980 and 1990 [27]. During the same time, the percentage of women who were overweight increased 38%, which may have been related to the change in the GL of the diet or the fact that the percentage of women who smoked declined 41%. Other dietary factors improved, such as the consumption of fewer trans fats, the increase in the ratio of polyunsaturated to saturated fat intake, the increase in cereal ﬁber, and the increase in omega-3 fatty acids. None of these factors was thought to cause the increase in body weight, except the change in the GL of the diet. These data provide a compelling relationship between body weight and GL of the diet.

PHYSIOLOGICAL EFFECTS OF A LOW-GLYCEMIC-LOAD DIET Ludwig et al. [35,37] and others have conducted an elegant series of studies identifying the physiological basis for why a low-GL diet may be effective at promoting satiety, reducing body weight, and lowering the risks of many chronic diseases of aging. Physiological changes were characterized by their sequential effects at three stages postprandially.

EARLY POSTPRANDIAL PERIOD Within 2 hours of ingesting a high-GL, carbohydrate-containing food or meal, blood glucose concentrations can be more than double that of an eucaloric meal with a low GL [35,37]. (These data were obtained from measurements from obese adolescents.) These higher blood glucose levels trigger the release of increased amounts of insulin to reduce them. High circulating insulin levels favor anabolism, thereby signaling the storage of all incoming nutrients (mainly lipids and carbohydrates) as fat in the adipocytes (lipogenesis) or as glycogen stored in muscle and the liver (glycogenesis). The disappearance of these substrates from the blood is rapid, and upon their disappearance hunger sets in. The constant exposure to high-GL foods and meals may promote the development of insulin resistance, mainly because the pancreas is required to regularly secrete high amounts of insulin throughout the day. When circulating insulin levels are elevated, lipolysis is inhibited, thereby making it difﬁcult to use body fat stores for energy and to lose weight. Similarly, glycolysis is suppressed because glucose levels are maintained at normal levels or may even be elevated, depending on how much insulin resistance is already present. Some have argued that habitual consumption of high-GL diets has no effect on the risk of insulin resistance [30], but others refute this [37]. What is particularly problematic is that Americans tend to snack frequently on high-GL foods, which causes hyperinsulinemia and creates a state of anabolism most of the time.

MIDDLE POSTPRANDIAL PERIOD Within 2 to 4 hours after the ingestion of a high-GL meal, nutrients are almost completely absorbed from the gastrointestinal tract [35,37]. Glucagon is the counter-regulatory hormone that is released in response to insulin, and an elevated ratio of insulin/glucagon persists from the early 2-hour phase. This skewed ratio may drive blood glucose concentrations down, even to the point of creating a hypoglycemic state. Glucose serves as the primary fuel for the brain, and hunger sets in when the brain senses food deprivation. The other major fuel source of the body is free fatty acids, which are also suppressed by the exaggerated insulin/glucagon ratios. Thus, both of the body’s key metabolic hormones are unbalanced, which leads to hunger because the body is without its two major fuel sources.

LATE POSTPRANDIAL PERIOD Within 4 to 6 hours after ingestion of a high-GL meal, the low circulating concentrations of glucose and free fatty acids stimulate the release of counter-regulatory hormones (i.e., glucagons, epinephrine, cortisol, and growth hormone) [35,37]. This is the body’s attempt to release the recently stored

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energy sources. Glucagon and cortisol primarily cause the release of glycogen, thereby increasing blood glucose concentrations. Fat is mobilized from the adipocytes primarily by epinephrine and growth hormone, which restores free fatty acids levels to normal; however, if insulin levels are still elevated at this time, these catabolic processes are blunted, so it is possible that an individual will remain hungry beyond the 4 hours after eating a high-GL meal. Thus, high-GL meals and snacks promote the hunger that can lead to obesity by fostering more frequent snacking. In contrast, a low-GL meal or snack does not induce such dramatic hormonal shifts [35,37]. Low-GL foods take longer to digest and absorb, thereby minimizing the impact on hyperglycemia and hyperinsulinemia. In addition, the liver can undergo glycolysis and release glucose, and the adipocytes can undergo lipolysis to release free fatty acids; thus, hunger is avoided and stored substrates can be mobilized to promote weight loss. Also, insulin resistance is curtailed, as insulin levels rarely go into super-physiologic range. These glycemic and insulinemic changes seen in adolescents were conﬁrmed in obese, adult women [16]. In a crossover design, the subjects on separate occasions consumed low-GL and highGL test meals (breakfast and lunch). Glucose and insulin AUC were signiﬁcantly higher following the high-GL meals compared to the low-GL ones. Serum free fatty acids were suppressed by both meals by 3 hours postprandially, but they were then raised signiﬁcantly more in the low-GL meal group by the fourth and ﬁfth hour (p < 0.05); however, glucagon concentrations did not differ signiﬁcantly between the two test meals as found earlier [35]. Diaz et al. [16] speculated that carbohydrate oxidation would be favored and fat oxidation reduced, but this did not occur. The short-term period for the changes in insulin concentrations during this feeding study likely explained why no differences were observed in fuel partitioning between the two dietary regimens. In contrast, when insulin is infused in a step-wise manner at nonphysiological levels for a long time (>100 minutes), such differences in substrate utilization are observed.

EFFECT OF GLYCEMIC LOAD ON HUNGER Hunger, satiety, and satiation have long been associated with the GI or GL of the diet [36,53]. Satiation is the sensation of fullness that develops during the process of a meal and contributes to its termination. Satiety is the sensation of fullness between one meal and the next. Hunger is the degree of appetite suppression between one meal and the next. Looking at the totality of the published studies (reviewed elsewhere), all three sensations are affected by the GL and GI of the diet. The lower the GI or GL of the day’s foods consumed, the earlier satiation occurs, the longer satiety is, and the less of a sensation of hunger there is before each meal [36,53]. On average, total daily caloric intake was 20% greater after consumption of a high-GL meal than after a low-GL meal [53]. To emphasize the importance of this relationship between food consumption and GL, one laboratory has developed a validated satiety index of commonly consumed foods [26] that can be used by overweight and obese individuals to make better food choices on a weight-loss regimen. These investigators found that isoenergetic servings of a variety of foods differed greatly for hunger and satiety, and the predictability of these effects was related to the GI of the individual foods. Clinical support exists for a low-GL diet in curtailing hunger and promoting satiety [1,18,36, 37,53]. Two studies have shown that less hunger occurs within 6 days of consuming a low-GL diet compared to a high-GL diet [1,18]. In both short-term studies, subjects reported that they were less hungry while following a low-GL diet and ate 25% fewer calories compared to when they consumed a high-GL diet. Another group of investigators measured both hormonal changes and hunger to conﬁrm that the two are related [35]. Twelve obese adolescents were evaluated on three separate occasions using a crossover design protocol. Eucaloric test meals were consumed at breakfast, but each varied by GL (low, medium, and high). Subjects were monitored during the subsequent 5 hours, and selected blood chemistries, including relevant hormones, were measured. The voluntary

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caloric intake after the test meals was 53% higher in the medium-GL meal and 81% higher in the high-GL meal compared to the low-GL meal. The difference in energy intakes was supported by how hungry the subjects felt. Using a 10-point analog hunger scale, subjects were consistently less hungry following consumption of the low-GL meal, intermediate after the medium-GL meal, and most hungry following the high-GL meal. The researchers demonstrated that serial hormonal changes were responsible for the different degrees of hunger [35]. The measured AUC for plasma insulin levels was 52% higher for the highGL meal compared to the low-GL meal. The mean plasma glucose nadir was 42% lower after the high-GL meal compared to both the low-GL and medium-GL meals. Thus, the high-GL meal produced the greatest adverse effect on glycemia (i.e., greatest hypoglycemia) and the greatest insulin secretion, further exacerbating falling blood glucose levels. Plasma glucagon levels predictably rose after the low-GL meal but were suppressed about 10% for the medium-GL and high-GL meals. This was likely related to the presence of hyperinsulinemia. Finally, the serum free fatty acids were suppressed the most after ingestion of the high-GL meal compared to the other two diets. To compensate for this, the counter-regulatory hormones epinephrine and growth hormone were higher following the high-GL meal compared to the low-GL meal, causing free fatty acids to increase. These results suggest that a single meal can have an immediate and profound metabolic consequence that can last up to 5 hours. The degree of hunger was supported by the metabolic changes that occurred postprandially. A subsequent study, however, did not support the relationship between changes in glycemic and insulinemic responses and hunger [2]. Thirty-nine healthy adults consumed either high-GL foods or low-GL foods for 8 days. Appetite sensation and blood tests were performed before and 2 hours following breakfast and lunch on days 1 and 8. The magnitude of the glycemic and insulin responses did not differ between the diets at any time point, nor did the caloric intake between the groups; thus, no close relationship between hunger and blood glucose and insulin levels was observed. This study was short term, however, and was conducted in normal-weight volunteers. The randomized prospective studies and epidemiological data would suggest a beneﬁt of the lowGL in controlling appetite and weight (see below).

GLYCEMIC LOAD AND WEIGHT LOSS Several studies have conﬁrmed that low-GL diets promote weight loss [5,19,62,68], but others have not found a beneﬁt [11,51].

FAVORABLE STUDIES Short-term data showed that obese children (n = 64) who consumed a low-GL diet lost more weight than those who followed a high-GL, low-fat, energy-restricted diet (n = 43) [62]. After 4 months, the low-GL group experienced a –1.53 kg/m2 change in BMI, and the control group had a –0.06 kg/m2 change. In contrast to the high-GL group, the low-GL diet group was instructed to eat to satiety and lost more weight. The same laboratory followed 14 obese adolescents 13 to 21 years of age for 1 year [19]. The dietary protocols were the same as above. At 12 months, both BMI (–1.3 ± 0.7 kg/m2 vs. 0.7 ± 0.5 kg/m2; p = 0.02) and fat mass (–3.0 ± 1.6 kg vs. 1.8 ± 1.0 kg; p = 0.01) decreased signiﬁcantly in the low-GL group compared to the high-GL, energy-restricted, low-fat group, respectively. Insulin resistance, measured by means of homeostasis model assessment (HOMA), increased less in the low-GL group. Despite no energy restriction, the low-GL group ate fewer calories at the 12-month measurement compared to the high-GL group, respectively (1621 ± 159 kcal vs. 1439 ± 104 kcal). Although hunger and satiety were not measured, it seemed that those in the low-GL group were more satisﬁed because they lost more weight while eating fewer calories.

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A couple of small pilot studies showed the ease with which a low-GL diet could be followed by free-living overweight children and adults [5,68]. Children were recruited from a pediatrician’s ofﬁce [68]. They received a brief description of the diet and a handout categorizing the foods based on their GI value; sample meal plans were also provided. Subjects were monitored for 12 weeks, and calorie counts and food frequency questionnaires were obtained. Although 34 children were enrolled in the study, only 15 completed it; of these, 14 lowered the GI scores of their diets and decreased carbohydrate intake by 73 g compared to baseline (p < 0.02). Mean caloric intake decreased by 292 kcal/day (p < 0.02), leading to 12 of the 15 children losing weight. The participants and their parents described the diet as easy to understand. These promising data provided a protocol to assist busy pediatricians with a tool to help children lose weight. The effect of a low-GL diet to promote weight loss was assessed in free-living overweight and obese adults living in Grand Rapids, MI [5]. All were recruited from a newspaper advertisement. The study lasted 8 weeks, and the subjects were instructed on the diet at baseline. They were weighed on the same scale at baseline, week 4, and week 8. At these visits, they also had their waist circumference measured. Each in-between week, the subjects were called by the study coordinator to assess compliance. Instructions for the low-GL diet included the following: • • • • •

• • •

Consume two servings of low-fat dairy each day. Eat two servings of fruit per day. At lunch and dinner, consume low-GL, low-starch vegetables, eating at least two cups of different kinds at each meal. Eat 4 ounces of meat protein (beef, pork, veal, poultry, ﬁsh, shellﬁsh) at lunch and dinner. Limit high-GL, starchy vegetables (potatoes, corn, rice), grain-based foods (breads, pasta, salty snacks), ﬂour-based foods (pastries, cakes, cookies, donuts), candy, and sugarcontaining beverages including juices. For breakfast, consume a low-GL meal replacement shake made with skim or 1% milk, preferably including one of the day’s servings of fruit. Use the low-GL snack bars provided as in-between-meal snacks at least once a day. Take the appetite-suppressant (soluble ﬁber and chromium) capsules provided before meals.

Of the 20 individuals who began the study, 17 completed 4 weeks, and 14 of those completed all 8 weeks. The study included 6 males, of which 5 completed the entire study, and 11 females, of which 9 completed it. All participants consumed the meal replacement shake at breakfast, and only two participants did not use the snack bars. All used the capsules to control hunger, but most used them only twice a day. The entire group lost an average of 10 lb after 8 weeks, which is consistent with a good, weightreducing diet of about 1 to 2 lb/week (Table 20.2). Males lost more (17 vs. 5 lb) than females, primarily because one male lost 37 lb, thereby skewing the average upward. Waist circumference averaged a decrease of 1.75 in., with males and females being about even (–1.6 vs. –1.8 in., respectively). This may reﬂect an improvement in insulin sensitivity. Subjects in this study did not complain of hunger after the ﬁrst week, and no clinically relevant side effects were reported. The participants reported that the diet was easy to follow. These data are consistent with earlier reports showing that weight loss can be achieved without hunger. The previous studies supported the notion that a low-GL diet reduces hunger, which led to weight loss. Others have suggested that a low-GL diet may also affect energy metabolism [1]. Ten moderately overweight subjects participated in two 8-day feeding regimens. The purpose of the study was to determine if metabolic adaptations to energy restriction differed between eucaloric, energy-restricted, high-GL, and low-GL diets. The subjects consumed each diet for 6 days and then were followed for 2 more days using the same diet but without the energy restriction. Two of the

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TABLE 20.2 Changes in Weight and Anthropometric Dataa Parameter Weights (lb) Baseline Week 4 change Week 8 change Waist circumference (in.) Baseline Week 8 change Body mass index (kg/m2) Baseline Week 8 change a

Males

Females

233 (182–322) –10 (2–21) –17 (1–37)

210 (144–318) –3 (0–6) –5 (0–11)

44 (39–49) –1.6 (0–3.3)

41 (33–48) –1.8 (0.5–3.5)

33 (25–39) –2.3 (0–5)

34 (25–51) –1 (0–1.8)

Data are presented as means and ranges.

Source: Data from Bell, S.J. et al., Nutra World, 8, 50–51, 2005.

ﬁndings from this study helped explain how a low-GL diet may promote weight loss, above and beyond hunger control [1]. First, serum leptin concentrations decreased to a greater extent between day 0 and day 6 with the low-GL diet than the high-GL diet. This is what would have been expected, because serum leptin concentrations and carbohydrate intake are positively associated. The lowGL group consumed a smaller percentage of energy from carbohydrates compared to the high-GL group (43% vs. 67%). In addition, the lower serum leptin concentrations seen in the low-GL group were also predictable because insulin is a leptin secretagogue. The mean AUC for insulin was 50% lower in the low-GL group compared to the high-GL group (478 ± 82.2 pmol⋅hr/L vs. 700 ± 98.4 pmol⋅hr/L; p = 0.01). Second, resting energy expenditure declined signiﬁcantly less (p =.0.04) in the low-GL (4.6%) compared to the high-GL (10.5%) diet during the energy-restricted phase. This difference, coupled with the greater decrease in serum leptin concentrations, may help explain how a low-GL diet could promote weight loss.

UNFAVORABLE STUDIES Five-day food records were examined from over 179 elderly subjects (≥65 years of age) [15]. Subjects were clustered according to the GL of the diet and by gender. In both sexes, those who followed a low-GL diet compared to those consuming a high-GL diet weighed signiﬁcantly less (p < 0.001), ate fewer grams of carbohydrates (p < 0.06), and had signiﬁcantly higher Healthy Eating Index scores (p < 0.001); however, the BMIs of the groups did not differ. It may be that all that the low-GL regimen offers is better eating habits, with a more nutrient-rich diet. That alone may suggest that the low-GL regimen promotes a lessening of disease risk rather than weight loss. A couple of laboratories did not ﬁnd that the low-GI diet promoted weight loss [11,51]. Fiftythree free-living adults were randomly assigned to receive a behavioral weight loss program (BWLP) and an energy-restricted, low-fat diet and were encouraged to exercise; another group received all of these, plus education about the GI value of foods (BWLP+GI) [11]. In the BWLP+GI group, despite consuming a lower-GI diet and having more knowledge about how to select lowGI foods, no signiﬁcant differences in weight, fat loss, or BMI were observed after one year; however, the dietary GL for the day dropped in both groups, so differences would be difﬁcult to detect between the two treatment modalities. Also, the dietary GL for the day in the BWLP+GI group still exceeded 100 (112.2 ± 51.7), which may not have been low enough to control appetite and promote weight loss.

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Other investigators similarly found no beneﬁt of a low-GL diet beyond energy restriction [51]. Twenty-nine obese subjects were assigned to one of three energy-restricted dietary regimens for 36 weeks — a high-GL diet (dietary GL for the day was 272), a low-GL diet (dietary GL for the day was 172), or a high-fat diet (40% of the calories from fat). During the ﬁrst 12 weeks, all subjects were provided their meals. During that phase of the study, each group experienced a signiﬁcant weight loss (around 10 kg) and improvement in insulin sensitivity, which was measured by HOMA. No differences among the groups were detected within these parameters, except that the HOMA values differed between the low-GL and high-fat regimen at week 12 (p < 0.03, with the low-GL being signiﬁcantly better). A subgroup (n = 22) continued on their assigned diet for another 24 weeks. The groups were similar at the end of this period in that the weight loss was maintained and insulin sensitivity continued to improve, but no beneﬁt was observed in the lowGL diet over the high-GL or high-fat diets. During the free-living phase, the GL of all groups was similar [51]. All subjects reduced portion sizes, which lowered the GL of the overall diet. This is an interesting ﬁnding in and of itself, in that it may be sufﬁcient to concentrate on portion size rather than GL to achieve weight loss. In addition, dietary fat intake increased in all groups and approximated their prescreening levels. The study was small, and about one fourth of the subjects dropped, out making it difﬁcult to fully assess the effect of a low-GL diet. Unlike earlier studies where insulin sensitivity was assessed, these data did not corroborate those ﬁndings [35,37]. As with most weight-loss studies, conﬂicting data usually appear in the medical literature. The physiological responses to a high-GL diet were not supported in the study by Raatz et al. [51], which will likely provoke more studies evaluating the effect of a low-GL diet on weight loss. Others who did not ﬁnd favorable results suggested that the concept of low-GL diets was only effective at breakfast, following an overnight fast [28]. These investigators found the same variation in blood sugar levels after consuming high-, middle-, and low-GL meals at all times during the day except after breakfast. These similarities throughout the day were likely driven by snacking, which so many individuals do. In addition, cortisol levels are highest in the early morning, so postprandial blood sugar levels responded more predictably at that time (i.e., lower for the low-GL meals). Another group [49] suggested that overweight individuals with relatively greater insulin secretion in response to a glucose tolerance test (GTT) lost more weight than those who responded normally; thus, patient screening by GTT response may improve the chances of losing weight. Nevertheless, most of the previous studies showed that weight loss could be achieved without hunger and that changes in metabolic parameters supported the change in body weight.

GLYCEMIC LOAD AND DISEASE Unlike the relatively few studies showing that a low-GL diet promotes weight loss, many more are available showing that following a low-GL diet for a long time (for up to 10 years) leads to risk reduction of a whole host of medical conditions, including CVD and type 2 diabetes.

META-ANALYSES Two meta-analyses reviewed the effect of low-GL diets on chronic conditions [7,43]. Opperman et al. [43] included 16 studies in their analysis, which had major outcomes as the change in markers of carbohydrate and lipid metabolism. The low-GL diets signiﬁcantly reduced fructosamine by –0.1 mmol/L (95% conﬁdence interval [CI], 0.20–0.00; p = 0.05), hemoglobin (Hgb) A1c by 0.27% (95% CI, 0.5–0.03; p = 0.03), and total cholesterol by –0.33 mmol/L (95% CI, 0.47–0.18; p < 0.0001) and tended to reduce low-density lipoprotein (LDL) cholesterol in patients with type 2 diabetes by –0.15 mmol/L (95% CI, 0.31–0.00; p = 0.06) compared to high-GL diets. No changes were observed in high-density lipoprotein (HDL) cholesterol and triglyceride levels. From this study, the use of a low-GL diet appears beneﬁcial at reducing total cholesterol levels and improving the overall metabolic control of diabetes. Another group of investigators [7] used

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meta-analysis to evaluate the effect of low-GL diets on improving overall glycemic control in individuals with diabetes as assessed by fructosamine or Hgb A1c. The 14 studies identiﬁed included 356 subjects (203 with type 1 and 153 with type 2 diabetes) who were randomly assigned to consume the low-GL or high-GL diets for 12 days to 12 months. The Hgb A1c was reduced by 7.4% more with the low-GL diet than the high-GL diet. Choosing low-GL foods had a clinically useful effect on glycemic control in patients with diabetes.

CARDIOVASCULAR DISEASE The incidence of CVD has declined since 1980, but dietary strategies such as the low-GL diet continue to be explored to reduce the incidence even further [27]. The effect of a low-GL diet on cardiovascular health is of particular interest, because for the past two decades patients with CVD or at risk for it were provided low-fat, high-carbohydrate diets, which had inherently high GLs [17]. Some have expressed a concern that such a diet increases the risk of CVD rather than reducing it because of the high-GL nature of the diet. Epidemiological data and short-term studies exploring the effect of low-GL diets on CVD risk are reviewed separately. Epidemiological Data A 10-year study including over 75,000 women 38 to 63 years old suggested that regular consumption of a high-GL diet from reﬁned carbohydrates increased the risk of coronary heart disease (CHD), independent of other cardiac risk factors [32]. Using validated food frequency questionnaires to compute the sum of the GL of all the foods consumed in a day (i.e., dietary GL), those in the lowest quintile (dietary GL = 117) were assigned a relative risk (RR) of 1.0 for CHD risk. The other quintiles had RRs of 1.01 (dietary GL = 145), 1.25 (dietary GL = 161), 1.51 (dietary GL = 177), and 1.98 (dietary GL = 206) (p for trend < 0.0001). These data reﬂected adjustment of age, smoking status, and other CHD risk factors. Classifying carbohydrate intake merely according to simple or complex did not yield signiﬁcant outcomes as compared with classifying carbohydrates according to GL. A subset of the previous population (n = 244) had high-sensitivity C-reactive protein (hs-CRP) concentrations measured, and these were compared to the dietary GL [34]. This measurement is an indicator of CVD risk, especially of ischemic heart disease. A signiﬁcant and positive relationship was seen between the dietary GL and hs-CRP (p for trend < 0.01). The difference in hs-CRP between the lowest and highest dietary GL was twofold. The association was even more pronounced when the women were segmented by BMI ≥ 25 kg/m2 or BMI < 25 kg/m2. The mean hs-CRPs were higher at each dietary GL quintile, suggesting an added effect of body weight on CVD risk. These data showed that a high-GL diet led to increased body weight, which was positively related to hs-CRP, a risk factor for CVD. Both of these large-scale studies indicated a signiﬁcant relationship between the GL of the diet and the risk of CVD. Short-Term Studies The effect of a low-GL diet on reducing CVD risk factors was seen in young [20,47] and older adult [18,45,60,61] subjects. During a 12-month study, 23 young adults ages 18 to 35 years consumed either an ad libitum low-GL diet or an energy-restricted, low-fat diet (<30% of the energy) [20]. Body weight decreased in both groups at 6 months (about 8%) and remained below baseline at 1 year (about 6.5%); no differences were observed between the two groups. Compared to the conventional, low-fat diet, the low-GL diet group experienced a signiﬁcantly greater mean decline in serum triglycerides (p < 0.005) and a reduction in plasminogen activator inhibitor, which increased in the control group. These markers are associated with CVD events and should be controlled throughout life. As CVD takes many decades to develop, a low-GL diet may be appropriate for young adults to reduce its risk later on.

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Others observed similar changes in CVD risk markers [47]. After having lost 10% of body weight young adults who consumed a low-GL diet experienced signiﬁcant reductions in insulin resistance (p = 0.01), serum triglyceride concentrations (p = 0.01), C-reactive protein levels (p = 0.03), and blood pressure compared to the conventional low-fat diet (as above). This study again conﬁrmed that the low-GL diet reduces CVD risk markers. Interestingly, these investigators determined that energy expenditure reduced less after weight loss in the low-GL diet, which theoretically afforded an 80-kcal/day advantage compared to those consuming the low-fat diet. Whether this caloric difference occurs long-term is unknown but worth exploring. Middle-aged adults (average age, 47 ± 11 years) also experienced improvement in CVD risk factors with a low-GL diet compared to the American Heart Association (AHA)-recommended, low-fat diet [18]. Twelve overweight men (BMI = 33 ± 3.5 kg/m2) consumed each diet ad libitum for 6 days, in a crossover design. Signiﬁcant adverse changes occurred while following the AHA diet: a 28% increase in serum triglycerides and a 10% reduction in HDLcholesterol levels, which increased the cholesterol/HDL-cholesterol ratio. During the low-GL phase, serum triglycerides decreased 35%, peak particle LDL size increased (1.6%), and plasma insulin levels measured either fasting or during the day were lower compared to the AHA diet. During this part of the study, the subjects consumed 25% fewer calories during the low-GL phase compared to the AHA diet. These same subjects then consumed the AHA diet, but energy intake was set at the amount consumed while following the low-GL diet in the ﬁrst part of the study [18]. There was a trend for the HDL cholesterol to decrease, leading to a signiﬁcant increase in the cholesterol/HDLcholesterol ratio (p < 0.0001). In addition to these unfavorable effects on CVD risk, the subjects reported an increase in hunger (p < 0.0002) and a decrease in satiety (p < 0.007) while on this diet compared to a low-GI diet. These results support a role for a low-GL diet in reducing CVD risk and question the role of the recommended AHA diet. Another study in middle-aged adults showed that a low-GL diet reduced risk factors associated with CVD [61]. During the 10-week trial, healthy, overweight subjects experienced a 10% decrease in LDL-cholesterol levels (p < 0.05) and a trend toward reducing total cholesterol levels (p < 0.07). Others were randomized to a high-GL group. However, unlike other studies, no differences in energy intake, body weight, or fat mass were observed between the two dietary regimens. Regardless, the low-GL diet again was shown to be favorable at reducing CVD risk. Fifty-seven middle-aged subjects (average age, 48 years) with elevated LDL-cholesterol levels consumed either a low-fat, low-GL diet or a low-fat diet only for 12 weeks [60]. Despite a reduction in the dietary GI and dietary GL in the low-fat, low-GL group, the blood lipids did not differ between the groups at any time, except for HDL-cholesterol levels, which decreased signiﬁcantly in the low-fat group (p = 0.05). This blood lipid did not change in the low-fat, low-GL group. These ﬁndings support the earlier study of Dumesnil et al. [18], which questioned the wisdom of a low-fat diet for reducing the risk of CVD. A small, retrospective study suggested that use of a low-GL diet preoperatively before coronary artery bypass surgery may shorten hospital stay [45]. During the 4 weeks prior to surgery, patients who were randomized to a low-GL diet, but not those in the high-GL diet group, had improved glucose tolerance and greater adipocyte insulin activity at the time of surgery, which resulted in a signiﬁcantly shorter length of hospitalization (7.06 ± 0.38 days vs. 9.53 ± 1.44 days; p < 0.05). Thus, a low-GL diet may beneﬁt patients who already have CVD.

TYPE 2 DIABETES More data exist in support of the use of a low-GL diet for the prevention and management of type 2 diabetes than for CVD. This makes sense because the GI and GL were developed initially to help manage blood sugar control in these patients.

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Epidemiological Data Five large-scale studies assessed the effect of consuming a low-GL diet over extended periods of time and in different age groups [30,50,54,55,58]. Young women, ages 24 to 44 years, were followed for 8 years during which an assessment of their dietary intake was obtained as it related to ﬁber and the GL of carbohydrates [58]. Of the 91,249 women included in the study, 741 developed type 2 diabetes. After adjustment of other factors that could predict the development of diabetes, overall GL of the diet was signiﬁcantly associated with it (p for trend = 0.001). A 59% increase in the diabetes risk was observed between the highest quintile of GI and the lowest. Fiber from cereals and fruits were inversely associated with the risk of diabetes, as well. These authors speculated that the reason for this signiﬁcant association was because high-GI foods produced higher blood glucose concentrations and a greater insulin demand than did low-GI foods. It is possible that chronically increased insulin demand results in pancreatic exhaustion that can result in glucose intolerance. In addition, high-GI diets may directly increase insulin resistance. An older, healthy group of women (over 120,000) were followed for 6 years to determine the risk of type 2 diabetes [55]. Both the dietary GI and dietary GL were positively associated with the risk of diabetes. Combining a low cereal ﬁber intake and a high dietary GL resulted in an RR of diabetes of 2.50 (95% CI, 1.14–5.51); thus, the incidence of diabetes may be reduced by incorporating more cereal ﬁber into the diet as well as following a low-GL diet. Older men were also shown to be at increased risk of type 2 diabetes if they regularly consumed a high-GL diet [50]. In another large-scale study in older men (n = 51,529), 40 to 75 years old, the GI and GL of the diet were inversely associated with adiponectin concentrations (p for trend = 0.005). Of this population, 780 developed type 2 diabetes during the 8-year study. A 13% difference for GI and 18% difference for GL was found between the lowest and highest quintiles for serum adiponectin. Adiponectin is an adipose-secreted cytokine that is present at low levels in the plasma of patients with type 2 diabetes. In contrast to GI and GL, dietary ﬁber and magnesium were associated with higher levels of this cytokine; thus, adiponectin may become a new risk factor for type 2 diabetes, and the GI and GL appear to be positively related to it. Large-scale, cross-sectional studies conducted in men and women revealed mixed results as to the relationship between the GL of the diet and the risk of type 2 diabetes [30,54]. In a group of over 75,000 non-diabetic men and women, 30 to 60 years old, GI and GL were not predictive of developing insulin resistance as estimated by HOMA [30]. Insulin resistance developed in 5675 subjects. The risk of developing type 2 diabetes was signiﬁcantly and inversely associated with dietary ﬁber, which was a confounding variable that reduced the effectiveness of GI and GL on HOMA. The results of this study differ from others but support the recommendation for increasing ﬁber intake through carbohydrate-rich foods such as cereals, fruits, and vegetables to prevent insulin resistance and to reduce the risk of type 2 diabetes. Others found ﬁber intake to be a more important predictor of insulin sensitivity than GI or GL [31]. Participants were selected from an ongoing study (Insulin Resistance Atherosclerosis Study) and were selected based on glucose tolerance status (i.e., normal or impaired). Subjects underwent a dietary assessment that included data on ﬁber intake and the GI and GL of the diet. In addition, they underwent measurements of insulin sensitivity (Si), fasting insulin, acute insulin response (AIR), disposition index, BMI, and waist circumference. No association was observed between GI and these measurements. Relationships between these measurements and digestible carbohydrate and GL were entirely explained by energy intake. In contrast, ﬁber intake was associated positively with Si and disposition index and inversely associated with fasting insulin, BMI, and waist circumference, but not AIR. This was the ﬁrst report to address the relationship of GI and GL with direct measure of insulin sensitivity. Earlier reports [55,58] had hinted at a stronger relationship between GI and GL and insulin and blood sugar control, but with these data it appeared that ﬁber intake is a more important aspect of the diet. Unfortunately, the type of ﬁber (soluble or insoluble) was not determined.

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In contrast to the aforementioned studies [30,31], older individuals 70 to 80 years old appeared to show a beneﬁt of the low-GL diet in improving markers that predict type 2 diabetes [54]. From a sample of over 3000, the number of men and women were nearly equal for those who participated in the study. For men, the dietary GI was positively associated with 2-hour glucose levels after a 75-g challenge (p for trend = 0.04) and fasting insulin concentrations (p for trend = 0.004). It was inversely associated with thigh intramuscular fat (p for trend = 0.02). Dietary GL was inversely associated with visceral abdominal fat (p for trend = 0.02) only. For women, dietary GI and GL were not signiﬁcant for any markers. This is the only study to identify differences between the genders. One of the problems with this study is that the investigators based the GI (and thus GL) on glucose rather than on the most commonly used standard, white bread. This produced GI and GL values that are lower than those based on white bread and in this study may explain the lack of statistical signiﬁcance for women and for other parameters in men (i.e., fasting blood glucose, glycated hemoglobin, or visceral abdominal fat). However, in the previous study, the investigators [30] used white bread as the standard, and no signiﬁcant relationships were found between GI and GL and diabetes risk either. Thus, basing the GI and GL on either standard cannot fully explain the discrepancy between these studies. From these large-scale cross-sectional and long-term studies, the relationship between GI and GL and the risk of type 2 diabetes cannot be ignored. Not all studies showed a positive result, but those that did were fairly convincing in showing such a relationship. Short-Term Study In a 4-week study in middle-aged men (around 50 years of age) with type 2 diabetes, those who consumed a low-GL diet improved glycemic control (fasting blood glucose and Hgb A1c) and glucose utilization compared with when they consumed a high-GL diet [52]. The only difference between the two dietary regimens was the GI of the carbohydrates consumed; the total grams of carbohydrate consumed was the same. Despite the short time span and the small differences between the groups, the study gives support for the long-term use of a low-GL diet for the management of type 2 diabetes. Despite the numerous studies showing the positive effects of a low-GL diet on the management of type 2 diabetes, the American Diabetes Association (ADA) had been conspicuously absent in saying anything on the subject until 2004 [59]. In a position statement from the ADA, these authors reviewed the available data regarding the type or source of carbohydrate on the prevention and management of diabetes. They asserted that the total grams of carbohydrate consumed was more important than the dietary GL; thus, in counseling patients with diabetes about their diets, they suggested that more importance should be placed on the amount rather than the type (low- or high-GI) of carbohydrate. The authors conceded that GI affects blood glucose control and that its consideration can provide beneﬁt beyond managing dietary carbohydrate intake, but they went on to state that the data showing that GI or GL can prevent the development of type 2 diabetes are unclear. Many studies exist that show the beneﬁt of consuming a low-GL diet to prevent and manage type 2 diabetes. Others do not show such relationships. It seems prudent to provide a low-GL diet to reduce body weight because blood glucose control and blood lipid levels will likely improve.

OTHER CONDITIONS The GL of the diet has been investigated for its possible effects on other diseases (Table 20.3). These include blood pressure [65], stroke [42], colorectal cancer [39,41], pancreatic cancer [40], breast cancer [25], cholecystectomy [63], and diseases of the eye [12,57]. Of these, the most promising relationships were seen between women developing breast cancer or needing a cholecystectomy.

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TABLE 20.3 Common Medical Conditions Affected by Dietary Glycemic Index or Glycemic Load Effect of Dietary Glycemic Index (GI) or Glycemic Load (GL)

Medical Condition

Ref.

Blood pressure

No change in blood pressure was observed after ingestion of 50 g of carbohydrate in a beverage.

Visvanathan et al. [65]

Risk of stroke

Neither GI or GL was signiﬁcantly associated with the risk of stroke in over 78,000 women followed for 18 years.

Oh et al. [42]

Risk of colorectal cancer

GL was related to risk of colorectal cancer in men (from over 50,000) but not women (from over 120,000) followed over 20 years.

Michaud et al. [39]

Risk of distal colorectal adenoma

Neither a high-GI nor high-GL diet was associated with colorectal adenoma in a large group of women (>34,000) followed for 18 years.

Oh et al. [41]

Risk of pancreatic cancer

GL was associated with an increased risk only in overweight and obese women and those who were sedentary, but not in normal weight women who were active from a largescale study (over 88,000) followed for 18 years.

Michaud et al. [40]

Risk of breast cancer

GL was associated with the risk of breast cancer in adulthood from data collected regarding what women ate in their teens.

Frazier et al. [25]

Risk of cholecystectomy

Higher intakes of total carbohydrate and a high-GI and highGL diet may enhance risk in women (over 120,000) followed for 16 years.

Tsai et al. [63]

Age-related cataract

GL was not related to the risk of cataracts in men (nearly 40,000) and women (over 70,000) followed for 12 years and 14 years, respectively.

Schaumberg et al. [57]

Risk of early cortical and nuclear lens opacities

GI was not associated with either eye condition based on 1717 women followed over 14 years.

—

Other conditions were not related to the GI or GL of the diet (i.e., blood pressure, stroke, agerelated cataracts, or early cortical and nuclear lens opacities). The GL of the diet was related to the risk of colorectal cancer in men but not women and with the risk of pancreatic cancer in overweight and obese women and in sedentary women but not normal weight women. Thus, in contrast to the numerous reports showing a relationship between dietary GL in reducing the risk of and in helping to manage CVD and type 2 diabetes, most other conditions do not seem to be affected by it.

HOW TO EAT A LOW-GLYCEMIC-LOAD DIET Some have argued that all obese patients should be counseled on a low-GL diet [4,29,46]. The science behind the diet is complex, and teaching the diet to patients may prove challenging. To meet all nutritional needs for macronutrients, micronutrients, and a low GL, the basic principles shown in Table 20.4 should be followed. Using this guide, most patients should be able to grasp these concepts and eat a healthier, more nutrient-dense diet. With this diet comes enhanced satiety, reduced hunger, weight loss, and a reduced risk of CVD and type 2 diabetes.

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TABLE 20.4 How To Follow a Low-Glycemic-Load Diet Food Group

Servings Per Day

Dairy (e.g., milk, cheese) Meat, ﬁsh, poultry, eggs

Two 8–10 ounces/day; one egg = one ounce

Fruits

Two pieces or two 1/2-cup servings

Nonstarchy vegetables

Unlimited

Starchy vegetables and unsweetened grain-based foods

3–5 servings per day; a serving is 1/2 cup, 1 slice, or 1 whole (e.g., potato) None, or use sparingly

Sweetened grain-based foods, candy, sugary beverages, salty snacks

Comments Use reduced-fat products to reduce energy intake. To reduce energy intake: (1) trim visible fat and skin; (2) cook with minimal added fats, sauces, and breaded coatings. If using canned or frozen, choose sugar-free to reduce energy intake. Avoid dried fruits and fruit juices. Use limited fats and sauces to reduce energy intake. Use fewer servings during active weight loss than during maintenance. Use none during active weight loss and sparingly during maintenance.

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Obesity: Epidemiology, Pathophysiology, and Prevention Michaud, D.S., Fuchs, C.S., Liu, S., Willett, W.C., Colditz, G.A., and Giovannucci, E., Dietary glycemic load, carbohydrate, sugar, and colorectal cancer risk in men and women, Cancer Epidemiol. Biomarkers Prev., 14, 138–143, 2005. Michaud, D.S., Liu, S., Giovannucci, E., Willett, W.C., Colditz, G.A., and Fuchs, C.S., Dietary sugar, glycemic load, and pancreatic cancer risk in a prospective study, J. Natl. Cancer Inst., 94, 1293–1300, 2002. Oh, K., Willett, W.C., Fuchs, C.S., and Giovannucci, E.L., Glycemic index, glycemic load, and carbohydrate intake in relation to risk of distal colorectal adenoma in women, Cancer Epidemiol. Biomarkers Prev., 13, 1192–1198, 2004. Oh, K., Hu, F.B., Cho, E., Rexrode, K.M., Stampfer, M.J. et al., Carbohydrate intake, glycemic index, glycemic load, and dietary ﬁber in relation to risk of stroke in women, Am. J. Epidemiol., 161, 161–169, 2005. Opperman, A.M., Venter, C.S., Oosthuizen, W., Thompson, R.L., and Vorster, H.H., Meta-analysis of the health effects of using the glycemic index in meal-planning, Br. J. Nutr., 92, 367–381, 2004. Parcell, A.C., Drummond, M.J., Christopherson, E.D., Hoyt, G.L., and Cherry, J.A., Glycemic and insulinemic responses to protein supplements, J. Am. Diet. Assoc., 2004. 104, 1800–1804, Patel, V.C., Aldridge, R.D., Leeds, A., Dornhorst, A., and Frost, G.S., Retrospective analysis of the impact of a low glycaemic index diet on hospital stay following coronary artery bypass grafting: a hypothesis, J. Hum. Nutr. Diet., 17, 214–247, 2004. Pawlak, D.B., Ebbeling, C.B., and Ludwig, D.S., Should obese patients be counselled to follow a low-glycaemic index diet? Yes, Obes. Rev., 3, 235–243, 2002. Pereira, M.A., Swain, J., Goldﬁne, A.B., Rifai, N., and Ludwig, D.S., Effects of a low-glycemic load diet on resting energy expenditure and heart disease risk factors during weight loss, JAMA, 292, 2482–2490, 2004. Pi-Suyner, X., Do glycemic index, glycemic load, and ﬁber play a role in insulin sensitivity, disposition index, and type 2 diabetes?, Diabetes Care, 28, 2978–2979, 2005. Pittas, A.G., Das, S.K., Hajduk, C.L., Golden, J., Saltzman, E. et al., A low-glycemic load diet facilitates greater weight loss in overweight adults with high insulin secretion but not in overweight adults with low insulin secretion in the CALERIE Trial, Diabetes Care, 28, 2939–2941, 2005. Qi, L., Rimm, E., Liu, S., Rifai, N., and Hu, F.B., Dietary glycemic index, glycemic load, cereal ﬁber, and plasma adiponectin concentration in diabetic men, Diabetes Care, 28, 1022–1028, 2005. Raatz, S.K., Torkelson, C.J., Redmon, J.B., Reck, K.P., Kwong, C.A. et al., Reduced glycemic index and glycemic load diets do not increase the effects of energy restriction on weight loss and insulin sensitivity in obese men and women, J. Nutr., 135, 2387–2391, 2005. Rizkalla, S.W., Taghrid, L., Laromigeuiere, M., Huet, D., Boillot, J. et al., Improved plasma glucose control, whole-body glucose utilization, and lipid proﬁle on a low-glycemic index diet in type 2 diabetic men: a randomized controlled trial, Diabetes Care, 27, 1866–1872, 2004. Roberts, S.B., High-glycemic index foods, hunger, and obesity: is there a connection?, Nutr. Rev., 58, 163–169, 2000. Sahyoun, N.R., Anderson, A.L., Kanaya, A.M., Koh-Banerjee, P., Kritchevsky, S.B. et al., Dietary glycemic index and load, measures of glucose metabolism, and body fat distribution in older adults, Am. J. Clin. Nutr., 82, 547–552, 2005. Salmeron, J., Manson J.E., Stamper, M.J., Colditz, G.A., Wing, A.L., and Willett W.C., Dietary ﬁber, glycemic load, and risk of non-insulin-dependent diabetes mellitus in women, JAMA, 277, 472–477, 1997. Samaha, F.F., Iqbal, N., Seshadri, P., Chicano, K.L., Daily, D.A. et al., A low-carbohydrate as compared with a low-fat diet in severe obesity, N. Engl. J. Med., 348, 2074–2081, 2003. Schaumberg, D.A., Liu, S., Seddon, J.M., Willett, W.C., and Hankinson, S.E., Dietary glycemic load and risk of age-related cataract, Am. J. Clin. Nutr., 80, 489–495, 2004. Schulze, M.B., Liu, S., Rimm, E.B., Manson, J.A.E., Willett, W.C., and Hu, F.B., Glycemic index, glycemic load, and dietary ﬁber intake and incidence of type 2 diabetes in younger and middle-aged women, Am. J. Clin. Nutr., 80, 348–356, 2004. Sheard, N.F., Clark, N.G., Brand-Miller, J.C., Franz, M.J., Pi-Sunyer, F.X. et al., Dietary carbohydrate (amount and type) in the prevention and management of diabetes, Diabetes Care, 27, 2266–2271, 2004.

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Shikany, J.M., Goudie, A., and Oberman, A., Comparison of a low-fat/low-glycemic index diet to a low-fat only diet in the treatment of adults with hypercholesterolemia, Nutr. Res., 25, 971–981, 2005. Sloth, B., Krog-Mikkelsen, I., Flint, A., Tetens, I., Bjorck, I. et al., No difference in body weight decrease between a low-glycemic-index and a high-glycemic-index diet but reduced LDL cholesterol after 10-wk ad libitum intake of the low-glycemic-index diet, Am. J. Clin. Nutr., 80, 337–347, 2004. Spieth, L.E., Harnish, J.D., Lenders, C.M., Raezer, L.B., Pereira, M.A. et al., A low-glycemic index diet in the treatment of pediatric obesity, Arch. Pediatr. Adolesc. Med., 154, 947–951, 2000. Tsai, C.-J., Leitzmann, M.F., Willett, W.C., and Giovannucci, E.L., Glycemic load, glycemic index, and carbohydrate intake in relation to risk of cholecystectomy in women, Gastroenterology, 129, 105–112, 2005. Valdes, A.M., Andrew, T., Gardner, J.P., Kimura, M., Oelsner, F. et al., Obesity, cigarette smoking, and telomere length in women, Lancet, 366, 662–664, 2005. Visvanathan, R., Chen, R., Horowitz, M., and Chapman, I., Blood pressure responses in healthy older people to 50 g carbohydrate drinks with differing glycaemic effects, Br. J. Nutr., 92, 335–340, 2004. Wolever T.M.S., Jenkins, D.J.A., Jenkins, A.L., and Josse, R.G., The glycemic index: methodology and clinical implications, Am. J. Clin. Nutr., 54, 846–854, 1991. Wolever, T.M.S., Vorster, H.H., Bjorck, I., Brand-Miller, J., Brighenti, F. et al., Determination of the glycaemic index of foods: interlaboratory study, Eur. J. Clin. Nutr., 57, 475–482, 2003. Young, P.C., West, S.A., Ortiz, K., and Carlson, J., A pilot study to determine the feasibility of the low glycemic index diet as a treatment of overweight children in primary care practice, Ambul. Pediatr., 4, 28–33, 2004. Jenkins, D.C., Glycemic index of foods: a physiological basis for carbohydrate exchange, Am. J. Clin. Nutr., 34, 362–366, 1981.

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Obesity Prevention: 21 Beyond The Anti-Aging Effects of Caloric Restriction Kurt W. Saupe and Jacob D. Mulligan CONTENTS Introduction ....................................................................................................................................265 Caloric Restriction and Life Span .................................................................................................265 Causes and Effects of Caloric Restriction.....................................................................................268 Effect of CR on Stem Cells and Regenerative Potential of Tissues .....................................268 Effects of CR on Fat and Adipokines ....................................................................................269 How Does Caloric Restriction Affect a Representative Organ System (Cardiovascular System)?....................................................................................269 Hemodynamics and Cardiac Contractile Function ................................................................270 Oxidative Damage...................................................................................................................270 Gene Expression .....................................................................................................................271 Will Caloric Restriction Work in Humans? ..................................................................................271 Effects of CR in Humans .......................................................................................................272 Caloric Restriction Mimetic Drugs................................................................................................273 References ......................................................................................................................................274

INTRODUCTION This chapter contrasts with much of the book in that, instead of focusing on treating obesity, we discuss the effects of lowering body mass in animals that are not overweight or obese to start. For the purposes of this chapter, caloric restriction (CR) is deﬁned as limiting caloric intake while providing adequate micronutrients. It should be emphasized that we are not treating obesity but are making relatively lean animals very lean while avoiding any malnourishment by increasing the nutrient density of the diet. CR is unique in that it signiﬁcantly increases the mean and maximal life span of a population. An important aspect of CR is that it does not simply prolong the survival of the organism in an aged or decrepit state; it actually confers a “young” phenotype to the organism. No other nongenetic interventions have emerged that produce similar beneﬁts.

CALORIC RESTRICTION AND LIFE SPAN People throughout history have unsuccessfully looked for a “fountain of youth,” but in the early decades of the 20th century several groups reported that life span in rodents could be signiﬁcantly lengthened by restricting the amount of food they were given [46,48,51]. Over the subsequent years, the observation that a CR diet could extend life span was built upon with several fundamental observations. CR has been shown to extend both mean and maximal life spans of a colony of 265

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100

Non-CR 25% CR 55% CR 65% CR

Survival (%)

75

50

25

0 0

10

20

30

40

50

60

Age (months)

FIGURE 21.1 Effects of increasing levels of caloric restriction on survival in mice. Caloric restriction causes a parallel rightward shift in the survival curve, increasing both average and maximal life span. (From Weindruch, R. et al., J. Nutr., 116, 641–654, 1986. With permission.)

animals, causing a parallel rightward shift in the survival curve, as shown in Figure 21.1 [72]. Particularly noteworthy is the increase in survival of the oldest members of the colony. The fact that CR does not just square off the survival curve by preventing early deaths is a strong indication that CR actually retards aging. Subsequent studies have established that the improved survival of CR animals appears to be caused by a delayed onset of age-associated diseases, including cancer and neurodegenerative diseases. The amount of life-span extension afforded by CR is related to two main dosing factors: the age at which CR is initiated and the severity of CR. Regarding the ﬁrst factor, if CR is initiated either too early or too late in life, the beneﬁcial effects of CR are lessened; for example, if CR is initiated before an animal is mature (prior to weaning in a rodent), any beneﬁts of CR may be obscured. On the other hand, the later in life (after maturity) CR is initiated, the less life span will be extended; for example, an equivalent level of CR (approximately 40% less than ad libitum calories) will increase life span in a mouse by approximately 9, 6, and 3 months when it is started at 3, 14, or 19 months of age, respectively [14,41,72]. In other words, starting CR during late middle age yields only approximately a third of the life-span extension as does starting CR during early adulthood. A second critical dosing factor is the degree to which food intake is restricted [72]. It is interesting to note the generally linear increase in mean and maximal life span that occurs as caloric intake is reduced, with no minimal point deﬁned where further reduction in caloric intake causes no further beneﬁt or even harm (Figure 21.2). Although at some point a reduction of caloric intake must decrease life span, this point (often assumed to be approximately a 65% reduction) has not been empirically deﬁned. The increase in life span is not simply due to preventing obesity. Although preventing obesity clearly has many health beneﬁts, even when very lean mice are used as the basis of comparison (such as the 25% restriction group in Figure 21.1), further restriction of food intake substantially increases life span. It bears repeating that the anti-aging and life-span extension afforded by CR

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267

60 Average

Maximum

Life span, months

55 50 45 40 35 30 25 20

40

60

80

100

120

140

Food intake, K-Cal per week

FIGURE 21.2 Effects of decreasing food intake on average and maximal survival. Note the linear increase in life span with decreasing levels of food intake; even at very low levels of food intake, life span is further increased by lessening food intake. (From Sohal, B.H. and Weindruch, R., Science, 273, 59–63, 1996. With permission.)

are in addition to the beneﬁts of preventing obesity. Surprisingly, the retardation of aging and extension of life span are not due simply to maintaining a low body weight or low percent body fat. This is most directly demonstrated by Holloszy et al. [28,29], who reported that exerciseinduced weight loss extended mean life span slightly but did not extend maximal life span. The retardation of aging and life-span extension with CR seem to be caused by metabolic adjustments to the chronic lack of food. The beneﬁcial effects of CR on life span occur in all species studied to date, including yeast, worms, mice, rats, and large mammals. In fact, the effects of CR are so robust that even in genetically long- or short-lived mice the effects of CR are preserved [32]. Thus, the effect of CR appears to superimpose on animals with a wide range of genetic backgrounds (Figure 21.3). An overriding unanswered question is to what extent CR will affect aging in long-lived mammals such as humans. The effects of CR have rapid on and off kinetics. Dhahbi et al. [14] have recently shown that, within the ﬁrst 8 weeks of starting a CR diet, survival is improved in aged mice. They also noted that the pattern of gene expression is altered within the ﬁrst 2 weeks of CR. Thus, the key molecular

p53–/– Mouse

44%

p53+/+ Mouse

37%

C3B10RF1 Mouse

56%

Sprague–Dawley Rat

32%

F344 Rat

39%

Labrador Retriever

16%

Hereford Cow

35% 0

5

10

15

FIGURE 21.3 Effects of moderate caloric restriction on survival across mammalian species. Even in relatively long-lived mammals and mice genetically engineered to have short or long lives, caloric restriction signiﬁcantly increases life span. (From Hursting, S.D. et al., Annu. Rev. Med., 54, 131–152, 2003. With permission.)

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trigger events that ultimately lead to the CR phenotype must occur within this time window, possibly as soon as the ﬁrst restricted day. Conversely, when a CR diet is stopped and animals are allowed to eat ad libitum, the beneﬁts of CR disappear quickly. The rapid kinetics of CR-mediated changes is a boost to the practicality of CR research. Depending on the endpoint being studied, it is possible to collect meaningful data in a timely manner, rather than conducting long-term studies. In fact, a current priority in this area of research is identifying biomarkers of longevity as surrogate endpoints and alternatives to life span. Furthermore, the time frame of CR-mediated changes gives important clues as to the molecular causes. It seems likely that many of the effects of CR may be similar to those effects that follow a short-term fast. The kinetics of CR effects is also of interest to those (both researchers and subjects) considering CR diet as treatment. Although the rapid onset of these effects might be encouraging, unfortunately the beneﬁts of CR accumulate relatively slowly, and it may take many months or years on the CR regimen to observe a noticeable impact on health. The emerging ﬁeld of CR mimetic drugs, however, may eventually decrease that time, or at least make the treatment period more feasible. CR mimetics are discussed later in this chapter. The increase in life span with CR can be seen using any one of a number of dietary regimens. The key common factor is a reduction in caloric intake without sacriﬁcing micronutrients. Interestingly, some data suggest that even intermittent fasting protocols that do not produce a profound weight loss still provide many of the beneﬁts of CR [4,7]. Life-span extension with CR is due largely to retardation of age-associated diseases, most importantly cancer. In rodents and other species that die largely of neoplastic disease, much of the life-span extension can be attributed to anti-cancer effects [32,70]. This inhibitory action of CR on carcinogenesis is effective in multiple species, for a variety of tumor types and for both spontaneous and chemically induced neoplasms. Fortunately, even relatively mild CR (20 to 30% less calories than ad libitum) can signiﬁcantly delay and lower the incidence rate of late-life neoplasms [58,72]. Also encouraging from the standpoint of applicability to humans is the fact that CR even initiated as late as middle age retards the development of tumors [71]. Although numerous theories as to the molecular basis for how CR prevents and slows cancer have been proposed (see Hursting et al. [32] and Weindruch [70] for reviews), the actual mechanisms remain unclear.

CAUSES AND EFFECTS OF CALORIC RESTRICTION Given the difﬁculty of voluntarily restricting food intake, there is a great deal of interest in understanding the molecular mechanisms underlying the effects of CR well enough to harness the powerful effects; however, ﬁnding a clear, universally satisfying explanation for how CR works has remained elusive. One major issue is that so many molecular and physiological variables are altered with CR that it is difﬁcult to tell the effects of CR from causes; for example, it has been widely observed that chronic CR causes a decrease in core body temperature [52], but the extent to which lowered body temperature and other CR-induced changes contribute to the CR phenotype of retarded aging is unknown. Although many theories of aging and CR have been well discussed over the past three decades, here we highlight two recent areas of investigation into the basis for the CR phenotype.

EFFECT

OF

CR

ON

STEM CELLS

AND

REGENERATIVE POTENTIAL

OF

TISSUES

One theory of aging is that the loss of tissue regenerative potential with age contributes to the aging phenotype. Aged tissues heal less effectively in response to acute injury, and a gradual decline in regeneration regarding basal tissue maintenance occurs [13,34,59]. This has been shown in both proliferative and postmitotic tissues [9,13,39,45]. It is thought that the decline in tissue regeneration with age occurs when stem or precursor cell function decreases to the point where the production of new cells can no longer match cellular turnover in the tissue, leading to a net loss of tissue

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function. Aging decreases the functional capacity of circulating stem cells of the hematopoietic and mesenchymal lineages [19,35], as well as resident tissue-speciﬁc precursors, such as the satellite cells in skeletal muscle [13]. Recent evidence has suggested that in some types of tissue CR increases regenerative potential or stem cell function. CR-mediated improvements in tissue function following acute injury include rescue of cardiac function in post-ischemic hearts [2,43] and enhanced hepatic regeneration following toxin-induced injury [6]. In the latter study, CR was thought to enhance hepatic regeneration by inducing apoptosis of damaged cells and promitotic signaling in healthy cells. The effect of CR on stem or primitive cells has been studied directly. In bone-marrow-derived hematopoietic stem cells, CR not only slowed aging of the stem cells but also enhanced function to the extent that in a repopulation assay stem cells from old CR mice outperformed stem cells from young mice fed ad libitum [12]. CR has also been shown to attenuate the age-associated reduction in T-cell precursors [50], and in another study CR reduced the number of senescent T-cells [64]. This suggests that CR may strengthen the regenerative potential of tissues in part by increasing the potency of the progenitor-type cell population. Recent evidence suggests that CR may exert its effects on regeneration via the circulation. Conboy et al. [13] demonstrated that the regeneration capacity in liver and muscle from old mice can be restored by cross-circulation with a young mouse. The simplest interpretation of this result is that the “CR effect” is carried in the blood stream, at least the part of the effect that is involved in enhancing cellular rejuvenation. Because CR confers a “young” phenotype on many aspects of the hormonal milieu (decreases insulin and IGF-1), it is not surprising that CR may improve tissue regeneration through the circulation [37]. Furthermore, hematopoietic stem cells, which are functionally improved by CR, move through the circulation to sites where they may be involved in tissue regeneration.

EFFECTS

OF

CR

ON

FAT

AND

ADIPOKINES

The recent recognition that white adipose tissue plays a central role in age-related pathologies such as type 2 diabetes and cancer, combined with the fact that white adipose tissue is dramatically remodeled by CR, has led to the suggestion that CR-induced changes in white adipose tissue may play a key role in the CR phenotype [38,56]. Recent experimental evidence indicates that fat is a dynamic endocrine organ that can become dysfunctional and not only secrete hormones that contribute to pathology but also shunt lipids to be stored in other organs, resulting in insulin resistance [24]. Our understanding of the biological signiﬁcance of the peptides and other substances secreted by adipose tissue (sometimes referred to as adipokines) and how they are affected by CR is in its infancy.

HOW DOES CALORIC RESTRICTION AFFECT A REPRESENTATIVE ORGAN SYSTEM (CARDIOVASCULAR SYSTEM)? Caloric restriction has long been established as having powerful anti-neoplastic effects, but more recently interest has grown in determining how CR affects other major causes of human mortality, especially cardiovascular diseases. This question has become particularly important with the dramatic increase in age-associated cardiovascular disease in recent decades. When evaluating the effects of CR on the cardiovascular system, the large majority of studies have been performed on rodents; however, several reports have studied non-human primates or human subjects despite the many methodological difﬁculties and limitations. The ﬁndings of these studies in rodents and primates can be divided into three broad categories with regard to the effect of CR on: (1) systemic hemodynamics and cardiac contractile function, (2) oxidative damage, and (3) gene expression.

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AND

CARDIAC CONTRACTILE FUNCTION

Caloric restriction has been reported to decrease blood pressure and heart rate in rodents [31,69] and blood pressure in non-human primates [47]. This heart rate and blood pressure lowering occurs in normotensive as well as hypertensive animal models and seems to be secondary to increases and decreases in parasympathetic and sympathetic tone, respectively. Mager et al. [44] showed that the decrease in heart rate and blood pressure caused by either CR or intermittent fasting was quickly reversed by switching the animal to an ad libitum diet. The most relevant data from humans comes from the study of a cohort that voluntarily underwent a CR diet regimen for a mean of 6 years [49]. In this study, Meyer et al. compared 25 CR volunteers (body mass index [BMI] = 20, percent fat [%fat] = 9) and 25 age-matched, non-obese controls (BMI = 27, %fat = 26). The CR group had lower systolic (102 vs. 113 mmHg) and diastolic (61 vs. 83 mmHg) blood pressure compared to the control group. Another study using similar subjects revealed an improved blood lipid proﬁle in the CR group [20]. CR increased high-density lipoprotein (HDL) cholesterol (48 vs. 63 mg/dL) and decreased both low-density lipoprotein (LDL) cholesterol (127 vs. 86 mg/dL) and triglycerides (147 vs. 48 mg/dL) compared to the control group. It should be noted that these studies (as is true of all studies on humans) carry important limitations — for example, small sample size and lack of strict control over subject diet intake. Furthermore, these subjects volunteered for CR rather than being randomly placed on CR by the investigators. This, at the very least, suggests a difference in lifestyle between the groups. Another important limitation of this study was the age of the subjects. At the relatively young mean age of 53, neither group would be expected to display a large age-associated decline in cardiovascular function. The effects of CR on cardiac contractile function are most often studied in the context of testing the ability of CR to reverse age-associated changes in left ventricular function. In rodents, CR generally attenuated age-associated changes in echocardiographically measured left ventricular function. Speciﬁcally, CR decreased peak atrial ﬁlling velocity and fraction [67]; intermittent fasting improved cardiac output, pressure work, and efﬁciency [65] and prevented the age-associated reduction in left ventricular contractility [11]. It should be noted that in mice and rats age-associated changes in the heart are relatively small and of unknown signiﬁcance, as mice generally do not die of heart disease. Thus, the extent to which CR-induced changes in left ventricular function contribute to life-span extension is probably minimal. In humans, however, the age-associated decline in cardiovascular function is a major health issue. Cardiovascular function was tested in the same voluntary CR cohort introduced above [49]. CR had no effect on systolic function (which declines little if at all with age) but caused improvement in diastolic function, an age-dependent parameter. Speciﬁcally, CR decreased peak A-wave velocity (53 vs. 46 cm/s) and increased the E/A wave ratio (1.2 vs. 1.6). CR also improved left ventricular chamber viscoelasticity and stiffness compared to control subjects. A critical aspect of the healthy heart is its ability to mitigate and recover from stress-induced damage. CR has proven beneﬁcial in this regard. In rodents, CR was shown to lower heart rate following ischemia [8,43] and swimming stress [69] and to blunt the hypertension-induced increase in the ratio of left ventricular weight to body weight [66]. Experimentally, one way to lessen ischemic damage is to subject the heart to short periods of ischemia prior to a prolonged period of ischemia (ischemic preconditioning). Aged hearts are especially sensitive to damage from ischemia and do not respond to this ischemic preconditioning [1,26]. CR has been shown to restore the beneﬁcial effect of pre-ischemic conditioning in the aged heart, as interpreted by improved developed pressure recovery and increased cardiac output following ischemia [2,43]. This effect of CR has been combined with exercise to achieve an additive result [3].

OXIDATIVE DAMAGE A key hypothesis for the cause of cellular aging is the accumulation of oxidative damage to proteins, lipids, and DNA. The majority of oxidative damage is caused by the production of reactive oxygen species (ROS) in the mitochondria. It is thought that, with aging, ROS production is increased and

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removal of ROS is decreased [25]. Although there is some disagreement on the details, considerable evidence exists that CR improves control over oxidative damage in the heart; for example, the production of ROS was shown to be decreased by 6 weeks of CR [62], although another study showed no change after 4 months of CR [54]. There is more agreement on the expression of enzymes that remove ROS. CR has been demonstrated to increase the levels of catalase, glutathione peroxidase, thioredoxin reductase, and superoxide dismutase [10,16,18,60]. Oxidative damage is also reduced by the presence of antioxidant or reducing molecules in the cell. CR corrects the ageassociated decline in reduced glutathione and coenzyme Q [10,36,57], although one study showed a surprising decline in α-tocopherol levels with CR [36]. Importantly, CR has been shown not only to reduce ROS levels but also to reduce actual oxidative damage to protein [42,53], lipids [16,18], and DNA [63]. Some studies showed a duration dependence. Gredilla et al. [22] demonstrated a decrease in oxidative damage to DNA with 12 months of CR but not with 8 weeks. Forster et al. [21] showed that 12 months of CR decreased protein oxidation, but 6 weeks was less effective. This group also showed that the CR effect was completely lost within a few weeks of being switched back to an ad libitum diet.

GENE EXPRESSION Two research groups have measured the effects of CR on global cardiac gene expression in mice using microarrays. The scope of these studies makes them exceptionally useful for seeing the larger picture of how CR affects the biochemical landscape of the heart. Lee et al. [40] found that, of over 5000 genes analyzed in the heart, 312 were altered by at least 50% with age, and 831 were altered by at least 50% with CR. This study revealed a gene expression pattern that suggests that aging results in a downregulation of fatty acid metabolism (the preferred fuel substrate in the healthy heart) and a subsequent upregulation of glucose metabolism. CR, however, reversed much of this age-dependent “fuel-switching” pattern. Additionally, CR was shown to induce genes involved in DNA repair and to downregulate genes involved in programmed cell death (apoptosis). Recently, Dhahbi et al. [15] compared gene expression in both short- and long-term CR, and the effect of going back to an ad libitum diet after the CR diet. Eight weeks of CR produced 19% of the gene expression changes as 22 months of CR, in line with studies showing that, although many changes occur quickly, the beneﬁt of CR increases with time. Interestingly, 97% of CRinduced changes in gene expression were completely reversed within only 8 weeks of the animals switching back to an ad libitum diet. In summary, caloric restriction has a profound effect on the physiology and biochemistry of the heart. By and large, the available data suggest that this effect is a positive one; however, many important details about how CR affects the human cardiovascular system are lacking due to the sparse human data available, being primarily from observations of overweight subjects in experiments that were not strictly controlled. Although the beneﬁt of CR is quite robustly illustrated in many experimental models in non-humans, more meaningful insights should come from additional well-controlled studies in non-obese humans.

WILL CALORIC RESTRICTION WORK IN HUMANS? One of the most frequently asked questions in the ﬁeld of CR is: “Will a CR diet work in humans, and if it does, will the sacriﬁces be worth it?” Much of the answer to this question depends on whether one is discussing disease prevention or anti-aging and extension of maximal life span. It is clear that some level of CR would provide most Americans with an important degree of disease prevention, as the data in Table 21.1 indicate [20]; however, the question of whether CR retards aging and extends maximal life span in humans is more complicated. Several theoretical reasons for believing that CR will not provide these kinds of beneﬁts to humans are discussed extensively

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TABLE 21.1 Effects of Chronic Caloric Restriction on Blood Pressure and Blood Lipids in Humans Value Parameter

Pre-CR

1 Year CR

Present

BMI (kg/m )

24.5 ± 2.6

20.9 ± 2.4

19.5 ± 2.1

Total cholesterol (mg/dL)

194 ± 45

161 ± 31

157 ± 38

LDL cholesterol (mg/dL)

122 ± 36

89 ± 24

86 ± 17

HDL cholesterol (mg/dL)

43 ± 8

58 ± 13

65 ± 24

Total/HDL cholesterol ratio

4.1 ± 1

2.8 ± 0.5

2.5 ± 0.4

Total triglycerides (mg/dL)

149 ± 87

72 ± 35

54 ± 15

Systolic blood pressure (mmHg)

132 ± 15

112 ± 12

97 ± 8

Diastolic blood pressure (mmHg)

80 ± 11

69 ± 7

59 ± 5

2

Note: Values are means ± SD for 12 individuals. Source: Fontana, L. et al., Proc. Natl. Acad. Sci. USA, 101, 6659–6663, 2004. With permission.

elsewhere [17,55]. They include the suspicion that humans will not be willing or able to restrict calories to the required levels at an early enough age to garner any signiﬁcant beneﬁts. Because it is unlikely that survival curves such as those shown in Figure 21.1 will ever be generated to directly answer this question, we must look at available data. Additionally, the question of “Is it worth it?” can only be answered when the costs and beneﬁts of various CR regimens are known. The obvious costs include nearly constant hunger, which does not seem to dissipate with time. This issues raises the interesting philosophical question of whether or not a person would extend his or her life by a few years if it meant being almost constantly hungry. Clearly, various people would answer this question very differently, and the hope is that they could make informed choices based on complete knowledge of the costs and beneﬁts. Currently, however, we have only a poor idea of the beneﬁts and costs in humans. It should be recognized that the importance of studying the basic biological causes of CR-induced retardation of aging does not depend on a “yes” answer to the question of “Is it worth it?” because this area of research may lead to a pharmacological way of reproducing some of the beneﬁts of CR.

EFFECTS

OF

CR

IN

HUMANS

Recently, it has been demonstrated that humans can voluntarily submit to a CR diet in at least two settings. The ﬁrst is self-selected individuals who have decided to follow a CR diet [20,49]. Despite the obvious methodological problems, this approach has provided some intriguing data, particularly when longitudinal data are available from before the CR was initiated in the individual (Table 21.1) [20]. It would be difﬁcult to argue that these changes in blood pressure and blood chemistry are not desirable consequences of voluntary restriction of caloric intake. Note that the pre-CR BMI is within the non-obese normal range, suggesting that these individuals reﬂect the general American population prior to initiating CR in an important way. Data from these individuals are intriguing but relatively uncontrolled with regard to some factors, such as composition of the diet, that may contribute to improved cardiovascular health; however, these individuals clearly demonstrate that at least some people can restrict caloric intake to low chronic levels with impressive cardiovascular beneﬁts.

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A second group of individuals that has voluntarily undergone CR is composed of those involved in a National Institutes of Health (NIH)/National Institute on Aging (NIA)-sponsored randomized multicenter trial (Comprehensive Assessment of the Long-Term Effects of Reducing Intake of Energy, or CALERIE) [27]. In part of this long-term research effort, 48 healthy, sedentary adults 27 to 49 years old were randomized to one of four groups: (1) controls (weight maintenance), (2) 25% CR, (3) 12.5% CR plus exercise, or (4) 890 kcal/day until 15% decrease in body weight. Importantly, the subjects entered the study overweight (BMI = 28; %fat = 32), so some of the effects noted may be due to normalization of body weight. Over the 6 months of the study, the CR and CR plus exercise groups lost weight at a rate of approximately 3 lb/month, whereas the 890 kcal/day group lost approximately 23 lb in 10 weeks, after which body weight was maintained. Several noteworthy ﬁndings arose from this study. First, under these carefully controlled circumstances, the highly motivated volunteers were able to tolerate a moderate degree of caloric restriction. Second, some, but not all, biomarkers of CR established in rodents changed as predicted; for example, CR did not affect blood glucose or DHEA levels as one might expect from rodent data, whereas 6 months of CR signiﬁcantly decreased insulin levels in all three groups. Intriguingly, DNA damage, but not the levels of protein carbonyls, was decreased in all three CR groups. Longer term studies should yield interesting additional information.

CALORIC RESTRICTION MIMETIC DRUGS Given the above-mentioned difﬁculties and uncertainties regarding CR in humans, there is intense interest in trying to reproduce some of the beneﬁcial effects of CR pharmacologically [33,61]. As more information about the molecular basis for the effects of caloric restriction becomes available, the search for compounds that mimic the effects of CR becomes more rational and focused. Because the beneﬁts of CR are not directly linked to weight loss, a weight loss drug per se is not the goal. In general, the two pharmacological strategies for CR mimetics are ﬁnding drugs that reproduce the general metabolic state of food deprivation and ﬁnding agonists/antagonists of speciﬁc molecules that are thought to be upstream in the pathway by which CR retards aging. In the ﬁrst category is the structural analog of glucose, 2-deoxy-D-glucose (2-DG), which acts as a competitive inhibitor of glycolysis. Although 2-DG has shown great therapeutic potential in some settings, the extent to which it mimics the effects of CR at nontoxic doses appears limited [33]. A second member of this category is insulin sensitizers, such as the commonly used antidiabetes drug metformin. The rationale for this approach centers on the observation that CR causes a broad insulin sensitization of tissues that has been implicated in the anti-aging phenotype of CR animals. Consistent with a central role of endocrine effects of CR, studies in species including Caenorhabditis elegans, Drosophila, and rodents suggest that the CR-induced life-span extension may be related to alterations in insulin or insulin-like growth factor signaling that retard cellular aging [5,68]. Using microarray analysis of the liver, Dhahbi et al. [14] found that 8 weeks of metformin treatment in mice produced 75% of the changes in gene expression that were produced by long-term CR. To put this number in perspective, 8 weeks of CR produced only 71% of the changes in expression observed during long-term CR. This dramatic mimicking of CR by metformin was observed to a much weaker degree with other putative CR mimetics such as glipizide (16%), rosiglitazone (17%), or soy isoﬂavone extract (11%). Thus, not only does metformin show great potential as a CR mimetic, but it can also be inferred that insulin sensitization is relatively far upstream with regard to causing the broad changes in gene expression observed with long-term CR. In addition to drugs that reproduce the general effects of food deprivation, exciting recent work has also focused on agonists of speciﬁc molecules. Most notably, Howitz et al. [30] found that resveratrol (a naturally occuring polyphenol that is present in red grape skins and red wine) increases the replicative life span of yeast by stimulating the histone deacetylase sir2 [30]. This group also reported that resveratrol extends life span in Drosophila melanogaster and stimulates the mammalian homolog SIRT1. The extent to which these ﬁnding are applicable to mammals

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has not yet been determined. Some have speculated that the effects of CR on aging and longevity in mammals may be caused by a CR-induced increase in SIRT1 activity [23]. While the extent to which CR affects SIRT1 in mammals has not been clearly deﬁned, this is an area of great scientiﬁc interest.

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Obesity: Epidemiology, Pathophysiology, and Prevention Mager, D.E., Wan, R., Brown, M., Cheng, A., Wareski, P. et al., Caloric restriction and intermittent fasting alter spectral measures of heart rate and blood pressure variability in rats, FASEB J., 20, 631–637, 2006. Martin, K., Potten, C.S., Roberts, S.A., and Kirkwood, T.B., Altered stem cell regeneration in irradiated intestinal crypts of senescent mice, J. Cell. Sci., 111(Pt. 16), 2297–2303, 1998. Masoro, E.J., Subﬁeld history: caloric restriction, slowing aging, and extending life, Sci. Aging Knowl. Environ., 2003(8), RE2, 2003. Mattison, J.A., Lane, M.A., Roth, G.S., and Ingram, D.K., Calorie restriction in rhesus monkeys, Exp. Gerontol., 38, 35–46, 2003. McCay, C.M., Crowell, M.F., and Maynard, L.A., The effect of retarded growth upon the length of life span and upon the ultimate body size, Nutrition, 5, 155–172, 1989. Meyer, T.E., Kovacs, S.J., Ehsani, A.A., Klein, S., Holloszy, J.O., and Fontana, L., Long-term caloric restriction ameliorates the decline in diastolic function in humans, J. Am. Coll. Cardiol., 47, 398–402, 2006. Miller, R.A. and Harrison, D.E., Delayed reduction in T cell precursor frequencies accompanies dietinduced lifespan extension, J. Immunol., 134, 1426–1429, 1985. Osborne, T.B., Mendel, L.B., and Ferry E.L., The effect of retardation of growth upon the breeding period and duration of life in rats, Science, 45, 294–295, 1917. Overton, J.M. and Williams, T.D., Behavioral and physiologic responses to caloric restriction in mice, Physiol. Behav., 81, 749–754, 2004. Pamplona, R., Barja, G., and Portero-Otin, M., Membrane fatty acid unsaturation, protection against oxidative stress, and maximum life span: a homeoviscous-longevity adaptation?, Ann. N.Y. Acad. Sci., 959, 475–490, 2002. Pamplona, R., Portero-Otin, M., Requena, J., Gredilla, R., and Barja, G., Oxidative, glycoxidative and lipoxidative damage to rat heart mitochondrial proteins is lower after 4 months of caloric restriction than in age-matched controls, Mech. Ageing Dev., 123, 1437–1446, 2002. Phelan, J.P. and Rose, M.R., Why dietary restriction substantially increases longevity in animal models but won’t in humans, Ageing Res. Rev., 4, 339–350, 2005. Picard, F. and Guarente, L., Molecular links between aging and adipose tissue, Int. J. Obes. (Lond.)., 29(Suppl. 1), S36–S39, 2005. Rebrin, I., Kamzalov, S., and Sohal, R.S., Effects of age and caloric restriction on glutathione redox state in mice, Free Radic. Biol. Med., 35, 626–635, 2003. Rehm, S., Rapp, K.G., and Deerberg, F., Inﬂuence of food restriction and body fat on life span and tumour incidence in female outbred Han:NMRI mice and two sublines, Z. Versuchstierkd., 27, 240–283, 1985. Roh, C. and Lyle, S., Cutaneous stem cells and wound healing, Pediatr. Res., 59, 100R–103R, 2006. Rohrbach, S., Gruenler, S., Teschner, M., and Holtz, J., The thioredoxin system in aging muscle: key role of mitochondrial thioredoxin reductase in the protective effects of caloric restriction?, Am. J. Physiol. Regul. Integr. Comp. Physiol., 291, R927–R935, 2006. Roth, G.S., Lane, M.A., and Ingram, D.K., Caloric restriction mimetics: the next phase, Ann. N.Y. Acad. Sci., 1057, 365–371, 2005. Sanz, A., Gredilla, R., Pamplona, R., Portero-Otin, M., Vara, E. et al., Effect of insulin and growth hormone on rat heart and liver oxidative stress in control and caloric restricted animals, Biogerontology, 6, 15–26, 2005. Sohal, R.S., Agarwal, S., Candas, M., Forster, M.J., and Lal, H., Effect of age and caloric restriction on DNA oxidative damage in different tissues of C57BL/6 mice, Mech. Ageing Dev., 76, 215–224, 1994. Spaulding, C.C., Walford, R.L., and Effros, R.B., The accumulation of non-replicative, non-functional, senescent T cells with age is avoided in calorically restricted mice by an enhancement of T cell apoptosis, Mech. Ageing Dev., 93, 25–33, 1997. Starnes, J.W. and Rumsey, W.L., Cardiac energetics and performance of exercised and food-restricted rats during aging, Am. J. Physiol., 254, H599–H608, 1988. Swoap, S.J., Boddell, P., and Baldwin, K.M., Interaction of hypertension and caloric restriction on cardiac mass and isomyosin expression, Am. J. Physiol., 268, R33–R39, 1995.

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Taffet, G.E., Pham, T.T., and Hartley, C.J., The age-associated alterations in late diastolic function in mice are improved by caloric restriction, J. Gerontol. A Biol. Sci. Med. Sci., 52, B285–B290, 1997. Tatar, M., Bartke, A., and Antebi, A., The endocrine regulation of aging by insulin-like signals, Science, 299, 1346–1351, 2003. Wan, R., Camandola, S., and Mattson, M.P., Intermittent fasting and dietary supplementation with 2-deoxy-D-glucose improve functional and metabolic cardiovascular risk factors in rats, FASEB J., 17, 1133–1134, 2003. Weindruch, R., Effect of caloric restriction on age-associated cancers, Exp. Gerontol., 27, 575–581, 1992. Weindruch, R. and Walford, R.L., Dietary restriction in mice beginning at 1 year of age: effect on life span and spontaneous cancer incidence, Science, 215, 1415–1418, 1982. Weindruch, R., Walford RL., Fligiel, S., and Guthrie D., The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake, J. Nutr., 116, 641–654, 1986. Sohal, B.H. and Weindruch, R., Oxidative stress, caloric restriction, and aging, Science, 273, 59–63, 1996.

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Supplement 22 Dietary Carbohydrate Digestion Inhibitors: A Review of the Literature Jay Udani, Mary Hardy, and Ben Kavoussi CONTENTS Introduction ....................................................................................................................................280 Background .............................................................................................................................281 Carbohydrate Digestion ..........................................................................................................281 Carbohydrate Digestion Inhibitors (Starch Blockers): Mechanism of Action ......................282 Methods to Test for Carbohydrate Malabsorption .................................................................283 Hydrogen Breath Testing.................................................................................................283 Ileal Fluids .......................................................................................................................283 Blood Tests ......................................................................................................................283 Glucagon-Like Peptide 1.................................................................................................283 Glucagon ..........................................................................................................................284 Gastric Inhibitory Polypeptide ........................................................................................284 Serial Serum Acetate .......................................................................................................284 C-Peptide..........................................................................................................................284 Stool Tests for Carbohydrate Malabsorption ..................................................................284 Urine Tests for Carbohydrate Malabsorption..................................................................284 Clinical Studies for Carbohydrate Digestion and Absorption ......................................................284 Unpuriﬁed White Bean Products............................................................................................284 Carbolite Starch Blocker Study (1982)...........................................................................284 Unpublished North Dakota State Study (1982) ..............................................................285 Commercial Alpha-Amylase Inhibitor Study (1983)......................................................285 13C-Enriched Starch Tracer Study (1983) .......................................................................285 American Journal of Clinical Nutrition Study (1983) ...................................................285 Partially Puriﬁed White Bean Extract Studies .......................................................................286 Partially Puriﬁed White Bean Extract (1984) .................................................................286 Partially Puriﬁed White Bean Extract (1986) .................................................................286 Partially Puriﬁed White Bean Extract (1987) .................................................................286 Partially Puriﬁed White Bean Extract (1988) .................................................................286 Partially Puriﬁed White Bean Extract (1989) .................................................................287 Non-Kidney-Bean Alpha-Amylase Inhibitors ........................................................................287 Tendamistat (HOE 467) Study (1983) ............................................................................287 Tendamistat (HOE 467) Studies (1984)..........................................................................287 Wheat Alpha-Amylase Inhibitor (1998)..........................................................................288 279

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Phase 2® White Bean Extract Studies for Reducing Glucose Excursion..............................288 University of Scranton (September 2001) ......................................................................288 University of Scranton (November 2001).......................................................................288 University of Scranton (May 2002) ................................................................................288 University of Scranton (September 2003) ......................................................................289 Glycemic Index Lowering Study (2005) ........................................................................289 Carbohydrate Digestion Inhibitor Studies for Weight Loss..........................................................289 White Kidney Bean Extracts: Partially Puriﬁed ....................................................................289 Norwegian Study (2000) .................................................................................................289 Phase 2® White Bean Extract Clinical Studies for Weight Loss...........................................289 Italian Study (2001).........................................................................................................289 Northridge Hospital Study (2002)...................................................................................291 Leiner Softchew Study (2003) ........................................................................................291 TheraSlim™ Study (2003) ..............................................................................................292 SCUHS Study (2004) ......................................................................................................292 Safety..............................................................................................................................................293 Discussion ......................................................................................................................................293 Conclusion......................................................................................................................................294 Disclosures .....................................................................................................................................294 References ......................................................................................................................................294

INTRODUCTION The estimated prevalence of diabetes worldwide for the year 2000 was 177 million people ages 20 to 79 years, of whom 85 to 95% had type 2 diabetes [2]. The total prevalence of diabetes in the United States for all ages in 2002 was estimated to be 18.2 million people (6.3% of the population), of which an estimated 13.0 million people were diagnosed and the remaining 5.2 million undiagnosed [3]. As for obesity, it affects nearly one third of the adult American population (approximately 60 million) and remains the second leading cause of unnecessary deaths in the United States [4]. In response to these interrelated health epidemics, the medical community and the lay public have turned to various caloric restriction strategies, both for reducing body mass to treat obesity and for the glycemic control required in diabetes. These strategies aim to alter glucose and carbohydrate metabolism, control insulin production, and alter the cellular response to insulin. Among these products are carbohydrate digestion inhibitors such as alpha-amylase inhibitors and alpha-glucosidase inhibitors. The proposed mechanism of action of these products appears to stem from their ability to partially inhibit, or delay, the breakdown of complex carbohydrates into absorbable constituents (mono- and disaccharides). This inhibition may lead to a delay in the absorption rate of glucose, a decrease in the subsequent insulin rise, a decrease in plasma triglycerides (TAG), an increase in high-density lipoprotein (HDL), the prevention of adipose deposition, and the control of hunger through a variety of mechanisms. It is also theoretically possible that these products decrease the total number of calories absorbed from complex-carbohydrate-containing foods. Either way, and regardless of the mechanism of action, carbohydrate digestion inhibitors have the potential to decrease insulin resistance and possibly contribute to weight loss. The general public is already using many other methods for weight loss and glucose control, such as nonprescription products (herbs, vitamins, and nutritional supplements), as well as meal replacement preparations (shakes, low-caloric frozen diners). Because scientiﬁcally rigorous studies have not been performed on many of these products, in many cases, safety and efﬁcacy have taken a back seat to marketing.

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In this chapter, we review the evidence for the efﬁcacy of a category of nutritional supplements known as carbohydrate digestion inhibitors, or starch blockers. This has been an area of great interest and debate since the 1980s, and we have chosen to review the clinical evidence from that time forward to provide a historical perspective on the utilization of nutritional alpha-amylase inhibitors.

BACKGROUND Alpha-amylase is a digestive enzyme secreted by the salivary glands and by the pancreas and is responsible for breaking down starch for absorption. Recent interest in low-carbohydrate diets has heightened the public’s desire to reduce their carbohydrate intake. If a substance were to competitively bind alpha-amylase and inhibit its enzymatic activity, it could prevent the digestion and subsequent absorption of complex carbohydrates. Such a product would be of particular interest to those who have become very concerned with the carbohydrate content of their food. The purpose of this review is to evaluate the scientiﬁc and historical background of nutritional alpha-amylase inhibitors to determine their therapeutic value as an adjunctive treatment for diabetes and obesity.

CARBOHYDRATE DIGESTION Dietary carbohydrates are found in three forms: plant-based starches, animal-based glycogen, and disaccharides found in fruit, milk, and reﬁned sugars. Of these, starch accounts for the largest percentage of the carbohydrate found in human food. The two main sources of dietary starches are naturally occurring starches and processed starches. Naturally occurring starches, found in vegetables, fruits, cereals, and legumes, are primarily complex carbohydrates. Processed starches are derived from natural sources but are further processed, puriﬁed, or reﬁned. They are used mainly in convenience foods as thickeners, bulking agents, ﬁllers, and as a base for color and ﬂavors. Under normal conditions, the digestion of carbohydrates begins in the mouth with amylase produced by the salivary glands and continues in the duodenum by amylase and other enzymes produced by the exocrine pancreas. Acids (such as HCl in the stomach) and enzymes (such as alpha-amylase secreted by the salivary glands and by the pancreas) are responsible for digesting carbohydrate oligosaccharides (of molecular weight >100,000) into dextrins (polysaccharides), which get hydrolyzed to glucose (monosaccharides). The end result of carbohydrate digestion is the production of mono- and disaccharides that are absorbed by the brush border of the small intestine. The ﬁnal conversion from disaccharides to monosaccharides occurs during absorption. Although starch hydrolysis by amylase is the rate-limiting step in starch digestion [5], alternative pathways of carbohydrate digestion include small-bowel wall brush border mucosal glucoamylases and maltase [7,11]. Once absorbed, these sugars are delivered to the liver via the portal vein and enter into intermediary metabolism. Glucose in excess of the immediate energy requirements is converted into fatty acids and triglycerides and stored either as glycogen in the liver and skeletal muscle or as adipose tissue. Despite their biochemical similarities, starches vary greatly in their digestibility. Certain noncereal starches (potatoes and legumes) are more complex and more difﬁcult to digest than cereal starches. In addition, certain naturally occurring food starches, such as banana starch and 2 to 5% of potato starch, are resistant to amylase [8]. The ingestion of easily digested highly processed, puriﬁed, or reﬁned starches results in a more rapid production and absorption of glucose. The relative amount of glucose released during digestion of carbohydrate is the glycemic load, and complex starches have a relatively low glycemic load compared to reﬁned carbohydrates such as sugar. The slowing of starch digestion based on the type of starch can be exploited clinically by adding complex carbohydrate, such as ﬁber, to more reﬁned carbohydrate to slow glucose absorption and blunt the insulin response to a sharp glucose peak. Also, it has been noted that the addition of ﬁber to carbohydrates is more effective in reducing the postprandial glucose curve (as measured by the glycemic index) when incorporated into the food rather than when taken before the food [6].

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It has also been noted that the pancreas continuously produces amylase in response to nutrient ingestion [7] and that the pancreas secretes more amylase than is necessary to digest a particular carbohydrate nutrient load [8]. Absolute levels of amylase vary with age, sex, and the health of the pancreas, and the levels are found to be higher in the elderly, especially in women in the third and fourth decades of life when compared with men; however, starch digestion is not affected by pancreatic disease unless the amylase output is signiﬁcantly decreased to a very low level [9]. It has been noted that only 4% of the produced alpha-amylase is required to digest large amounts of starch and, conversely, that greater than 96% of pancreatic alpha-amylase has to be blocked to induce carbohydrate malabsorption and the resulting presence of undigested carbohydrate in the gut [7]. Carbohydrates not digested and absorbed in the small bowel are fermented by the symbiotic bacteria in the colon [10]. It is felt that anaerobic bacteria (such as bacteroides and clostridia) are responsible for this fermentation because the addition of metronidazole can reduce the response to a colonic sucrose load [11]. This fermentation process produces CO2 gas, short-chain fatty acids, organic acids, and hydrogen gas [12], which can be measured by a standard hydrogen breath test (H2BT).

CARBOHYDRATE DIGESTION INHIBITORS (STARCH BLOCKERS): MECHANISM OF ACTION Blocking alpha-amylase may prevent or delay the digestion of complex carbohydrates, as the breakdown of starch into simple sugars cannot proceed without amylase. The end result of blocking this enzyme may be a decrease in the glucose absorption rate or in the total number of calories absorbed from carbohydrate-containing food. One strategy consists of mixing starchy staples (rice, wheat, corn, etc.) with legumes (beans, lentils, etc.). Legumes have been shown to safely inactivate intraduodenal alpha-amylase and reduce starch digestion. A very general study on the use of various bean ﬂours to lower the glycemic index of starch foods was published by Layer et al. in 1985 [13]. It found that the white kidney bean (Phaseolus vulgaris) extract had the highest salivary and pancreatic alpha-amylase inhibition rate among legumes. The literature also indicates that the preparation and level of grinding of bean ﬂours have been found to affect postprandial glycemic and insulin levels to an important degree. White kidney bean extracts bind to alpha-amylase in noncompetitive fashion, optimally at a pH of 5.5, forming a 1:1 molar complex [14]. Similar binding can be seen at neutral pH, as well. White bean extracts are not expected to have any activity on the brush-border enzyme maltose/glucoamylase as evidenced by an in vitro study [12]. In addition to the glucose- and calorie-reducing potential, alpha-amylase inhibitors may contribute to the control of hunger and appetite by other mechanisms: •

•

•

Satiety — Satiety might be induced through two indirect mechanisms of action. The white kidney bean has been shown to decrease gastric inhibitory polypeptide, which decreases stomach motility. In addition, increasing the delivery of carbohydrates to the ileum (small intestine) may itself cause a slowing of gastric motility [15,16]. Insulin — By decreasing the effective glycemic index of a particular food, the alphaamylase inhibitor may decrease the magnitude of the insulin response, which in turn decreases hunger. Leptin – Elevated triglycerides induce leptin resistance and elevate leptin levels. Lowering triglycerides reduces leptin levels, which may induce the desired anorectic effect by increasing leptin transport across the blood–brain barrier [17]. Alpha-amylase inhibitors may be effective in lowering triglycerides [18], and as such they may increase the effectiveness of leptin.

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It must be noted that, according to the literature, the coingestion of saturated and monounsaturated fats with starches raises the blood glucose response area. The insulin rise is reported by Rasmusen et al. [67] to be signiﬁcant for the coingestion of butter but less for olive oil. Reportedly, the triacylglycerol response also increased in a dose-dependent manner with the fat content of the meals, regardless of the type of fat. The mechanism by which saturated fatty acids increase insulin release is not precisely known but so far appears to involve physiological mechanisms other than that of alpha-amylase inhibition [19].

METHODS

TO

TEST

FOR

CARBOHYDRATE MALABSORPTION

Hydrogen Breath Testing Hydrogen breath testing is an accepted method of determining carbohydrate malabsorption [20–22]. When determining carbohydrate malabsorption, orocecal transit time can be measured as well [22]. As colonic bacteria ferment carbohydrates into organic acids, CO2, and H2, a percentage of these gaseous byproducts are absorbed into the portal blood stream and are subsequently expired through the lungs. The lactulose H2BT is a valid measurement of the mean amount of starch that is metabolized in the colon by the bacterial fermentation process [23]. The large individual variations in the amount of H2 produced are due to the large individual variations in the composition of the colonic bacterial ﬂora. Determining baseline levels of H2 is not as important as measuring how much the H2 levels rise after lactulose reaches the colon. The sensitivity and speciﬁcity of the H2BT for detecting carbohydrate malabsorption with 10 g of carbohydrate approach 100% when the increase from baseline is considered positive at 15 ppm rather than at the traditional range of 20 ppm [21]. Approximately 15% of normal healthy subjects have colonic bacteria that do not produce hydrogen, even in response to carbohydrate malabsorption [24]. It is possible that starch malabsorption is underestimated in methane producers as well [25]. In addition, methane producers have more varied excretory patterns than non-methane producers [26]. Another study, however, demonstrated that methane production was elevated in the presence of carbohydrate malabsorption even when breath H2 did not change [27]. Population-based differences in the H2BT have been observed, as well; for example, the percentage of the general population who fail to respond to a lactulose challenge is 2% in the United States and as high as 20% in Israel. This may be due to dietary differences [28]. Ileal Fluids Ileal intubation or ﬂuid from subjects with ileostomies is the most reliable source for identifying carbohydrate malabsorption in the small bowel [10]. Data suggest, however, that the H2BT can detect the amount of carbohydrates that enter the colon almost as well as directly measuring ileal efﬂuent in subjects with ileostomies [29]. Blood Tests Several blood tests have been utilized to measure carbohydrate digestion or malabsorption. These are indirect markers, as none of them directly measures carbohydrates. In addition, some blood markers may be important in determining hunger and feeding behaviors that may be altered by the white kidney bean or similar substances. Glucagon-Like Peptide 1 Glucagon-like peptide 1 (GLP-1) is secreted after nutrient ingestion and promotes glucagonostatic activity as part of the enteroinsular axis. A study with acarbose, an alpha-glucosidase inhibitor, resulted in prolonged GLP-1 release in normal subjects [30].

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Glucagon Glucagon is a counter-regulatory hormone to insulin [31] that has been shown to be suppressed by acarbose [30]. Gastric Inhibitory Polypeptide Gastric inhibitory polypeptide (GIP) initiates stimulation of glucose-dependent insulin secretion. This hormone has been shown to be suppressed by acarbose [30] and by a partially puriﬁed white bean alpha-amylase inhibitor [16]. Serial Serum Acetate Serum acetate levels have not been shown to be an effective measurement of carbohydrate malabsorption [10]. C-Peptide C-Peptide is elevated in the presence of large glucose loads [16]. Stool Tests for Carbohydrate Malabsorption Although bomb calorimeter tests in a small number of subjects showed no difference in fecal calorie counts between white bean alpha-amylase inhibitor and placebo, this test has some limitations. If undigested carbohydrates were to be delivered to the colon, a portion of those calories may be fermented into gas. This would be identiﬁed by the H2BT but not by the bomb calorimeter. Urine Tests for Carbohydrate Malabsorption Urine ketones are present in the absence of digested carbohydrates. They may be a helpful marker for demonstrating the absence of carbohydrate absorption.

CLINICAL STUDIES FOR CARBOHYDRATE DIGESTION AND ABSORPTION The studies summarized below show the evolution of data from low-dose and unpuriﬁed white bean products through partially puriﬁed products to highly puriﬁed white bean extracts. It appears that these products may have a dose- and puriﬁcation-dependent effect. At the same time, a threshold level of greater than 90% inhibition of amylase is required before any carbohydrate malabsorption is seen. Below this threshold, incomplete inhibition of amylase may not have any signiﬁcant effect on carbohydrate malabsorption [32].

UNPURIFIED WHITE BEAN PRODUCTS The earliest studies of white-bean-based amylase inhibitors utilized crude bean extracts and failed to show effectiveness based on either fecal calorie excretion [8] or plasma glucose and insulin responses [12]. Carbolite Starch Blocker Study (1982) In 1982, the New England Journal of Medicine published a crossover study that tested the ability of a crude extract to inhibit the digestion of a high-carbohydrate meal. First, the GI tracts of ﬁve healthy subjects between the ages of 25 and 34 were cleansed using an electrolyte solution [8].

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The subjects were given a standardized meal consisting of 100 g of spaghetti and 50 g of white bread along with 1000 mg of the Carbolite starch blocker or an identical-looking placebo. They then ate a test meal consisting of 100 g of starch which had been labeled with 51CrCl3, a nonabsorbable marker. The subjects each took a 500-mg tablet of the test product or placebo, ate half of the meal, and then took the second tablet. Subjects then fasted for 14 hours. Stools were collected and a bomb calorimeter was used to measure fecal calories. No differences were found in fecal calorie excretion between those who were given the placebo and those who were administered the test product. The authors admit that some calories may have been converted to gas and that the calories that could not be accounted for [8] would have been better identiﬁed by the H2BT and not by the bomb calorimeter [7]. Unpublished North Dakota State Study (1982) Prior to a test meal, seven subjects received 500 mg of an unpuriﬁed starch blocker or a placebo in a crossover study to test the short-term effect of the starch blocker on glucose levels. The test meal consisted of instant mashed potatoes in the quantity of 1 g of starch per kg of ideal body weight. Blood glucose levels were followed at 30, 60, 90, 120, and 180 minutes postprandially. No adverse events were seen. The glucose levels of the treated subjects were signiﬁcantly lower at 60 and 90 minutes. The study reported a 38% reduction in blood glucose with treatment and concluded that the starch-block meal resulted in 38% less starch digestion compared to the control meal [7]. This conclusion is not supported by the evidence presented. Commercial Alpha-Amylase Inhibitor Study (1983) Six healthy adult males were given a commercial alpha-amylase inhibitor or a placebo in a crossover trial with a 7-day washout between trials. The authors report no effect on the postprandial glucose, insulin, or H2BT after a standardized starch-containing meal [33]. The amylase inhibitor was crushed and mixed in with the meal rather than given as a capsule. It was postulated that this delivery mechanism may have subjected the active ingredient to stomach enzymes, thereby inactivating the ingredient [7]. 13

C-Enriched Starch Tracer Study (1983)

Five obese but otherwise healthy women were sequentially given three meals of corn ﬂour enriched with 13C. They received one of two different starch blockers (Calorex brand or Starchex brand) or a placebo 10 minutes before each meal. Detailed descriptions of the starch blockers were not provided in the Materials and Methods sections to characterize the differences between the two active products. Subjects were followed for 6 hours after each meal, and no differences were observed in the rate of breath 13CO2 production, insulin, or glucose between the groups [34]. American Journal of Clinical Nutrition Study (1983) Hollenbeck et al. [12] reported in 1983 in the American Journal of Nutrition the results of a randomized, double-blind, placebo-controlled crossover study using the hydrogen breath test to determine the efﬁcacy of a crude bean extract (Paciﬁc International Laboratories). In this study, six healthy subjects were given a standardized test meal. (Eight subjects were screened for the study, but two were dropped from the ﬁnal analysis because one had been taking antibiotics and one did not respond to the lactulose breath test.) The meal consisted of 686 kcal, of which 55% was carbohydrate (50% starch and 50% sucrose). The subjects received either 500 mg of Phaseolamin 2250® (white kidney bean) or a placebo with their meals and then had hydrogen breath tests every 30 minutes for 300 minutes. The study found no differences between the treated and placebo groups; however, it is noted that only 198 calories came from starch. The majority (71%) of the

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carbohydrate load was in the form of sucrose, which is not affected by alpha-amylase; thus, this may not have been an appropriate test meal. Glucose levels were also not found to be statistically signiﬁcant different between the treated and placebo groups.

PARTIALLY PURIFIED WHITE BEAN EXTRACT STUDIES A research group from the Mayo Clinic developed a partially puriﬁed white bean product and published a series of studies on this product in the 1980s. This puriﬁed bean-derived amylase inhibitor has been shown to signiﬁcantly reduce duodenal, jejunal, and ileal amylase activity by more than 95% for 1 to 2 hours after ingestion. It has also been shown to increase postprandial delivery of total carbohydrates (including glucose polymers) to the distal small bowel as evidenced by increased breath hydrogen levels. In addition, this bean extract has been documented to reduce early postprandial plasma glucose rise by 85% and to eliminate the late postprandial glucose fall to below fasting levels. It has also been shown to reduce the postprandial plasma insulin levels [15]. Partially Purified White Bean Extract (1984) A study of seven healthy, non-obese subjects who underwent gastroduodenal intubation demonstrated that the increasing concentrations of a partially puriﬁed white bean extract caused the inhibition of amylase in a dose-dependent manner. Patients were subjected to continuous infusions of amino acids designed to stimulate the pancreatic secretions. Simultaneously, a continuous aspiration of gastric and duodenal contents was also performed following instillation of the white bean extract. Amylase activity was measured from these aspirations, and this study demonstrated a 94%, 99%, and 99.5% inhibition of amylase at 2.0-, 3.5-, and 5.0-mg/mL infusions, respectively, of the amylase inhibitor. Despite this almost complete inhibition, H2 breath testing did not change for up to 4 hours after the infusion [14]. Partially Purified White Bean Extract (1986) Four healthy, non-obese volunteers were intubated with an oroileal tube prior to ingesting 50 g of rice starch with placebo or 5 g of white bean extract or 10 g of white bean extract. Part of the placebo and white bean extract dose were given at the beginning of the meal to inactivate the alphaamylase present in the intestinal lumen before the meal. The remainder of the dosage was delivered during the middle of the meal. The white bean extract signiﬁcantly reduced duodenal, jejunal, and ileal intraluminal amylase activity by more than 95% in as soon as 15 minutes and for as long as 2 hours. It also increased the delivery of carbohydrates to the small bowel by 22 to 24% (as measured by oroileal tube aspiration) and increased the breath H2 concentrations signiﬁcantly between 30 and 90 minutes after the meal. Additionally, it signiﬁcantly lowered the glucose, insulin, C-peptide, and gastric inhibitory polypeptide levels [15]. Partially Purified White Bean Extract (1987) Eight healthy subjects with a positive breath H2 test to lactulose (deﬁned as >10 ppm increase over baseline) were given 2.0 g or 2.9 g of partially puriﬁed white bean extract mixed in water with a standardized meal. The placebo and the 2.0-g dose did not result in any change in the H2BT. The 2.9-g dose showed a signiﬁcant increase in the H2BT between 45 and 180 minutes after the meal. It was estimated that less than 2% of the meal was malabsorbed with the 2.0-g dose and that 18% of the meal was malabsorbed with the 2.9-g dose. At 2.9 g, glucose, C-peptide, and GIP were also signiﬁcantly decreased [32]. Partially Purified White Bean Extract (1988) Six type 2 diabetics were given between 4 and 6 g of partially puriﬁed white bean extract with standardized meals (55% carbohydrate, 25% fat, and 20% protein, with 5 g ﬁber per day) for 3

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weeks. The inhibitor signiﬁcantly reduced postprandial plasma glucose, C-peptide, insulin, and GIP levels at 7, 14, and 21 days. H2BT was signiﬁcantly increased as well at 7, 14, and 21 days. In addition, the delivery of increased amounts of carbohydrates to the small intestine caused a decrease in GIP, which decreases insulin levels and slows gastric emptying [16]. A signiﬁcant increase in diarrhea was reported during the ﬁrst week of inhibitor use which spontaneously resolved even though the serum and breath markers still demonstrated the ongoing effectiveness of the product to induce carbohydrate malabsorption. It was felt that this was due to changes in the metabolism of carbohydrates by the colonic ﬂora [16]. It was concluded as well that the overall increased carbohydrate load to the colon caused the colonic bacteria to alter their carbohydrate metabolism and to start producing metabolites other than short-chain fatty acids and lactic acid. This more efﬁcient digestion reduced the severity of the initial diarrhea symptoms seen with the carbohydrate malabsorption [16]. Partially Purified White Bean Extract (1989) After intubation with an oroileal tube, 18 healthy subjects were given a test meal, immediately followed by infusion of the amylase inhibitor or placebo into the stomach. The amylase inhibitor signiﬁcantly reduced the absorption of complex carbohydrates from the terminal ileum. In addition, the presence of carbohydrates in the ileum slowed gastric emptying. Signiﬁcantly decreased concentrations of gastric inhibitory polypeptide and neurotensin were seen in the active treatment group along with signiﬁcantly decreased amounts of peptide YY [35].

NON-KIDNEY-BEAN ALPHA-AMYLASE INHIBITORS Two non-kidney-bean extracts have been studied for amylase inhibitory effects: tendamistat (HOE 467) and a wheat-based amylase inhibitor (WAI). Tendamistat is a proteinaceous alpha-amylase inhibitor that appears to induce antibodies that bind to porcine amylase [36]. Wheat amylase inhibitors are a byproduct of gluten and wheat starch production, and intraduodenal animal studies have shown that 4 mg/mL delivered to the duodenum can inhibit 90% of intraluminal amylase [37]. Tendamistat (HOE 467) Study (1983) In 1983, six subjects participated in a randomized three-way crossover study in which they received 200 g of white bread followed sequentially by a placebo or 100 or 200 mg of tendamistat (HOE 467) [13]. The subjects’ blood was drawn serially for 3 hours after each intervention. Plasma glucose concentrations were measured as an indirect marker of carbohydrate digestion and absorption. Both tendamistat dosages showed signiﬁcant differences in plasma glucose compared with the placebo. The difference between the 100-mg and 200-mg dosages was not signiﬁcant. Tendamistat (HOE 467) Studies (1984) Tendamistat (HOE 467) was also utilized in two studies published by the same authors in 1984. In the ﬁrst study, nine subjects participated in a double-blind crossover study comparing the effect of tendamistat, 5 g of guar, or a placebo when given with a 100-g maize meal (consisting of 85.5 g of starch). Serial blood draws were taken up to 3 hours after the meal to measure serum glucose levels. The area under the curve for the treatment group was signiﬁcantly decreased compared with both the guar and the placebo groups [13]. The second study enrolled six subjects in a doubleblind crossover study in which escalating dosages of tendamistat (12.5 mg, 25 mg, and 50 mg) or placebo were given along with a 100-g maize meal (consisting of 85.5 g of starch). Again, serial serum glucose levels were drawn for 3 hours after each meal. The results showed statistically signiﬁcant reductions in glucose levels in all of the active groups compared with the placebo group. The signiﬁcance of the differences between dosages was not reported. One subject in the 25-mg tendamistat group reported loose stools, but no other adverse events were reported [38].

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Wheat Alpha-Amylase Inhibitor (1998) Twelve subjects were given a wheat alpha-amylase inhibitor along with a standardized breakfast consisting of 55% carbohydrates. The study found that the wheat amylase inhibitor delayed carbohydrate absorption and reduced peak postprandial plasma glucose levels in 10 of 12 subjects (p < 0.05). Breath H2 levels were increased in 11 of 12 subjects (p = 0.02), and increases were generally less than 20 ppm. Signiﬁcant reductions were also seen in GIP levels (p < 0.05). Signiﬁcant increases were seen in peptide YY levels (p < 0.05), as well as a trend toward increases in human pancreatic polypeptide levels (p = 0.07). There were no reports of diarrhea or bloating [37].

PHASE 2® WHITE BEAN EXTRACT STUDIES

FOR

REDUCING GLUCOSE EXCURSION

The following studies have all been performed on a proprietary white bean extract known as Phase 2®. The Phase 2® brand bean-extract is a water-extract of the common white bean (Phaseolus vulgaris), which has been shown in vitro to inhibit the digestive enzyme alpha-amylase [8,12,15,39]. Phase 2® was previously sold as Phaseolamin 2250®. This product is purported to have a higher concentration of the active component of the white bean, and the manufacturer claims that it is different than the unpuriﬁed or partially puriﬁed white bean products described above. University of Scranton (September 2001) In 2001, ten healthy (non-diabetic, non-obese) subjects participated in a randomized, double-blind, crossover, single-meal study comparing Phase 2® with a placebo. After an overnight fast, all subjects were given a standardized meal containing 60 g of carbohydrates (white bread) with either 1500 mg of Phase 2® or a placebo. Plasma glucose was then measured every 30 minutes for 4 hours. After 1 week, the subjects crossed over and repeated the procedure with the opposite intervention. The Phase 2® group demonstrated lower average glucose levels at all time points after baseline and showed an average 57% reduction in the area under the curve compared with the placebo group. No adverse events were observed, and statistical analysis between groups was not provided [40]. University of Scranton (November 2001) The single-meal study was repeated in 2001 with ten subjects who were required to remain sedentary during the active portion of the study to reduce variability in orocecal transit time. The study was modiﬁed to include serial blood draws for only 2 hours instead of 4 hours. Two of the ten subjects did not complete the study, and four were excluded because they were classiﬁed as “poor/nonabsorbers as the area under the glucose-time curve was negative,” a potential source of bias for this study. The results of this study were therefore limited to four known responders. The dose of the Phase 2® remained at 1500 mg, and the 60-g carbohydrate content of the meal was from white bread. The Phase 2® group did not demonstrate statistically signiﬁcant differences at any individual time point; however, the area under the curve was calculated to be 85% lower than the placebo curve (p < 0.05) for a small group of responders [41]. University of Scranton (May 2002) Seven subjects participated in a crossover study comparing 750 mg of Phase 2® with a placebo given after a standardized meal containing 64 g of carbohydrates (including 6 g of dietary ﬁber and 19 g of sugars) [42]. Serial plasma glucose levels were taken for 2 hours after the consumption of the meal and Phase 2® or the placebo. Glucose levels were lower on average for subjects at all time points in the Phase 2® group except at 20 minutes, where the values were equivalent. The overall area under the curve was 28% lower in the Phase 2® group compared with placebo. Statistical signiﬁcance was not reached for any time point or for the area under the curve comparison, presumably because the small number of subjects did not provide enough statistical power to discriminate between groups.

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University of Scranton (September 2003) A three-arm crossover study was performed on 20 subjects comparing 515 mg of Phase 2® with 750 mg of Phase 2® (in powder form mixed in with the food) and with placebo [43]. The standardized meal was the same as for the 2002 study (64 g of carbohydrates, including 6 g dietary ﬁber and 19 g sugars). Serial glucose levels were measured every 10 minutes for 60 minutes using the OneTouch® Ultra blood glucose monitoring system. The 750-mg Phase 2® group demonstrated signiﬁcantly lower blood glucose levels at 10, 20, and 30 minutes (p < 0.01) compared with both the 515-mg dose and with the placebo. The area under the curve was also lower in the 750-mg Phase 2® group compared with the two other groups but did not reach statistical signiﬁcance (p < 0.1). The 515-mg Phase 2® group also showed signiﬁcantly lower blood glucose at 10, 20 (p < 0.01), and 30 (p < 0.05) minutes compared with placebo. Glycemic Index Lowering Study (2005) An open-label, six-arm crossover study was performed following the Food and Agriculture Organization methodology for glycemic index (GI) testing. The GI of white bread was tested without and with the addition of Phase 2® capsules and powder, each in dosages of 1500 mg, 2000 mg, and 3000 mg. Reductions were seen in the GI of white bread at all dosages and formulations except the 1500-mg capsule dose. The only dose and formulation combination to reach statistical signiﬁcance was the 3000-mg powder dose, which demonstrated a reduction of 20.23 or 39.07% (p = 0.0228) [44].

CARBOHYDRATE DIGESTION INHIBITOR STUDIES FOR WEIGHT LOSS WHITE KIDNEY BEAN EXTRACTS: PARTIALLY PURIFIED Norwegian Study (2000) One of the ﬁrst studies on the use of a white kidney bean extract for weight loss was conducted in Norway and published in 2000 [45]. This randomized, double-blind, placebo-controlled trial utilized a test product containing a proprietary blend of 200 mg of a white kidney bean extract, 200 mg of inulin (from chicory root), and 50 mg of Garcinia cambogia. Tablets were described as weighing 650 mg each, but the ingredients accounting for the remaining 200 mg were not described. Forty overweight (but otherwise healthy) subjects with BMIs between 27.5 and 39 were randomized and instructed to take 2 tablets of the test product after all 3 meals for 12 weeks. Subjects were also instructed to follow a 1200-kcal/day, low-fat diet. A total of 7 subjects dropped out of the study (6 in the placebo arm, 1 in the active arm); however, all of these subjects were included in an intent-to-treat analysis. After 12 weeks, the active group lost an average of 3.5 kg (7.7 lb; p = 0.001), and the placebo group lost 1.3 kg (2.86 lb; p > 0.05). The BMIs decreased by 1.3 kg/m2 (p = 0.01) in the active group and by 0.5 (p > 0.05) in the placebo group. Percent body fat (as measured by bioelectrical impedance) decreased by 2.3% (p = 0.01) in the active group and by 0.7% (p > 0.05) in the placebo. Between-group analysis was not provided for weight loss, BMI, or percent body fat. No adverse events were reported in any group.

PHASE 2® WHITE BEAN EXTRACT CLINICAL STUDIES

FOR

WEIGHT LOSS

See Table 22.1. Italian Study (2001) A European study utilizing the Phase 2® product for weight reduction was conducted in Italy in 2001 [46]. Sixty overweight subjects (5 to 10 kg over ideal body weight) participated in a randomized, double-blind, placebo-controlled clinical trial consisting of a 30-day run-in phase followed

Year

2001

2002

2003

2003

2003

Study

Italian study

Northridge study

TheraSlim™ study

SCUHS study

Leiner study N = 60

N = 25

N = 60

N = 27

12

4

12

8

4

Duration (weeks)

1000 mg 3×/day

1000 mg 2×/day

1000 mg 2×/day

1500 mg 2×/day

500 mg 1×/day

Phase 2® Dosage

Active Placebo

Active Placebo

Active Placebo

Active Placebo

Active Placebo

Group

6.9 –0.8

6.0 4.7

–0.96 0.27

3.79 1.65

6.45 0.766

Total Weight Loss (lb)

0.575 –0.06

1.5 1.175

–0.08 0.02

0.47 0.21

1.61 0.19

Average Weekly Weight Loss (lb/week)

Statistical Significance

p = 0.029, between group statistical analysis

p < 0.0001, compared with baseline p < 0.0001, compared with baseline p > 0.05, between group statistical analysis

p = 0.4003, between group statistical analysis

p > 0.05, between group statistical analysis

p < 0.001, between group statistical analysis

290

N = 60

Number of Subjects

TABLE 22.1 Phase 2® Human Clinical Studies

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by a 30-day active phase. Subjects were between the ages of 20 and 45 and were 5 to 15 kg overweight; their weight had been stable during the preceding 6 months. During the run-in phase, subjects were educated to consume 2000 to 2200 calories/day with the complex carbohydrate intake concentrated in one of the two main meals of the day. In addition, subjects were asked not to change their current activity or exercise. Subjects received either 444.8 mg of Phase 2® or a placebo before the main carbohydrate-containing meal of the day. The active group lost an average of 2.933 kg (6.45 lb) in 30 days compared with an average of 0.348 kg (0.766 lb) in the placebo group (p < 0.001). Body composition was measured with bioelectrical impedance. The active group demonstrated a 10.45% reduction in body fat compared with a 0.16% reduction in the placebo group (p < 0.001). Waist and hip circumferences measured in a standard way showed the same pattern as well. The active group demonstrated 2.93-cm and 1.48-cm reductions, respectively, compared with 0.46-cm and 0.11-cm reductions in the placebo group (p < 0.001). No adverse events were reported. Northridge Hospital Study (2002) A 2002 randomized, double-blind, placebo-controlled study of 39 obese subjects (BMIs, 30 to 43) were randomly allocated to receive either 1500 mg of Phase 2® or an identical placebo [47]. Twenty-seven subjects completed the study (14 active and 13 placebo). Subjects were instructed to take the test product with at least 8 oz. of water at lunch and dinner each day for 8 weeks. Subjects were also instructed to consume a controlled high-ﬁber/low-fat diet at the beginning of the study that provided 100 to 200 g of complex carbohydrate intake per day. Subjects were also directed to eat the majority of their carbohydrates during lunch and dinner, as those were the meals at which the Phase 2® or placebo were taken. Carbohydrate intake was recommended for the subjects on the basis of estimated daily maintenance carbohydrate requirements, and dietary compliance was reinforced at return visits. The study results at 8 weeks demonstrated that the active group lost an average of 3.79 lb (an average of 0.47 lb/wk) compared with the placebo group’s average loss of 1.65 lb (an average of 0.21 lb/wk). The difference was not statistically signiﬁcant (two-tailed p = 0.35). Similar trends were seen at 2, 4, and 6 weeks. Triglyceride levels in the Phase 2® group were reduced by an average of 26.3 mg/dL, compared with the 8.2-mg/dL drop seen in the placebo group (p = 0.07). The trend favors treatment, but results did not achieve statistical signiﬁcance. Several secondary outcomes were measured during the study, including body fat percentage, waist and hip circumferences, energy level, hunger, appetite, HbA1c, and total cholesterol. For each of these secondary measures, no clinically or statistically signiﬁcant differences were identiﬁed between the active and the placebo group. No adverse events occurred that were felt to be due to the active product. Abdominal pain, bloating, and gas were experienced by one placebo subject, and one active group subject complained of an increased incidence of tension headaches while in the active phase of the trial. Safety data, including serum markers of electrolytes, kidney, and liver function, were obtained at time 0 and at 8 weeks. No clinically signiﬁcant changes were identiﬁed. Leiner Softchew Study (2003) An unpublished 12 week study of Phase 2® in a soft-chew formulation was completed in 2003 [48]. In this randomized, double-blind, placebo-controlled trial of 60 overweight individuals, subjects were given 1000 mg of Phase 2® before each meal (6 500-mg soft chews per day). Subjects received education on proper eating habits and the importance of exercise but were not given a speciﬁc diet or exercise regimen. The results of this study demonstrated statistically signiﬁcant weight reduction in the active group compared with placebo at weeks 6 (p = 0.013), 8 (p = 0.031), and 12 (p = 0.029). The amount of weight lost by the active group at 12 weeks was 6.9 lb (average of 0.575 lb/wk), while the placebo group gained 0.8 lb. No adverse events were reported.

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TheraSlim™ Study (2003) A 24-week randomized, double-blind, placebo-controlled, crossover to open-label study was performed in 2003 [49]. Sixty overweight and obese subjects were randomized to receive either 1500 mg of TheraSlim™ (1000 mg of Phase 2® and 500 mg of fennel [Foeniculum vulgare] seed powder) or a placebo with lunch and dinner. After 12 weeks, all subjects were continued on TheraSlim™ in an open-label fashion and followed for another 12 weeks. Subjects were asked to eat a diet in which lunch and dinner contained 100 to 200 g of carbohydrates. The primary outcomes changed from baseline in weight, BMI, blood pressure, cholesterol, insulin, and glucose. Data analysis was performed at the end of the 12-week, randomized, placebo-controlled trial, as well as for each of the arms (active and placebo) as they crossed over to the open-label active arm for an additional 12 weeks. During the randomized, placebo-controlled portion of the trial, none of the primary outcomes demonstrated signiﬁcant differences from placebo; however, both total cholesterol (–10.7 mg/dL vs. +1.6154 mg/dL; p = 0.0693) and low-density lipoprotein (LDL) cholesterol (–10.22 mg/dL vs. +1.5 mg/dL; p = 0.0719) showed positive trends in favor of the active product. Exploratory analysis was performed by stratifying the groups by BMI and by compliance. In this analysis, the group stratiﬁed as medium BMI demonstrated statistically signiﬁcant weight loss compared with placebo (–4.825 lb vs. +1.78 lb; p = 0.0341). The active group received the product in a blinded fashion for 12 weeks then in an open-label fashion for an additional 12 weeks. At the end of 24 weeks, this group demonstrated a signiﬁcant reduction in both systolic (–4.9 mmHg; p = 0.0403) and diastolic (–6.4 mmHg; p = 0.0002) pressure compared with their own baseline. The placebo group that crossed over to receive the active product during the second 12-week study period demonstrated a signiﬁcant reduction in cholesterol (–10.4 mg/dL vs. +1.6154 mg/dL; p = 0.0396) and a trend toward signiﬁcance in the reduction of LDL (–8.115 mg/dL vs. +1.5 mg/dL; p = 0.066) in favor of the active product. No adverse events were reported after 24 weeks of usage [49]. SCUHS Study (2004) In 2003, 27 overweight subjects (BMIs, 25 to 30) participated in a 30-day randomized, doubleblind, placebo-controlled trial of 1000 mg of Phase 2 ® or an identical placebo twice a day [50]. Subjects were also given nutritional guidelines to standardize their caloric intake at 1800 kcal/day. Breakfast and lunch were provided to increase compliance. In addition, subjects met with a personal trainer to establish an exercise program and each had a counseling session with a behavioral psychologist to identify psychological barriers to weight loss. Twenty-ﬁve subjects completed the study, and no adverse events were reported. At 4 weeks, the active group had lost 6.0 lb and the placebo group 4.7 lb. Although both groups lost signiﬁcant weight compared with their baseline (active, p = 0.0002; placebo, p = 0.0016), between-group analysis was not signiﬁcant (p = 0.4235). For exploratory analysis, subjects were stratiﬁed by dietary carbohydrate intake. In this analysis, the tertile that took in the most carbohydrates demonstrated signiﬁcantly greater loss of body weight compared with the placebo group (8.7 lb vs. 1.7 lb; p = 0.0412). The same tertile demonstrated a signiﬁcantly greater loss in inches around the waist (3.3 in. for the Phase 2® group and 1.3 in. for the placebo group; p = 0.01). Additional parameters were analyzed for changes from baseline. These parameters were stratiﬁed by BMI, total carbohydrate intake, and net carbohydrate intake, as well. None of these parameters, including hip size, triglycerides, fasting glucose, total cholesterol, appetite control, hunger, energy level, and percent body fat, demonstrated any signiﬁcant differences between groups or from baseline to the end of the study.

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SAFETY Starch is an inactive solute and therefore does not dissolve, absorb, or react with nutrients such as vitamins or minerals. There is no evidence nor any reason to suspect that preventing the absorption of starch affects the absorption of any other nutrients. It is theoretically possible that the additional bulk of unabsorbed starch, along with the accompanying water, will pass through the gastrointestinal tract and that it may carry with it some undigested nutrients or pills [11]. This has never been demonstrated, but the theoretical possibility should be kept in mind as physicians consider recommending this type of product. Animal studies on acute and chronic toxicity have been performed on Phase 2® [51] and have not demonstrated any histological or laboratory toxicities. In one study of an alpha-amylase inhibitor based on partially puriﬁed white bean [16], there was a signiﬁcant increase in diarrhea during the ﬁrst week. The diarrhea spontaneously resolved, even though the serum and breath markers still demonstrated the ongoing effectiveness of the product to induce carbohydrate malabsorption. It was believed that this was due to changes in the metabolism of carbohydrates by the colonic ﬂora. Six recent human studies utilizing carbohydrate digestion inhibitors for weight loss (n = 286) revealed no side effects or toxicities. Anecdotal evidence [52,53] of an increase in gas and bloating has been reported at supratherapeutic doses (three times recommended dose) of the product, but never in a controlled clinical study. Acarbose (Precose™) is a prescription alpha-glucosidase inhibitor approved for use in the United States. Although no documentation suggests that acarbose and Phase 2® have any structural or other similarities other than a similar mechanism of action, it is relevant to note that 62 incidents (out of 3 million patient years) of liver enzyme abnormalities have been reported in diabetic patients treated with acarbose [54]. In addition, acarbose has been shown to affect digoxin bioavailability but not the absorption or disposition of sulfonylureas or metformin [55]. Acarbose does not increase the risk of hypoglycemia, even in the fasted state. If side effects such as ﬂatulence, diarrhea, or abdominal discomfort occur, they generally diminish in frequency and intensity after the ﬁrst few weeks of therapy. The safety and effectiveness of acarbose in pediatric patients have not been established [55]. Alpha-glucosidase inhibitors cause side effects such as diarrhea by increasing the amount of short-chain polymers (disaccharides and trisaccharides), which accumulate in the lumen of the gut. These polymers attract a great deal of water and cause an osmotic diarrhea. Alpha-amylase inhibitors, by contrast, cause the accumulation of longer chain carbohydrates, and there are fewer of them compared with the number of short-chain polymers; therefore, they do not cause a similar osmotic load and produce less diarrhea [32]. In addition, without the osmotic load, colonic bacteria may be better able to metabolize large quantities of starch without producing diarrhea [16].

DISCUSSION The current data on carbohydrate digestion inhibitors in general and alpha-amylase inhibitors in particular demonstrate several trends. Animal and human data do not show any speciﬁc adverseevent proﬁles attributed to the clinical use of these products. In addition, data from preliminary single-meal studies suggest alpha-amylase inhibitors might be effective in decreasing the absorption of glucose from a carbohydrate-containing meal or might increase the time period over which a single load of carbohydrates is digested. These changes form the basis for the hypothesized mechanism of action of alpha-amylase inhibitors in reducing the glycemic index. The beneﬁts of reducing the effective glycemic index of food are apparent in the diabetic population [56], as well as in preventing diabetes [57,58] and reducing the risk of cardiovascular disease in women [59].

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The potential role of a reduced glycemic index diet in weight control is intriguing [60–66] and may account for part of the mechanism of action for the role of carbohydrate digestion inhibitors in weight management. We previously stated that there are no substitutes for caloric restriction and exercise in the treatment of obesity. Carbohydrate digestion inhibitors may only play an adjunctive role in the management of glucose regulation and weight loss. Their best use may be for patients who are trying to adhere to low-carbohydrate diets but who occasionally crave complex-carbohydrate-rich foods. These products may enable such patients to decrease the effective glycemic index of these foods, which may contribute to weight management.

CONCLUSION The dataset for carbohydrate digestion inhibition in general and alpha-amylase inhibition in particular remains promising but preliminary. Future directions in research should include studies with larger numbers of subjects and should be run for longer periods of time. In addition, as the datasets become available from the studies currently underway, a meta-analysis may be appropriate in the future. These steps are necessary to conﬁrm the glucose and weight management claims for this potentially therapeutic product category.

DISCLOSURES JU discloses that he has ongoing research support from Pharmachem Laboratories and has provided consulting services to Pharmachem Laboratories. The authors do not have any ﬁnancial interest in Pharmachem Laboratories, the Phase 2® product, or any other commercial product.

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Volek, J.S. and Feinman, R.D., Carbohydrate restriction improves the features of metabolic syndrome; metabolic syndrome may be deﬁned by the response to carbohydrate restriction, Nutr. Metab. (Lond.), 2, 31, 2005. IDF, Diabetes Atlas, International Diabetes Federation, Brussels, Belgium, www.eatlas.idf.org. AOA, AOA Fact Sheets, American Obesity Association, Washington, D.C., www.obesity.org. CDC, National Diabetes Fact Sheet, Centers for Disease Control and Prevention, Atlanta, GA, www.cdc.gov/diabetes/pubs/estimates.htm. Hiele, M., Ghoos, Y., Rutgeerts, P., and Vantrappen, G., Starch digestion in normal subjects and patients with pancreatic disease, using a 13CO2 breath test, Gastroenterology, 96(2, Pt. 1), 503–509, 1989. Wolever, T.M., Vuksan, V., Eshuis, H., Spadafora, P., Peterson, R.D. et al., Effect of method of administration of psyllium on glycemic response and carbohydrate digestibility, J. Am. Coll. Nutr., 10(4), 364–371, 1991. U.S. Food and Drug Administration, In the Matter of the Complaint Against General Nutrition Corporation General Nutrition Centers, P.S. Docket No. 15/115, October 31, 1983. Bo-Linn, G.W., Santa Ana, C.A., Morawski, S.G., and Fordtran, J.S., Starch blockers: their effect on calorie absorption from a high-starch meal, N. Engl. J. Med., 307(23), 1413–1416, 1982. Hiele, M., Georges Brohee Prize, 1988–1989. Assimilation of nutritional carbohydrates: inﬂuence of hydrolysis, Acta Gastroenterol. Belg., 54(1), 3–11, 1991. Cummings, J.H. and Englyst, H.N., Measurement of starch fermentation in the human large intestine, Can. J. Physiol. Pharmacol., 69(1), 121–129, 1991. Lembcke, B., Folsch, U.R., Caspary, W.F., Ebert, R., and Creutzfeldt, W., Inﬂuence of metronidazole on the breath hydrogen response and symptoms in acarbose-induced malabsorption of sucrose, Digestion, 25(3), 186–193, 1982. Hollenbeck, C.B., Coulston, A.M., Quan, R., Becker, T.R., Vreman, H.J. et al., Effects of a commercial starch blocker preparation on carbohydrate digestion and absorption: in vivo and in vitro studies, Am. J. Clin. Nutr., 38(4), 498–503, 1983.

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van Dam, R.M., Visscher, A.W., Feskens, E.J., Verhoef, P., and Kromhout, D., Dietary glycemic index in relation to metabolic risk factors and incidence of coronary heart disease: the Zutphen Elderly Study, Eur. J. Clin. Nutr., 54(9), 726–731, 2000. Wolever, T.M., Jenkins, D.J., Vuksan, V., Jenkins, A.L., Wong, G.S., and Josse, R.G., Beneﬁcial effect of low-glycemic index diet in overweight NIDDM subjects, Diabetes Care, 15(4), 562–564, 1992. Pereira, M.A., Swain, J., Goldﬁne, A.B., Rifai, N., and Ludwig, D.S., Effects of a low-glycemic load diet on resting energy expenditure and heart disease risk factors during weight loss, JAMA, 292(20), 2482–2490, 2004. Boule, N.G., Haddad, E., Kenny, G.P., Wells, G.A., and Sigal, R.J., Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials, JAMA, 286(10), 1218–1227, 2001. Roberts, S.B., Glycemic index and satiety, Nutr. Clin. Care, 6(1), 20–26, 2003. Spieth, L.E., Harnish, J.D., Lenders, C.M., Raezer, L.B., Pereira, M.A. et al., A low-glycemic index diet in the treatment of pediatric obesity, Arch. Pediatr. Adolesc. Med., 154(9), 947–951, 2000. Frost, G.S., Brynes, A.E., Bovill-Taylor, C., and Dornhorst, A., A prospective randomised trial to determine the efﬁcacy of a low glycaemic index diet given in addition to healthy eating and weight loss advice in patients with coronary heart disease, Eur. J. Clin. Nutr., 58(1), 121–127, 2004. Ebbeling, C.B., Leidig, M.M., Sinclair, K.B., Hangen, J.P., and Ludwig, D.S., A reduced-glycemic load diet in the treatment of adolescent obesity, Arch. Pediatr. Adolesc. Med., 157(8), 773–779, 2003. Rasmussen, O., Lauszus, F.F., Christiansen, C., Thomsen, C., and Hermansen, K., Differential effects of saturated and monounsaturated fat on blood glucose and insulin responses in subjects with noninsulin-dependent diabetes mellitus, Am. J. Clin. Nutr., 63, 249–253, 1996.

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Vegetarian Diets in the 23 Prevention and Treatment of Obesity Kathryn T. Knecht, Hien T. Bui, Don K. Tran, and Joan Sabaté CONTENTS Introduction ....................................................................................................................................299 Studies of Vegetarian Diets and Obesity .......................................................................................300 Observational Studies .............................................................................................................300 Factors Affecting the Impact of a Vegetarian Diet ................................................................301 Intervention Studies ................................................................................................................304 Nutritional Differences Between Vegetarian and Non-Vegetarian Diets ......................................306 Possible Mechanisms for Speciﬁc Dietary Components ..............................................................307 Energy .....................................................................................................................................307 Proteins....................................................................................................................................308 Carbohydrates .........................................................................................................................309 Fiber ........................................................................................................................................309 Dietary Fats.............................................................................................................................309 Does the Decrease in BMI Associated with a Vegetarian Diet Imply Better Health?.................310 Conclusions ....................................................................................................................................310 Acknowledgments ..........................................................................................................................311 References ......................................................................................................................................311

INTRODUCTION Vegetarian diets of varying degrees of restriction may be adopted for cultural, religious, or health reasons. In 2003, an estimated 2.8% of adults in the United States reported no consumption of meat, poultry, or seafood and thus could be described as vegetarian, while 1.8% omitted all animal-derived products (including milk, eggs, and honey) and could be described as vegan [1]. The ofﬁcial position statement of the American Dietetic Association and Dietitians of Canada states that: “Appropriately planned vegetarian diets are healthful and nutritionally adequate, and provide health beneﬁts in the prevention and treatment of certain diseases” [2]. Speciﬁcally, vegetarian diets have been linked with a decrease in the risk of ischemic heart disease [3,4] and other obesity-related disorders [5]. The topic of vegetarian diets and obesity has been reviewed by one of the authors and others; in general, body mass index (BMI) has been found to be lower in both men and women in vegetarians vs. non-vegetarians [3,4,6,7]. The discussion that follows in this chapter emphasizes results published within the last 5 years. This chapter ﬁrst describes observational studies of populations who have self-selected either vegetarian or non-vegetarian diets, then factors that might affect the outcome of these observational

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studies. Subsequently, intervention studies of vegetarian diets are discussed, followed by an elaboration of potential mechanisms by which vegetarian diets might affect body weight.

STUDIES OF VEGETARIAN DIETS AND OBESITY OBSERVATIONAL STUDIES In Europe, the Oxford cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC) recruited a signiﬁcant proportion of vegetarians among its 57,496 subjects [8]. Categories studied included meat-eaters (omnivores), ﬁsh-eaters (ﬁsh but no meat or poultry), lacto-ovo vegetarians (milk and eggs but no ﬂesh foods), and vegans. Several analyses of these data indicated that meat-eaters had a higher mean BMI and higher incidence of being overweight (25 > BMI > 29.9 kg/m2) or obese (BMI > 30 kg/m2), even when correction was made for non-dietary factors [9–14]. Body weight parameters for non-vegan vegetarians (e.g., lacto-ovo) or for those who eat ﬁsh but not meat were between those for meat-eaters and vegans [10,12,13], and only the BMI of meateaters was within the overweight range [9,10]. The U.K. Women’s Cohort Study, with 35,372 participants, also demonstrated a lower BMI for vegetarians than for meat-eaters, although two groups of ﬁsh-eaters had average BMIs as low as or lower than those of vegetarians. Only the meateating group had a BMI as high as the cut-off for the deﬁnition of overweight (25.0 kg/m2) [15]. In the 5292 subjects of the Oxford Vegetarian Study, meat-eaters had a higher prevalence of being overweight or obese than non-meat-eaters (including ﬁsh-eaters) and a higher mean BMI [16]. In a study population from the EPIC–Oxford study, all dietary groups tended to increase BMI during a 5-year follow-up period, but vegans and ﬁsh-eating women showed less gain than did meat-eaters. Interestingly, individuals who converted to a more vegetarian diet during the 5-year period had the smallest weight gain, and those reverting from a more vegetarian diet had a weight gain greater than any other group, including meat-eaters [17]. Results from the 55,459 members of the Swedish Mammography cohort also demonstrated that omnivores were heavier than semivegetarians, lactovegetarians, or vegans, with a higher BMI and risk of being overweight or obese; however, in none of these diet groups was the mean BMI > 25 [18]. Alewaeters et al. [19] found that 326 male and female Flemish vegetarians had a lower BMI than corresponding reference populations, with only the male reference cohort having mean BMIs in the overweight range. In the United States, studies of the Seventh-Day Adventist population have shown an inverse correlation between vegetarianism and obesity. The teachings of this denomination endorse a healthy lifestyle, and approximately 50% of a cohort of 34,192 Californian Seventh-Day Adventists ate meat less than once a week. Within this population, BMI was signiﬁcantly associated with diet, with only male and female vegetarians and female semivegetarians (poultry or ﬁsh, <1×/week) having mean BMIs below 25 [5]. Seventh-Day Adventist vegetarians in Barbados also showed a decreased risk of obesity compared to non-vegetarian Seventh-Day Adventists [20]. A vegetarian diet is also a tenet of Buddhism, and predominantly Tzu-Chi Buddhist nuns comprised a cohort of 49 Taiwanese vegetarians. These women had lower BMI, body weight, and waist and hip circumference than 49 age-matched omnivorous controls who were predominantly local hospital employees [21]. Among the 459 members of the Baltimore Longitudinal Study of Aging, vegetarianism per se was not addressed, but a diet high in fruit, vegetables, whole grains, and dairy and low in red and processed meat was associated with the lowest baselines and smallest increases in BMI and waist circumference over time [22]. Only this healthy diet resulted in a mean BMI that started and remained within the normal range. Data from the 13,313 respondents in the Continuing Survey of Food Intake by Individuals showed a decreased BMI in self-deﬁned vegetarians vs. self-deﬁned non-vegetarians, with further decreases in BMI in self-deﬁned vegetarians who did not eat meat vs. those who did [23]. When vegetarianism in this cohort was deﬁned by the absence of meat (including poultry and ﬁsh) on the survey date, vegetarians so deﬁned had a lower BMI than any

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other group except for those reporting a high-carbohydrate diet adhering to the U.S. Department of Agriculture (USDA) food pyramid [24]. A cohort of 12 American vegetarian men had a nearly signiﬁcantly lower BMI but also lower fat-free weight than 11 non-vegetarian controls [25]. In the 1817-member British Columbia Nutrition Survey, the mean BMI was 2.6 kg/m2 lower in female vegetarians than in their non-vegetarian counterparts; BMI was only 0.8 kg/m2 lower in male vegetarians compared to male non-vegetarians. Only the 76 female vegetarians had a mean BMI within the normal range, and female vegetarians were found to have a lower waist circumference and a lower prevalence of being overweight or obese. The 30 male vegetarians had a 0.8-cm greater waist circumference than male non-vegetarians and a slightly greater incidence of being normal or overweight but a decreased incidence of obesity [26] Increased exercise by the female vegetarians may have accounted for the differences in body composition in this particular study. The above studies focused on adult populations. Decreased BMI and decreased prevalence of being overweight were also associated with vegetarianism in Turkish adolescents [27], although the mean BMI was within the normal range for vegetarians and non-vegetarians, both males and females. The BMI of 22 Polish vegetarian children was slightly lower than that of 13 omnivore controls (15.7 vs. 16.0 kg/m2), although the vegetarian children were older [28]. A study of 51 vegetarian children in Hong Kong found an increase in the prevalence of obesity relative to previously reported data from the local population [29], but a lack of physical activity in these children may have been a factor. Table 23.1 provides a summary of the previously described BMI data. Other anthropomorphic parameters were available in some but not all studies and thus were not put into tabular form. For male adults, a weighted average of available data resulted in mean BMI of 25.3 kg/m2 for meateaters and 23.8 kg/m2 for vegetarians, with a total of 12,692 meat-eaters and 4175 vegetarians [9,16,19,20,25,26]. For females, corresponding weighted BMIs were 24.6 and 23.2 kg/m2, with a total of 109,715 meat-eaters and 16,948 vegetarians [9,15,16,18–21,26,31]. For both males and females, the weighted-average BMI was 24.8 for 132,894 meat-eaters and 23.3 for 21,254 vegetarians [9,15,16,18–21,23,25,26,31]. In this analysis, data from only the most recent reports of the EPIC–Oxford cohort and the Continuing Survey of Food Intake by Individuals were used [9,23]. For males 6 feet in height, the calculated average difference of 1.5 kg/m2 in BMI between vegetarians and meat-eaters would correspond to a difference of 11 lb. Figure 23.1 presents data from a meta-analysis conducted by one of the authors. The difference between the BMIs of male vegetarians and non-vegetarians (24 studies) was 2.1 kg/m2, and a difference of 1.8 kg/m2 between the BMIs of female male vegetarians and non-vegetarians (36 studies) was found. Thus, previous literature and the data presented in Table 23.1 are consistent.

FACTORS AFFECTING

THE IMPACT OF A

VEGETARIAN DIET

The effect of a vegetarian diet may be varied by the length of time spent on the diet, the strictness of the diet, and the other lifestyle factors that may accompany vegetarianism; for example, it seems plausible that the effects of a vegetarian intervention might be most clearly seen with a longer time period. If overweight or obese individuals were to adopt a vegetarian diet in the short term as a means of weight loss, their presence in the vegetarian cohort would be likely to increase the mean body weight. In the EPIC–Oxford cohort and in a population of Seventh-Day Adventists in Barbados, the BMI was lowest for those who had been vegan or vegetarian for more than 5 years [14,20]. Mortality in the form of ischemic heart disease was also lower in those who had been vegetarian for more than 5 years. Appleby et al. [16], however, found that the BMIs of non-meateaters who had not eaten meat for more than 5 years were only slightly and not signiﬁcantly lower than those for individuals who had adopted a non-meat diet within the last 5 years. Similarly, individuals becoming vegetarian as adults (>20 years) were no heavier than life-long vegetarians). Interestingly, the BMI was higher for men and women becoming vegetarians as children than for life-long vegetarians [9].

EPIC–Oxford

EPIC–Oxford

U.K. Women’s Cohort Study

Oxford vegetarian study

Swedish mammography cohort

Flemish vegetarians

Adventist health study

Seventh-Day Adventists, Barbados

Davey et al. [13]

Cade et al. [15]

Appleby et al. [16]

Newby et al. [18]

Alewaeters et al. [19]

Fraser [5]

Brathwaite et al. [20]

Study Population

Rosell et al. [9]

Ref.

177/407

10,088/34,198

326/9659

242/55,459

284/5292

6478/35,372

21,436/65,429

16,083/45,962

Male Female

Male Female

Male Female

Female

Male Female

Female

Male Female

Male Female

Adults

Gender

25.1 27.8

26.2 25.9

25.7 24.6

24.7

23.2 22.3

25

24.9 24.3

25.2 24.2

Meat-Eater

— — 23.3a — — — —

22.1a 21.3a 23.4a 22.6a 22.1a 24.3a 23.7a

— —

—

23.3a

24.3 27

22.5 21.9

— —

Vegan

23.5 22.7

24.3a 23.5a

Vegetarian

BMI (kg/m2)

–0.8 –0.8

–1.9 –2.2

–2.1 –2.5

–1.3

–1.1 –1.0

–1.7

–0.9 –0.7 –1.4 –1.6

Difference, Meat-Eater vs. Vegetarian

302

Number of Vegetarians/Total Number

TABLE 23.1 Observational Studies on the Differences in BMI Between Vegetarian and Non-Vegetarian Diets

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Continuing Survey of Food Intake by Individuals

Continuing Survey of Food Intake by Individuals

Vegetarian men

British Columbia vegetarian adults

British Columbia vegetarian women

Haddad and Tanzman [23]

Kennedy [24]

Poehlman et al. [25]

Bedford and Barr [26]

Barr and Broughton [31]

Statistics provided; p < 0.05 vs. meat-eaters.

Polish vegetarian children

Ambroszkiewicz et al. [28]

a

Turkish adolescent vegetarians

Bas et al. [27]

Weighted average

Taiwanese vegetarian women

Hung et al. [21]

22/35

31/1205

90/193

106/1817

12/23

642/10014

334/13,313

49/98

Male and female

Male Female

Children

Male Female All

Female

Male Female

Male

Male Female

Male and female Ages 6–11 Ages 12–19 Age ≥20

Female

16

22.9 20.8

25.3 24.6 24.8

23.5

26.7 25.7

24.4

26.4 25.7

18.5 22.3 26.1

22

15.7

22.1a 19.8a

23.8 23.2 23.3

23.2

25.9 23.1a

—

— —

— — —

—

— —

—

–0.3

–0.8 –1.0

–1.5 –1.4 –1.5

–0.3

–0.8 –2.6

–1.7

–1.1 —

22.7

–1.2

—

25.2a 24.6a

–1.2 –2.3 –3.3

–1.1

— — —

—

17.3 20 22.8a

20.9a

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A possible complication in analyzing the effects of a vegetarian diet is that self-deﬁned vegetarians may not adhere strictly to a vegetarian diet. As a practical concession, those who ate meat or ﬁsh less than once a week or below 10 g/day have been deﬁned as “vegetarian” [15,20]. Even so, only 18% of a study population met this requirement, although 28% considered themselves vegetarian [15]. Newby et al. [18] found that groups of “semivegetarians,” “lactovegetarians,” and “vegans” all consumed some animal products but further reported that these discrepancies did not alter the conclusions of their study. Smith et al. [30] found that, of 59 self-reported college student vegetarians, 40 had included poultry and/or ﬁsh in their diet; of 90 vegetarian women in British Columbia, the percentages of women eating ﬁsh or other seafood, poultry, or red meat at least occasionally were 74.9%, 57.6%, and 22.4%, respectively [26]. Barr and Broughton [31] and Alewaeters et al. [19] reported that 5 to 14% of vegetarians ate chicken or ﬁsh. Haddad and Tanzman [23] reported that 214 of 334 “vegetarians” ate some meat, ﬁsh, or poultry on at least one of two dietary survey days. As they found that non-meat-eating “vegetarians” had a lower mean BMI than meat-eating “vegetarians,” it may be that the apparent effect of vegetarianism on leanness is weakened by the inclusion of meat-eating “vegetarians.” Conversely, when “vegetarian” was deﬁned as those who did not consume meat on a given study day, the numbers of vegetarians by deﬁnition were higher than for self-deﬁned vegetarians in the same cohort [23]. The BMI appears to be lower in vegetarians by any deﬁnition, but the combination of self-deﬁned vegetarianism and the lack of meat (including poultry and seafood) appeared to be the most effective [23]. Although decreased body weight is cited among the top reasons for choosing a vegetarian diet [27,30], a causal effect of vegetarian diet on weight loss cannot be established from cross-sectional studies. It may be that vegetarian populations may possess characteristics other than diet that may inﬂuence body weight. Vegetarians in general and vegans in particular have a decreased incidence of smoking and higher exercise levels and tend to be younger and of a higher social class [4,10–13, 15,16,19,26,31]. Vegetarians were also more likely to be female [1,26] and to have a higher nutritional supplement use [15,26] and lower prescription medication use [19]. Alcohol use was reported to be higher among meat-eaters relative to non-meat-eaters [4,5,10,11,16], although winedrinking was also reported to be higher in non-meat-eaters [23]. It may be, therefore, that vegetarianism serves as a marker of a health-seeking personality and that vegetarianism per se has no speciﬁc advantages. Barr and Broughton [31] found that a convenience sample of 193 current, former, and nonvegetarian women, health-conscious and demographically similar except for ethnic background and parity, did not differ signiﬁcantly with regard to BMI, weight, or self-assessed weight or health, although only formerly vegetarian women had BMIs in the mean overweight range. Men who became vegetarian after age 20 had a lower BMI before beginning a vegetarian diet than did a corresponding same-age group of meat-eaters [17]. In a negative light, vegetarianism was also linked with eating disorders in Turkish adolescents, although young vegetarians cited “taste preference” and “healthier diet” above “weight control” as reasons for their dietary practices [27,30]. Only 24% of a cohort of college students who had ever tried a vegetarian diet expected to lose weight, although 59% of the students who had at some point tried a weight-loss diet expected weight loss from a vegetarian diet [30].

INTERVENTION STUDIES A more direct analysis on the impact of vegetarian diets on body weight can be found with intervention studies (Table 23.2). Phillips et al. [32] examined the effect on 33 volunteers of a 6-month diet excluding meat but including ﬁsh. Although weight, BMI, and waist-to-hip ratio were not altered, signiﬁcant decreases were seen in mid-upper-arm circumference, skinfold measurements, percent body fat, and waist and hip circumferences. During a crossover study, 35 women reduced their weight and BMIs during a low-fat vegetarian diet phase lasting two menstrual cycles [33]. As

Postmenopausal women

Recent vegetarians

Toobert et al. [39]

Phillips et al. [32]

b

33

14

29

35

Number in Intervention/ Control Group

Results are signiﬁcantly different compared to control group. Other parameters of body fat show signiﬁcant change.

Obese postmenopausal women

Barnard et al. [37]; Turner-McGrievy et al. [38]

a

Premenopausal women

Barnard et al. [33]

Ref.

Study Population

Pre/post

Parallel

Parallel

Crossover

Type of Study

Diet excluding meat but including ﬁsh

Lifestyle intervention including mostly vegan diet

Low-fat vegan diet

Low-fat vegetarian diet phase

Dietary Intervention

TABLE 23.2 Direct Analysis on the Impact of Vegetarian Diets on Body Weight

Baseline

Usual care

National Cholesterol Education Program Step II guidelines

Placebo supplement phase

Control

6 months

24 months

14 weeks

2 menstrual cycles

Length of Study

0.3

1.4

0

—

2.1a

1.0a

0.1b

Control 0.9a

Intervention

Change in BMI

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with cross-sectional studies, results may be attributable to the personal characteristics of individuals amenable to a vegetarian diet and not to the diet itself. Preference, for example, may play an important role in the success of a diet [34]; however, Barnard et al. [33] found no demographic differences between 35 completers and 16 non-completers of their diet intervention. Delgado et al. [35] found that a 2-month transition from a Mediterranean diet to a lacto-ovo vegetarian diet did not affect the body composition of 14 individuals; however, study subjects were current or former physical education students who did not consume signiﬁcant quantities of fast food, so nutritional changes and possible room for weight improvement may have been minimal. Barnard et al. [33] found that individuals with initial BMIs < 22.0 kg/m2 lost less weight (in kg) than those with initial BMIs > 22 kg/m2. One aspect of a vegetarian diet that may be of practical beneﬁt is that long-term adherence to a vegetarian diet may be greater than adherence to a “weight-loss” diet. Smith et al. [30] reported that the median times a group of college students adhered to weight-loss diets and vegetarian diets were 3 months and 24 months, respectively. Loss of interest was more commonly cited as a reason for quitting for the weight-loss group than for the vegetarian group. The BMI was lower for students who had been on a vegetarian diet at any time than for those who had been on a weight-loss diet at any time (whether or not they had ever tried a vegetarian diet) or neither; mean BMIs for all groups were within the normal range. Barnard et al. [35] reported that a vegan diet had a high degree of acceptability among the 28 study participants. Several studies examine the effect of randomization to a vegetarian diet. Barnard et al. [35,36] and Turner-McGrievy et al. [37] studied 59 obese women assigned to either a low-fat vegan diet or a diet following the National Cholesterol Education Program Step II guidelines, with limits on fat, saturated fat, and cholesterol and percentages of energy from protein and carbohydrate at 15% and >55%, respectively. The vegan group had a greater decrease in body weight, BMI, and waist circumference over the 14 weeks period than did the Step II group, although the means of both groups remained in the obese range [37,38]. In a group of 14 women assigned to a lifestyle intervention including vegetarian diet, BMI decreased slightly but signiﬁcantly more than in a group of 11 controls [39].

NUTRITIONAL DIFFERENCES BETWEEN VEGETARIAN AND NON-VEGETARIAN DIETS Vegetarian and non-vegetarian diets are deﬁned by the presence or absence of meat and other animal products. Vegetarians presumably eat more plant-based foods to compensate for the missing animal products; thus, the nutrient proﬁle of vegetarian and non-vegetarian diets is likely to be different. Table 23.3 shows differences in dietary components reported for vegetarian and nonvegetarian diets. Vegetarian diets may facilitate weight loss for a number of different possible reasons, presumably mediated by the differences in composition. Lower concentrations of some dietary components and higher concentrations of others may each have their own effects. Vegetarian diets have been found for the most part to be lower in overall energy [9,12,13,15,21,24,32,33,35–38], protein [9,12,13,15,21,23–26,31,33,35–38], fat [12,15,21,23,25,26,33,35,36], saturated fat [9,12,13, 15,21,23,24,26,31–33,35–39], and cholesterol [26,31,33,35,36,38]. Vegetarian diets tended to be higher in ﬁber [9,12,13,15,21,23,25,26,31,33,36–38] and carbohydrate [9,12,13,15,23–26,31–33, 36–38]. Omega-3 polyunsaturated fatty acids (PUFAs) in diet and plasma, in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were reported to be lower in vegetarians [3,10,23], although effects on overall PUFA levels range from decreased to unchanged to increased [5,12,13,15,18,21,23,24,26,31,36–38]. Consumption of ﬁsh by “vegetarians” may affect omega-3 fatty acid levels [23]. Monounsaturated fatty acids were consistently lower in the diet of vegetarians [12,15,18,23,24,31,38]. Possible roles for each of these dietary components in affecting body weight will be discussed individually.

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TABLE 23.3 Dietary Components Reported in Vegetarian Diets Dietary Components Reported in Lower Concentrations in Vegetarian Dietsa

Dietary Components Reported in Higher Concentrations in Vegetarian Dietsb

Energy Protein Fat Saturated fat Cholesterol Omega-3 polyunsaturated fatty acids Monounsaturated fatty acids

Fiber Carbohydrate

a b

See References 3, 5, 9, 10, 12, 13, 15, 18, 21, 23–26, 31–33, 35–39. See References 9, 12, 13, 15, 21, 23–26, 31–33, 35–38.

POSSIBLE MECHANISMS FOR SPECIFIC DIETARY COMPONENTS ENERGY The balance of energy intake and expenditure determines whether a person will gain or lose weight, and a low-fat, lower-calorie diet (plus exercise) is a standard behavioral treatment for obesity [34]. Indeed, as described above, many analyses of vegetarian diets show a decreased energy (caloric) content, and decreased energy was correlated with weight loss [31]. Kennedy et al. [24] suggested that any diet sufﬁciently reducing energy intake should lead to weight loss. Decreased energy intake should not be confused with consciously restricted food intake, as total energy decreased with vegetarian diets even when food portions were not deliberately limited [32,37,38]; rather, a vegetarian diet was associated with decreased hunger scores [36]. A ﬁber-rich vegetarian diet is therefore typically less energy dense than a diet high in animal fats, and a high energy intake would be more difﬁcult to achieve. A ﬁber-rich, low-glycemic index diet, rich in fruits and vegetables, could contribute to an earlier feeling of satiety and decreased voluntary intake [40–44]. It should be noted that leptin, one of the hormones associated with satiety was decreased in 22 vegetarian children ages 2 to 10 years relative to 13 omnivore controls [28]. Leptin is primarily derived from adipocytes; thus, decreased leptin may be a consequence of decreased body fat [45]. Reports of decreased energy intake do not automatically correspond to decreased weight in those individuals [35]. Decreased energy expenditure and resting metabolic rate may counter decreased energy intake with vegetarian diets, negating some of the beneﬁcial effect of energy reduction [37]. The effects of a decrease in energy intake might be masked if heavier individuals were to underreport intake [46], had remained on a diet for too short a time for effects on weight to be noticed, or were within normal weight range and had no excess body fat to lose [35]. Furthermore, decreased energy intake may act in conjunction with other factors, as oily-ﬁsh-eaters consumed more calories than meat-eaters or vegetarians but had a lower BMI than any of the other groups [15]. Similarly, individuals lost more weight on a vegan diet than on a National Cholesterol Education Program Step II diet, although both had decreased energy intake [37]. Vegetarians in this latter study had less fat and more carbohydrate relative to the Step II group. It may be that macronutrient balance is important; therefore, the effects of the three main macronutrients (i.e., protein, fat, and carbohydrate) are considered individually.

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PROTEINS The removal of meat from the diet is a simple modiﬁcation that is easy to implement and maintain and that produces favorable changes in body composition [30–32,36]. The absence of red meat, primarily beef, was associated with a decreased BMI in Seventh-Day Adventists [5]. Meat contributes signiﬁcant amounts of protein as well as energy-dense saturated fat, and it may displace ﬁber- and nutrient-rich plant foods in the diet. Meat may also serve as a marker for general overnourishment. As described earlier, vegetarians typically eat less dietary protein than do meat-eaters. The exact mechanism of how this decrease in protein might affect weight loss is unclear. With regard to increased body weight of meat-eaters, it has been suggested that high protein early in life could result in increased insulin-like growth factor, which might lead to adipocyte replication as well as decreased growth hormone [47,48]; however, individuals becoming vegetarian as children were heavier than adult-onset vegetarians, and lifelong vegetarians were no different in BMI from adultonset vegetarians [9]. High-protein diets have in fact been used as an approach to weight loss, and it has been reported that the high protein content increases satiety and thermogenesis [49–52]. Protein preloads increased satiety relative to a glucose preload and corresponded with decreases in the appetite-inducing hormone ghrelin and increases in satiety-inducing cholecystokinin (CCK) and glucagon-like peptide 1 (GLP-1) [53,54]. Ghrelin was decreased more by a high-protein breakfast than a high-carbohydrate breakfast [55]. Increased satiety and decreased hunger and actual or desired food intake were noted for 19 and 57 subjects placed on a high-protein diet, although in these subjects ghrelin was increased [50,56]. Raben et al. [57], however, found no effect of high protein on postprandial satiety, and Nickols-Richardson et al. [49] found no difference in actual energy intake between high-protein and high-carbohydrate diets, although hunger scores were lower in the high-protein group. Diet-induced thermogenesis is deﬁned as the expenditure of energy required for absorbing, processing, and storing nutrients. Expressed as a percentage of the energy content of each macronutrient, reported values range from 20 to 30% for protein to 5 to 10% for carbohydrates and 0 to 3% for lipids [58]. A protein-rich diet, then, requires more energy to digest and store and should therefore, in theory, generate fewer calories left over for storage. Correspondingly, it might be expected that lower-protein vegetarian diets would be less thermogenic and more conducive to weight increase. Accordingly, Johnston et al. [51] observed increased thermogenesis and a slightly higher post-meal body temperature in volunteers after high-protein meals vs. high-carbohydrate meals; Raben et al. [57] reported 17% higher thermogenesis after a protein meal than after fat or carbohydrate meals; and Poehlman et al. [25] found a decreased postprandial thermic response in a group of 12 vegetarian men vs. a group of 11 normal controls. Weigle et al. [50], however, found that thermogenesis did not signiﬁcantly increase with a high-protein diet, and Barnard et al. [37] found an increased thermic effect in vegetarians compared to non-vegetarians. Thus, there appears to be no clear mechanism by which low protein per se could lead to decreased weight, and in fact an increased amount of protein might seem to be more effective in weight loss; however, plant-based and meat-based diets differ in amino-acid makeup as well as protein quantity. In particular, plant proteins contain more non-essential amino acids than do animal proteins. A higher intake of non-essential amino acids can tend to downregulate insulin and upregulate glucagon, thereby decreasing fat synthesis and increasing fat oxidation [47,59]. Taiwanese vegetarians who consumed large amounts of soy-based proteins had greater insulin sensitivity [21]. Relative decreases in essential amino acids have also been associated with lower levels of insulin-like growth factor 1 (IGF-1) in vegan women [60], possibly resulting in adipocyte stimulation [47]. Finally, a preload of plant protein in the form of tofu and mushroom mycoprotein had a greater effect on satiety than did chicken protein, and study participants did not compensate for the lower food intake at lunch by eating more at dinner [61]; however, pork protein produced higher total daily energy expenditure than soy protein [52], possibly because soy protein was less able to support energetically costly protein turnover.

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CARBOHYDRATES As discussed, vegetarian diets on average contain more carbohydrates than do meat-containing diets. Carbohydrate ingestion, which results in increased blood glucose, stimulates the secretion of insulin which in turn removes glucose from the blood and increases fat storage. Increased insulin would also promote more rapid onset of hunger by clearing glucose from the bloodstream more quickly [62]. In the liver, increased insulin after a high-carbohydrate meal has a fat-sparing effect, decreasing fat oxidation [57,63]. Carbohydrates would therefore appear to promote weight gain via the effects of insulin; however, sources of carbohydrates differ in regard to glucose release. In a vegetarian diet, carbohydrates may be more likely to come from fruits, vegetables, and unreﬁned grains with a lower glycemic index (GI) rather than from higher GI foods such as white bread [5,18,22,64]. Low-GI carbohydrates would release glucose more slowly and therefore produce less of an insulin response. Ad libitum use of low-GI carbohydrates in the diet appears to be associated with a lower body weight, although in isoenergetic studies body weight was not affected by glycemic index per se [57,65,66]. Overall, a lower glycemic load (GL), reﬂecting net quantity as well as quality of carbohydrate, seems to be related to reduced body weight [62,66–68]. Dietary carbohydrate may be better than dietary fat at suppressing postprandial ghrelin and increasing leptin. Both of these changes would increase satiety and decrease food intake [50,69], although Raben et al. [57] found no difference in satiety among meals rich in protein, reﬁned carbohydrate, or fat; however, satiety effects may be more relevant with low-GI foods.

FIBER Dietary ﬁber consists of nondigestible, plant-derived carbohydrates and lignin [70] and is increased in vegetarian diets. Data from 15 studies of 11 cohorts indicate a median increase in ﬁber intake of 7.3 g for vegetarian or vegan vs. meat-containing diets, with mean total ﬁber intake of 24.8 g for vegetarians [9,13,15,16,23,25,26,28,31,33,35–38]. In the Oxford Vegetarian Study, ﬁber was a factor that was associated with lower BMI in both men and women [16]. Increased ﬁber was associated with lower BMI in 2165 women but not 2374 men in the Continuing Survey of Food Intakes by Individuals [70]. Fiber was inversely associated with weight gain over an 8-year period in a prospective cohort of 27,082 men [44] and in a cohort of middle-aged women [43]. Weight gain in men was decreased by 2.51 kg for every 20 g/day fruit ﬁber, by 0.81 kg for every 20 g/day cereal ﬁber, and by 0.36 kg for every 20 g/day added bran [43], and an intake of 14 g/day of ﬁber for 2 or more days appeared to correspond with a 10% decrease in energy intake [72]. Pereira and Ludwig [73] discuss three mechanisms by which ﬁber could lower body weight. First, ﬁber has a low energy density. Because of its bulk and because of associated ﬂuid, ﬁber in the diet can lead to a fuller stomach and increased satiety. Increased satiety plus the lower palatability of ﬁber-rich foods could subsequently decrease energy intake. Second, changes in the consistency and movement of food in the gut can alter the generation of satiety-related hormones such as CCK, gastric inhibitory peptide (GIP), GLP-1, and insulin. Third, ﬁber fermentation generates short-chain fatty acids that can decrease hepatic glucose production and FFA, further affecting insulin secretion and sensitivity.

DIETARY FATS As described above, vegetarian diets on the average tend to be lower in fat than meat-containing diets, although Fraser [5] noted that the diet of Seventh-Day Adventist vegetarians was not necessarily low in fat. Low fat consumption and low fat in conjunction with ﬁber were associated with a lower BMI in men and women, respectively [71]. In the EPIC–Potsdam cohort, foods high in fat were correlated with increased weight gain in women [74]. High levels of dietary fat would not appear to be desirable with regard to weight loss. The high energy density of fats plays an important role in increasing energy intake and body weight [75], and fat as a palatable food suppresses satiety,

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possible through insulin or leptin resistance [76]. Furthermore, a high-fat diet has little thermogenic effect [58]. Dietary fat upregulates acyl CoA:monoacylglycerol acyltransferase (MGAT), an enzyme involved in fat absorption and storage [77]. It may be that the type of fat is as important as total fat content. Appleby et al. [16] found that consumption of animal fat, which is high in saturated fat, was a signiﬁcant factor contributing to low body mass in non-meat-eaters. Several studies have found that switching from saturated to monounsaturated fat decreased body fat [78–80]. Saturated fatty acids have been reported to produce less satiety and stimulate less fatty acid oxidation relative to unsaturated fats [81,82], although several later studies showed no difference in satiety or energy expenditure for several different sources of fatty acid [65,83–85]. Furthermore, saturated fat has been associated with a higher insulin resistance relative to monounsaturated fat [80,86,87], although again this association has not been consistently found [85,88]. Saturated fat is lower in a vegetarian diet [9,12,13,15,21,23,24,26, 31–33,35–39], but monounsaturated fatty acids have been reported to be lower as well [12,15,18, 23,24,31,38]. Omega-3 PUFAs were decreased [2,3,10,23], but effects on total polyunsaturated fats varied [5,12,13,15,18,21,23,24,26,31,36–38]. Although several mechanisms exist by which increased PUFA intake could lead to decreased obesity and insulin resistance [89], there is no clearly established role for polyunsaturated fats in obesity or insulin resistance in vivo [88,90].

DOES THE DECREASE IN BMI ASSOCIATED WITH A VEGETARIAN DIET IMPLY BETTER HEALTH? A presumption of this discussion is that a decreased body weight represents a healthy change. A counter-example might be the decreased body weight associated with the unhealthful practice of smoking. Smokers, for example, tend to have lower body weight, and smoking cessation is associated with weight gain [17], but overall the practice of smoking would not be considered beneﬁcial. It could also be that the lower BMIs result from reduced muscle mass; thus, the possibility must be considered that decreased body weight in vegetarians results from inadequate nutrition that could adversely affect health. Although vegetarian diets are considered to be appropriate and healthful [2], a poorly planned vegetarian diet could contribute to malnutrition; for example, vegetarians can be more likely to have dietary deﬁciencies in a number of micronutrients including B12 and vitamin D [3,23,31,38,91]. Perry et al. [64], however, found that adolescent vegetarians had a healthier diet than non-adolescent vegetarians, and vegetarian diets can be appropriately used to support athletic performance [3,91]. Vegetarians and especially vegans have lower levels of the omega-3 PUFAs that are considered protective in cardiovascular and other diseases, yet they have less ischemic heart disease [3,10]. A cohort of 30 male vegetarians was more likely to report heart disease than a comparison group of non-vegetarians; however, because they also were more likely to choose foods based on effects on heart disease and high blood pressure, it may be that cardiovascular problems were a cause and not a consequence of vegetarianism [26]. Vegetarians have less selfreported illness than meat-eaters [15], higher health perception, and less prescription drug use [19], although Barr and Broughton [31] found no differences in health assessment among health-conscious women with differing dietary patterns. Mortality from ischemic heart disease was decreased in vegetarian populations [4], although the corresponding decrease in an EPIC–Oxford cohort was not signiﬁcant and all-cause mortality increased slightly [11].

CONCLUSIONS A large body of evidence suggests that vegetarian populations have a decreased body weight compared to corresponding populations of non-vegetarians, although the increased health consciousness of individuals drawn toward vegetarianism may be a contributing factor. Intervention studies suggested beneﬁts from switching to a meatless diet, with the advantage that such diets

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may be more easily adopted and sustained than a standard weight-loss diet. Even periods as short as 14 weeks generated improvement; more beneﬁt was seen at >5 years, but lifelong vegetarianism did not appear to be necessary nor was strict adherence to a vegetarian diet required, as many “vegetarians” admitted consuming some ﬂesh foods, particularly ﬁsh and poultry. A number of possible mechanisms for the beneﬁts of a vegetarian diet have been suggested, resulting mostly from increases or decreases in dietary macronutrients. Meat and concomitantly protein, fat, and energy were decreased while carbohydrate and ﬁber were generally increased. An additional beneﬁt of a plant-based diet is presumably increased intake of plant antioxidants, polyphenols, and other phytochemicals. Although these components may be secondary to macronutrients in regard to protection from obesity, they may contribute to the cardiovascular and other health beneﬁts reported for vegetarian diets.

ACKNOWLEDGMENTS The authors wish to thank Ms. Maria Knecht for assistance with references, Ms. Angela Williams for formatting the manuscript, and Dr. Bruce Currie for editorial suggestions.

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The Vegetarian Resource Group, How many vegetarians are there?, Vegetarian J., 2003, http://www.vrg.org/journal/vj2003issue3/vj2003issue3poll.htm. American Dietetic Association; Dietitians of Canada, Position of the American Dietetic Association and Dietitians of Canada: vegetarian diets, J. Am. Diet. Assoc., 103(6), 748, 2003. Key, T.J., Appleby, P.N., and Rosell, M.S., Health effects of vegetarian and vegan diets, Proc. Nutr. Soc., 65(1), 35, 2006. Key, T.J. et al., Mortality in vegetarians and nonvegetarians: detailed ﬁndings from a collaborative analysis of 5 prospective studies, Am. J. Clin. Nutr., 70(3, Suppl.), 516S, 1999. Fraser, G.E., Associations between diet and cancer, ischemic heart disease, and all-cause mortality in non-Hispanic white California Seventh-Day Adventists, Am. J. Clin. Nutr., 70(3, Suppl.), 532S, 1999. Berkow, S.E. and Barnard, N., Vegetarian diets and weight status, Nutr. Rev., 64(4), 175, 2006. Sabaté, J. and Blix, G., Vegetarian Diets and Obesity Prevention in Vegetarian Nutrition, CRC Press, Boca Raton, FL, 2001, pp. 91–107. EPIC–Oxford Study of Nutrition and Health, http://www.epic-oxford.org/. Rosell, M., Appleby, P., and Key, T., Height, age at menarche, body weight and body mass index in life-long vegetarians, Public Health Nutr., 8(7), 870, 2005. Rosell, M.S. et al., Long-chain n-3 polyunsaturated fatty acids in plasma in British meat-eating, vegetarian, and vegan men, Am. J. Clin. Nutr., 82(2), 327, 2005. Key, T.J. et al., Mortality in British vegetarians: review and preliminary results from EPIC–Oxford, Am. J. Clin. Nutr., 78(3, Suppl.), 533S, 2003. Spencer, E.A. et al., Diet and body mass index in 38,000 EPIC–Oxford meat-eaters, ﬁsh-eaters, vegetarians and vegans, Int. J. Obes. Relat. Metab. Disord., 27(6), 728, 2003. Davey, G.K. et al., EPIC–Oxford: lifestyle characteristics and nutrient intakes in a cohort of 33,883 meat-eaters and 31,546 non-meat-eaters in the U.K., Public Health Nutr., 6(3) 259, 2003. Key, T. and Davey, G., Prevalence of obesity is low in people who do not eat meat, Br. Med. J., 313(7060), 816, 1996. Cade, J.E., Burley, V.J., and Greenwood, D.C.; U.K. Women’s Cohort Study Steering Group, The U.K. Women’s Cohort Study: comparison of vegetarians, ﬁsh-eaters and meat-eaters, Public Health Nutr., 7(7), 871, 2004. Appleby, P.N. et al., Low body mass index in non-meat-eaters: the possible roles of animal fat, dietary ﬁbre and alcohol, Int. J. Obes. Relat. Metab. Disord., 22(5), 454, 1998. Rosell, M., Appleby, P., Spencer, E., and Key, T., Weight gain over 5 years in 21,966 meat-eating, ﬁsh-eating, vegetarian, and vegan men and women in EPIC–Oxford, Int. J. Obes. (Lond.), 30(9), 1389–1396, 2006.

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24 The Atkins Paradigm Ariel Robarge and Bernard W. Downs CONTENTS Introduction ....................................................................................................................................315 Science Spawns Commercial Opportunities..................................................................................316 Outside the Box of Conventional Dogma .....................................................................................316 The Atkins Concept .......................................................................................................................316 Ketosis: How Does It Work? .........................................................................................................317 Does Ketosis Propel Fat Loss by a Metabolic Advantage? ..........................................................317 Energy and the Metabolic Bank Account......................................................................................317 The Atkins Contribution ................................................................................................................318 Conclusions ....................................................................................................................................319 References ......................................................................................................................................320

INTRODUCTION In the Beginning — It is important to state that this chapter is not an attempt to discredit Dr. Robert Atkins’ theory. In fact, his observations were right on the mark in general terms. This chapter hopes to put Dr. Atkins’ contribution, as controversial as it may be, into its correct context as a catalyst and vehicle for a major paradigm shift in our understanding of and approach to the causes and treatments of obesity and related disorders. Dr. Atkins was instrumental in removing our obsessive focus on fat being the greatest enemy with regard to disease prevention and treatment; however, to gain an understanding of the premise of the Atkins program, one must ﬁrst understand in what environment the Atkins program was created and what caused Dr. Atkins to pioneer this paradigm at that particular time. Recall that following World War II there was a sharp increase in refined and processed food production and consumption. The major characteristic of these foods was that they were rich in fats (they were also rich in sweeteners such as high-fructose corn syrup and invert sugar). This led to a passive overconsumption of high-fat, high-calorie foods (as well as high sugar consumption). Concomitant with this increase in high-fat foods was a significant increase in cardiovascular disease, diabetes, and obesity. These new dietary habits were recognized as problematic by the medical and nutrition establishment that ultimately, in response to the consequences of these dietary habits, mandated a “low-fat” lifestyle. The experts of the time stated what they believed to be the obvious conclusion: If we eat too much fat, we get fat; in other words, fat begets fat. At this point, the Food Guide Pyramid was developed with an emphasis on increasing dietary carbohydrate intake while reducing fat consumption. In hindsight, the ﬂaw with the new guidelines was that the carbohydrates emphasized (bread, rice, cereal, and pasta) were derived primarily from reﬁned processed sources, not necessarily whole, unprocessed grains. Americans were told that the majority of their food intake should be grain derived and that fats in any shape or form were to be avoided at all costs. All fats were thought to contribute to disease and obesity and should be avoided as much as possible.

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SCIENCE SPAWNS COMMERCIAL OPPORTUNITIES Responding to the commercial opportunities created by these new ofﬁcial guidelines, agribusiness and the food-processing industry jumped on the band wagon and began producing high-carbohydrate, low-fat reﬁned and processed alternatives, which eventually became the dogma of mainstream nutrition. This paradigm of low fat (high carbohydrate) became a societal mantra to the point of being a phobia. New dietary laws regarding nutrition, health, weight management, and disease treatment and prevention branded dietary fats as the villainous culprit responsible for a host of pathological disorders. An increasingly fat-obsessed society, including health professionals, business interests, and consumers alike, responded by adopting this paradigm, thus inciting the shift to high (reﬁned) carbohydrate consumption.

OUTSIDE THE BOX OF CONVENTIONAL DOGMA Dr. Atkins, a cardiologist, saw that several decades of high carbohydrate consumption were accompanied by a signiﬁcant increase in insulin resistance problems (metabolic syndrome X), such as cardiovascular disease, diabetes, hypertension, hyperlipidemia (high cholesterol, high triglycerides), and obesity. His approach was to eliminate carbohydrates from the diet as a means of treating these disorders. Initially, his focus was on improving health. It was not about obesity per se; rather, it was about anything that had to do with insulin resistance and related disorders. He consistently observed remarkable improvements in all of these insulin resistance problems, especially obesity, as a result of drastic changes made to his patients’ diets. He authored Dr. Atkins’ Health Revolution in 1988 to promote this new paradigm. To keep things in perspective, Dr. Atkins never promoted an unhealthy dietary lifestyle. Contrary to antagonists’ assertions, he never said, “Stop eating sugar and start eating pork rinds and bacon fat.” He simply recognized that reﬁned carbohydrates were particularly bad for patients who suffered from insulin resistance and heart disease. In practice, he found that by simply removing these foods from their diet the patients had remarkable improvements in all parameters of their health. Atkins proposed that a high-fat, high-protein diet gave a metabolic advantage that allows individuals to eat as much as they want and still lose weight. Subsequently, some studies have demonstrated an increase in the amount of weight lost on low-carbohydrate diets as opposed to the traditional low-fat, high-carbohydrate diets; however, this difference apparently disappears after the initial period of approximately 12 months [1]. Also, a careful meta-analysis of popular diets revealed that it was more likely the adherence to the low-carbohydrate approach that gave rise to a greater weight loss. The research has shown that when carbohydrates are reduced so drastically people spontaneously decrease calorie intake by approximately 1000 calories a day [2]. Fat and protein intake elicits a much greater sense of satisfaction and increased ketosis, also promoting a decrease in appetite, so the dieter is not struggling with constant hunger pains. On the other hand, an extremely high-carbohydrate diet that is low in fat tends not to be as satisfying and may cause swings in blood sugar that make compliance and adherence extremely difﬁcult. This difﬁculty is accentuated when the carbohydrates are primarily reﬁned. A recent 1-year comparison of four popular diet programs (Weight Watchers, Atkins, Ornish, and The Zone) showed that, at 1 year, weight loss was practically identical and was independent of the macronutrient ratio of the diet. It was almost exclusively correlated with (reduced) caloric intake [3].

THE ATKINS CONCEPT The Atkins diet is based on the theory that obesity is a result of carbohydrates and not calorie intake per se. Atkins claimed that carbohydrates are the only catalyst for insulin release, so, if you are eating foods that do not cause an increase in insulin levels, then you can eat all you want and lose weight. Fat and protein are allowed in unlimited quantities, and carbohydrates are signiﬁcantly reduced depending on the phase of the diet. Atkins proposed that, because insulin is involved in

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fat storage, weight loss is simply a matter of reducing insulin; therefore, an individual who stops eating carbohydrates will burn fat and lose weight more efﬁciently. This is why the initial phase of Atkins diet is so strict. An individual is allotted only 20 g of carbohydrates per day during the induction phase, which lasts 2 weeks. This facilitates a complete depletion of glycogen stores and an associated water loss of 3 to 5 pounds. The body then enters a state of ketosis, where it burns fats and proteins for energy as opposed to glucose.

KETOSIS: HOW DOES IT WORK? When carbohydrates are eaten, they are broken down to sugar and used as energy or stored as glycogen for later use. Insulin is released by the pancreas to carry the sugar to the cells where it can be burned for energy or stored as glycogen, and any excess is converted to fat. Atkins proposes that it is this chronic state of high blood sugar induced by our standard high-carbohydrate diet that leads to diabetes and obesity. Ketosis can be induced by carbohydrate restriction. In simple terms, the dieter switches to burning fat instead of sugar for energy. Ketones are carbon–oxygen fragments that are released during the breakdown of fats. Most people experience ketosis when carbohydrate intake falls below 40 g a day. Side effects include breath odor, loss of appetite, and constipation. Liver and kidney distress can occur in extreme states of ketosis, and chronic long-term ketosis may lead to organ distress or failure. The brain, red blood cells, and some organs, however, still rely on glucose for energy. The minimal amount recommended for proper functioning is 120 g a day. The body will go through a process of gluconeogenesis (conversion of proteins to glucose) to provide the essential blood sugar for those tissues. These proteins may be obtained through food or the body will pull proteins from lean body mass to provide the essential blood glucose. Some studies have shown that low-carbohydrate diets may cause a greater loss of lean body mass for this reason [4].

DOES KETOSIS PROPEL FAT LOSS BY A METABOLIC ADVANTAGE? Atkins claimed that a metabolic advantage occurs with ketosis, in that ketones (byproducts of fat metabolism) are excreted via the feces and urine, thus reducing metabolizable energy and allowing for greater fat loss. Atkins concluded that it is possible to eat more and lose weight because ketosis is metabolically efﬁcient. Carbohydrate intake blunts ketosis because the body no longer needs to break down fats to provide energy. This is why the Atkins program does not put a limit on total caloric intake for the day and instead focuses on drastically reducing carbohydrate consumption. More recent research has shown that the amount of energy lost as ketones is very minimal and does not make a signiﬁcant contribution to a metabolic advantage. A recent study compared 6 weeks of a ketogenic low-carbohydrate diet (KLC; 5% of calories from carbohydrates) to a nonketogenic low-carbohydrate diet (NLC; 40% of calories from carbohydrates). The authors concluded that, although both diets resulted in similar loss of weight and reduced insulin resistance, the KLC was associated with a number of adverse metabolic and emotional effects [5]. Although the study duration was for only 6 weeks and may be inadequate to assess longer term effects, it does suggest that any energy that may be lost via ketosis might not be sufﬁcient to offer a signiﬁcant enough metabolic advantage over other alternatives, especially in light of ketosis-induced metabolic consequences. Furthermore it calls into question the proposed tactical advantages that altering energy ratios may offer in weight management.

ENERGY AND THE METABOLIC BANK ACCOUNT Atkins also suggested that the energy cost of digesting and metabolizing a high-fat meal is greater than a meal high in carbohydrates; however, recent research examined the effects of high-carbohydrate/low-fat/high-protein meals (60:10:30) compared to low-carbohydrate/high-fat/low-protein

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meals (30:60:10) on 24-hour energy expenditure when consumed over a 36-hour period. The authors found that high-carbohydrate meals induce greater energy expenditure when coupled with a relatively higher protein intake (than fat) over high-fat/low-carbohydrate meals. In other words, higher fat meals resulted in a reduced thermic effect compared to the meals high in carbohydrates when the carbohydrates were accompanied by higher protein intake as well [6]. More recent research conﬁrms that protein intake is crucial in determining the intensity of the thermic effects [7]. The metabolic advantage of the low-carbohydrate paradigm has been difﬁcult to consistently verify. When patients have been studied in a metabolic ward where energy is provided, this metabolic advantage ceases to exist. Earlier research has shown that isocaloric amounts of proteins, fats, and carbohydrates elicit almost identical losses in fat tissue regardless of whether those calories are derived from protein, carbohydrate, or fat [8]. It is more likely that when people are in a state of ketosis they feel that they are eating more and losing weight because of the signiﬁcant decrease in appetite.

THE ATKINS CONTRIBUTION It is the authors’ opinions that, among other things, Dr. Atkins’ program gave rise to recognition of the importance of glycemic indexing (GI) as a means of evaluating the impact of carbohydrates on blood sugar, insulin, and metabolism. It is not our purpose to delve into the details of GI but just to note that this model of dietary management arose as a result of the awareness that carbohydrates have varying effects on metabolism relative to the efﬁciency with which they are converted to blood sugar. That sugar impact concept was the platform of the Atkins program and the reason for omitting carbohydrates from the diet to reverse insulin resistance disorders. The prevailing belief was that carbohydrates were the only macronutrient that stimulated release of insulin; however, according to recent research, we now know that that is not entirely correct. Proteins and fats also increased insulin production and release by the pancreas, but proteins and fats did not induce a proportional or concomitant rise in blood sugar; for example, beef intake raised insulin levels more than brown rice, and ﬁsh raised insulin more than pasta. Neither protein source raised blood sugar more than the carbohydrate sources; therefore, insulin is not just responsive to only carbohydrate consumption [9]. It is clear that the interplay of hormones, lifestyle, genetics, and metabolism are much more complicated than once thought and that the causes and treatments for obesity cannot be evaluated in such a simplistic one-dimensional manner; for example, an interrelationship of hormones is involved in digestion and the regulation of metabolism. Focusing on one aspect and disregarding other variables (especially for a short term) is not comprehensive and will not lead to optimal health, which is required to effectively address chronic obesity. Initially, such a drastic change in diet may yield some positive results, but this is short term because it does not address the root cause of the initial problem. Given the multidimensional aspects of human metabolism, in addition to insulin, a number of other hormones and neurotransmitters, such as ghrelin, leptin, cholecystokinin, serotonin, and dopamine (to name a few), along with genetic factors, need to be simultaneously addressed and included in the framework of a healthy metabolic and body recomposition program. The greatest minds in medicine and science (including Atkins) have zeroed in on speciﬁc aspects of metabolism (as the culprits or solutions) and analyzed them from the standpoint that those aspects hold the key to unlocking the mysteries to successful obesity management. It is sort of like the six blind men describing the structure of an elephant, with each one holding onto a different part of the animal. Each blind man gives an accurate description of the part of the elephant he is holding but falls short of giving a complete and totally accurate description of the whole elephant. We in (nutrition) science tend to do the same thing. It should be obvious that weight management, nutrition, and metabolism are interrelated and that more than one component is contributing to the rise in obesity. Science fails to make the correlation between multiple aspects of metabolism and instead focuses on one or two mechanisms without addressing the whole picture. As an example, the fat phobia was supported by research

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that showed fat calories are more easily stored as fat in the body and carbohydrates are preferentially burned for energy. This led to an interpretation that it was possible to eat as much as you wanted as long at it was low fat. People started eating generous amounts of processed, reﬁned, low-fat foods (offset mainly by high-fructose corn syrup) with the false idea that these foods did not contribute to weight gain and obesity. Clearly, a dominant consumption of reﬁned (nutrient deﬁcient) carbohydrates can lead to many unhealthy consequences. Atkins rightly condemned this type of lifestyle. In hindsight, the ﬂaw of the Atkins program, perhaps due more to commercial forces and requirements, was that it obsessed almost solely on insulin and carbohydrate metabolism, missing other critical issues that contribute both to obesity and long-term health. Successful solutions to the obesity epidemic will have to encompass, in practical terms, management of the multifaceted aspects of human metabolism, their relationship to genetic expressions and lifestyle (nutrition, personality proﬁles, stress, and environmental factors, among others), and the symbiotic relationship among all of these elements. As indicated, this includes not only physical laws but the emotional issues that affect digestion, metabolism, and food intake. Our focus should be on achieving long-term holistic health that emphasizes maintaining optimal body composition on an individual basis. There is no “one size ﬁts all” when it comes to weight management, and focusing on the bathroom scale as the primary assessment of one’s health is missing the mark. The scale is a poor measure of success with regard to weight loss. Many diets cause the loss of an excessive amount of lean body mass along with the loss of fat. Then, during the rebound effect, metabolism slows down, the body becomes more efﬁcient at storing fat, and brain chemicals are altered, which leads to an increase in food cravings, irritability, and obsession with food. Food consumed in its unprocessed whole form, as it was intended, provides the nutrients that fund the structure and function of the body. Often, science and research fail to take into consideration individual needs and lifestyle. The dieting cycle and severe restriction of calories commonly touted by weight-loss programs fail to consider the long-term effects on energy metabolism, structural competence, and health. History is showing us that drastically reducing calories or altering ratios and percentages is short sighted and will not work in the long run. When the body is deprived of nutrition and energy it sets up a cascade of events that leads to mood disorders, binging, and weight cycling that leave dieters feeling powerless and out of control with regard to their weight. Obesity can also not really be attributed to an individual’s lack of motivation or willpower. Focusing on one aspect of dietary manipulation fails to take into account that the body requires all nutrients for synergy and wellness of metabolism. The way to optimal and healthy body composition is tuning into the body and providing its essential needs for protein, carbohydrates, fats, vitamins, and minerals from whole foods. By focusing on eating a balanced diet that is primarily composed of fresh, whole, uncontaminated, and unreﬁned foods and by engaging in an active and vital lifestyle the body gets the energy, nutrients, and exercise it needs for optimal performance and is able to rid itself of unneeded fat stores. The body is preprogrammed to work efﬁciently, energetically, and effectively if it has all of its essential resources and a minimum of stressful, toxic, and burdensome challenges that threaten to dismantle the scaffolding of health (at a greater rate than it can be rebuilt). We are made only of food, air, water, and sunshine. The quality of our health and metabolism is a direct result of the quality of those resources and the attitude with which we meet life’s challenges.

CONCLUSIONS Dr. Atkins offered a strategy of reducing insulin-resistance-induced metabolic insult caused by an excessive consumption of the sort of carbohydrates that disturb the body’s insulin and blood sugar metabolism. In contrast to the low-fat/high-carbohydrate paradigm popular at that time and the juggernaut of failed tactics implementing that paradigm, as evidenced by the signiﬁcant increase in insulin resistance disorders, it can be concluded that Atkins was moving in the right direction.

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The old adage that “hindsight is 20/20 vision” certainly gives us a critical advantage in perspective over that of Atkins. More recent research reveals a few ﬂaws in the sweeping conclusions supporting the foundations of the Atkins paradigm; however, this does not completely dismantle the scaffolding of his premise that chronic insulin resistance and related disorders, especially obesity, cardiovascular disease, and diabetes, are exacerbated by the nemesis of excessive reﬁned carbohydrate consumption as a component of a lifestyle including other poor dietary habits. Atkins did not have the beneﬁt of research that has helped to improve our understanding of the many contributing factors to obesity, some of which was spurred in response to the power and popularity of the Atkins paradigm. To that point, Dr. Atkins was a courageous pioneer who ventured outside the box against conventional dogma, and he spurred renewed investigations into and helped establish scientiﬁc merit for the insulin-related issues he championed. To that extent, we owe him well-deserved accolades and a debt of gratitude.

REFERENCES [1] [2] [3]

[4]

[5]

[6]

[7] [8] [9]

Foster, G.D., Wyatt, H.R., Hill, J.O., McGuckin, B.G., Brill, C. et al., A randomized trial of a lowcarbohydrate diet for obesity, N. Engl. J. Med., 348(21), 2082–2090, 2003. Astrup, A., Meinert Larsen, T., and Harper, A., Atkins and other low-carbohydrate diets: hoax or an effective tool for weight loss?, Lancet, 364(9437), 897–879, 2004. Dansinger, M.L., Gleason, J.A., Grifﬁth, J.L., Selker, H.P., and Schaefer, E.J., Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial, JAMA, 293(1), 43–53, 2005. Noakes, M., Foster, P.R., Keogh, J.B., James, A.P., Mamo, J.C., and Clifton, P.M., Comparison of isocaloric very low carbohydrate/high saturated fat and high carbohydrate/low saturated fat diets on body composition and cardiovascular risk, Nutr. Metab. (Lond.), 3, 7, 2006. Johnston, C.S., Tjonn, S.L., Swan, P.D., White, A., Hutchins, H., and Sears, B., Ketogenic lowcarbohydrate diets have no metabolic advantage over nonketogenic low-carbohydrate diets, Am. J. Clin. Nutr., 83(5), 1055–1061, 2006. Westerterp, K.R., Wilson, S.A., and Rolland, V., Diet induced thermogenesis measured over 24h in a respiration chamber: effect of diet composition, Int. J. Obes. Relat. Metab. Disord., 23(3), 287–292, 1999. Westerterp, K.R., Diet induced thermogenesis, Nutr. Metab. (Lond.), 1(1), 5, 2004. Golay, A., Allaz, A.F., Morel, Y., de Tonnac, N., Tankova, S., and Reaven, G., Similar weight loss with low- or high-carbohydrate diets, Metabolism, 43(12), 1481–1487, 1994. Holt, S.H., Brand-Miller, J.C., and Petocz, P., An insulin index of foods: the insulin demand generated by 1000-kJ portions of common foods, Am. J. Clin. Nutr., 66, l264–1276, 1997.

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from 25 Polyphenols Fruits and Vegetables in Weight Management and Obesity Control Dilip Ghosh and Margot A. Skinner CONTENTS Introduction ....................................................................................................................................321 Association Between Fruit and Vegetable Consumption and Obesity .........................................322 Polyphenolics in Plants..................................................................................................................323 Fruits and Vegetables ..............................................................................................................323 Seeds, Nuts, and Culinary Herbs ...........................................................................................325 Tea ...........................................................................................................................................326 Mechanisms of Action ...................................................................................................................326 Glucose Uptake.......................................................................................................................326 Gluconeogenesis and Glycolysis ............................................................................................327 Adipogenesis and Lipolysis....................................................................................................328 Lipid Absorption and Metabolism..........................................................................................328 Appetite Control .....................................................................................................................329 Dietary Phytoestrogens ..................................................................................................................330 Food Sources...........................................................................................................................330 Role in Weight Management ..................................................................................................330 Exotic Fruits, Vegetables, and Herbs.............................................................................................330 Health Beneﬁts for Conditions Associated with Obesity..............................................................331 Conclusion......................................................................................................................................332 Acknowledgments ..........................................................................................................................332 References ......................................................................................................................................333

INTRODUCTION The World Health Organization has recognized the epidemic of obesity as one of the top ten global health problems [1]. In biological terms, obesity is the result of an imbalance between energy input (food intake) and energy expenditure. In most individuals, obesity appears as a multigenic, multifactorial disease, and estimations indicate that genetic determinants account for at least 50% of the obese phenotype, whereas the rest is due to the environment [2]. The current view of obesity indicates that the environment in developed countries promotes overconsumption of energy in terms of food and a reduction of energy expenditure. Obesity is related to several chronic and debilitating conditions including coronary artery disease, metabolic syndrome, hypertension, stroke, hyperlipidemia, diabetes,

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osteoarthritis, sleep apnea, gout, gallbladder disease, several cancers, and joint problems [3]. Recent studies predict that one in three Americans born in the year 2000 will develop diabetes in their lifetime [4], and a similar ominous future confronts nearly all developed nations. Drugs have been developed to ameliorate or prevent obesity, but the costs, efﬁcacy, and side effects must be considered. For centuries people have used plants for healing. Written records about medicinal plants date back at least 5000 years to the Sumerians [5]. Investigating new targets and perspectives may lead to better methods in the prevention and treatment of obesity and related diseases. The use of plants has the potential to keep the increasing prevalence of metabolic syndrome in check. Many people are using natural products and plant-based dietary supplements for weight loss. According to a recent survey, over 42% of adults in the United States reported using one or more forms of alternative medicines or dietary supplements [6]. More than 8000 polyphenolic compounds are found in foods of plant origin [7]; these compounds have been known for more than 20 years for their antioxidant properties, but it is now becoming clear that they may have other health beneﬁts, including a role in energy control and weight management. Dietary guidelines recommend an increase in fruit and vegetable consumption, and interpretation of epidemiological evidence infers that this may have an effect on weight management and obesity [8,9].

ASSOCIATION BETWEEN FRUIT AND VEGETABLE CONSUMPTION AND OBESITY Numerous health beneﬁts have been proposed to result from consuming a diet rich in fruits and vegetables. The association between fruit and vegetable intake and weight management is not well understood, and few studies have been speciﬁcally designed to address this issue. Short-term clinical studies have shown that substituting fruits and vegetables for foods with higher energy densities can be an effective weight management strategy [10]. Fruits and vegetables are high in water and ﬁber. Incorporating them into the diet can reduce the energy density of diet, promote satiety, and decrease energy intake [11]. Two epidemiological studies have been carried out on children and adolescents to examine the relationship between fruit and vegetable intake and body weight. In a 3-year prospective cohort study, it was concluded that the recommendation for the consumption of fruits and vegetables may be well founded but should not be based on a beneﬁcial effect on regulation of body mass index (BMI) in weight regulation [12]. In contrast, Lin and Morrison [13] concluded from their study that a higher fruit consumption was linked with lower body weight. In a recent review of epidemiological studies, Tohill et al. [14] tabulated and discussed 16 adult studies as well as 2 on children and adolescents. Of the 16 adult studies, 8 reported a signiﬁcant association between higher intake of fruit or vegetables and decreased weight status, but there were confounding effects. Of the 18 studies reviewed, only 2 examined the association between fruit and vegetable intake and anthropometric outcome of body weight as a primary objective. The authors make recommendations for future epidemiological studies to clarify the relationship. Another more recent study also demonstrated that increasing the intake of fruits and vegetables may reduce long-term risk of obesity and weight gain among middle-aged women [8]. Apple and pear intake has also been shown to be associated with weight loss in middle-aged overweight women in Brazil [15]. Participants who consumed either of the fruits for 12 weeks had a signiﬁcant weight loss compared to controls. Overall, reasonable evidence is emerging to support the claim that a diet enriched in fruits and vegetables may play a role in weight management. A concern, however, is that a high intake of fruit juice could promote the development of obesity, but results have not been consistent across studies [15,16]. Unfortunately, dietary patterns, such as combinations of different fruits and vegetables, are extremely complex, and extensive randomized trials are necessary to assess whether such dietary patterns will have a truly beneﬁcial impact on weight management. More intervention and epidemiologic studies are required to reach a conclusion regarding the relationship between fruit and vegetable consumption and weight management.

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POLYPHENOLICS IN PLANTS Phenolic compounds are abundant micronutrients in our diet, with an average consumption of around 1 g per day [17,18]. The polyphenolic content of fruits, vegetables, and other plant foods varies considerably, not only between different types but also among strains of the same type, depending on growing conditions and the time of harvest. Many are well known for their antioxidant activity.

FRUITS

AND

VEGETABLES

Fruits and vegetables are a particularly rich source of polyphenols. The polyphenolic contents of some common fruits and vegetables are shown in Table 25.1. Polyphenols belong to one of the major classes of plant secondary metabolites including phenolic acids, ﬂavonoids, lignans, stilbenes, coumarins, and tannins [19]. Several thousand have been discovered in edible plants, and they are divided into different groups according to their structure and complexity [20,21] They appear to protect the plant from stress and infection [22], which makes it not surprising that they should have biological effects in animals and humans. Polyphenols are a group of chemical substances characterized by the presence of more than one phenolic group. The phenolic acids are phenols with only one ring. Those that predominate in fruits and vegetables are derivatives of hydroxybenzoic acid and hydroxycinnamic acid and differ by hydroxylations and methoxylations of their aromatic ring. The content of hydroxybenzoic acids is generally low in fruits and vegetables, except in blackberry, raspberry [23], black currant, red currant, and horseradish [24]. Hydroxycinnamic acids are common, particularly caffeic acid, which is found in plums, apples, apricots, blueberries, and tomatoes [25]. Other predominant members of this group include ferulic acid, p-coumaric acid (the dominant simple phenolic in citrus), and chlorogenic acid, which is present in many common pip and stone fruits and berries [26], as well as vegetables such as avocado, carrot, and eggplant. Defatted soy preparations also contain many of these, with p-coumaric and ferulic acid being dominant in some preparations, but salicylic acid being the principle phenolic acid in others [27]. Processing can alter the form and concentration of these compounds considerably. Fruit may also contain phenolic amines, including tyramine, dopamine, and serotonin. Banana and pineapple are examples of two fruits that are rich in serotonin. Flavonoids are another large group of phenolic compounds; they have a basic skeleton composed of three rings (Figure 25.1). They are classiﬁed into six families according to their substitution pattern: anthocyanins, ﬂavones, isoﬂavones, ﬂavonols, ﬂavanones, and ﬂavanols. The anthocyanins are responsible for the red, blue, and purple color of many plants — for example, the red skins of radishes, the blue hue of blueberries, and the dark purple skin of eggplants. More than 500 different anthocyanins have been identiﬁed in plants [7]. Generally, fruits contain from two to six different anthocyanins, but some grape varieties can contain 16 or more [28]. The six anthocyanidins commonly found in plants are classiﬁed according to the number and position of hydroxyl groups on the ﬂavan nucleus and are named cyanidin, delphinidin, malvidin, peonidin, pelargonidin, and petunidin. Their stability during processing depends on the composition of the food as well as the physical and chemical environment. Flavonols and ﬂavones are generally present in foods both as aglycones and glycosides. Commonly found ﬂavonols include kaempferol, quercetin, and myricetin and their derivatives. A combination of kaempferol and quercetin is most frequently found in fruits [25], although quercetin derivatives are found in many vegetables, including potatoes, onions, and fennel. Soybean is a rich source of isoﬂavones, such as diadzin and genistin (7-monoglycosides), which during soaking may be hydrolyzed to their aglycones: daidzein and genistein. Two other groups of ﬂavonoids, the ﬂavones and ﬂavanones, are found mainly in celery, capsicum, and citrus fruits and include derivatives of apigenin, luteolin, naringenin, and hesperidin. Catechin, a monomeric ﬂavanol, is present in most fruits, with apricots, peaches, apples, and gooseberries having the highest levels. Gallocatechin and epicatechin are also found in some fruits, particularly peaches, red currants, black currants, and apples.

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TABLE 25.1 Polyphenol Sources

Polyphenols Hydroxybenzoic acid Protocatechuic Gallic acid p-Hydroxybenzoic acid Hydroxycinnamic acid Caffeic acid Chlorogenic acid Coumaric acid Ferulic acid Sinapic acid

Anthocyanins Cyanidin Pelargonidin Peonidin Delphinidin Malvidin

Flavonols Quercetin Kaempferol Myricetin

Source

Polyphenol Content by Weight (mg/kg) or Volume (mg/L)

Blackberry Raspberry Black currant Strawberry Blueberry Kiwi Cherry Plum Aubergine Apple Pear Chicory Artichoke Potato Corn ﬂour Flour (wheat, rice, oat) Cider Coffee Aubergine Blackberry Black currant Blueberry Black grape Cherry Rhubarb Strawberry Red wine Plum Red cabbage Yellow onion Curly kale Leek Cherry tomato Broccoli Blueberry

80–270 60–100 40–130 20–90 2000–2200 600–1000 180–1150 140–1150 600–660 50–600 15–600 200–500 450 100–190 310 70–90 100–500 350–1750 7500 1000–4000 1300–4000 250–5000 300–7500 35–4500 2000 150–750 200–350 20–250 250 350–1200 300–600 30–225 15–200 40–100 30–160

The plant polyphenols capable of precipitating proteins from aqueous solutions are known as tannins. They may also form complexes with compounds such as polysaccharides. Depending on their chemical structure, they are subdivided into hydrolyzable and condensed tannins. Hydrolyzable tannins in fruits such as strawberry, raspberry, and blackberry are usually present in combination with condensed tannins [29,30]. Condensed tannins, the proanthocyanidins, are more widely found than the hydrolyzed tannins and can be present in the ﬂesh of fruit but are primarily in the skin and peel. Procyanidins isolated from fruit are dimers, oligomers, and polymers of certain ﬂavanols with average molecular weights ranging from 2000 to 4000 Daltons [25]. Tannins are responsible for the astringency in many edible fruits, particularly before ripening, and tannin content may decrease during maturation. Those present in beans and peas, which may make up to 2% of total polyphenolics, are located mainly in the seed coat.

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TABLE 25.1 (cont.) Polyphenol Sources

Polyphenols Myricetin (cont.)

Flavones Apigenin Luteolin Flavanones Hesperetin Naringin Eriodictyol Isoﬂavones Daidzein Genistein Glycitein

Monomeric ﬂavanols Catechin Epicatechin

Source

Polyphenol Content by Weight (mg/kg) or Volume (mg/L)

Black currant Apricot Apple Beans (green or white) Black grape Tomato Black tea infusion Green tea infusion Red wine Parsley Celery Capsicum pepper Orange juice Grapefruit juice Lemon juice

30–70 25–50 20–40 10–50 15–40 2–15 30–45 20–35 2–30 240–1850 20–140 5–10 215–685 100–650 50–300

Soy ﬂour Soybeans (boiled) Miso Tofu Tempeh Soy milk Chocolate Beans Apricot Cherry Grape Peach Blackberry Apple Green tea Black tea Red wine Cider

800–1800 200–900 250–900 80–700 430–530 30–175 460–610 350–550 100–250 50–220 30–175 50–140 130 20–120 100–800 60–500 80–300 40

Source: Adapted from Manach, C. et al., Am. J. Clin. Nutr., 79, 727, 2004.

SEEDS, NUTS,

AND

CULINARY HERBS

Nuts, like beans and peas, contain characteristic arrays of phenolic acids, ﬂavonoids, and tannins, which again are associated with their coat or hull; for example, the bronze coloration of peanut hulls is due to the presence of tannins, but the fruit (nut meat) is practically tannin free. In coffee and cocoa, phenols play an important role in the formation of ﬂavor. Green coffee beans contain many chlorogenic acid isomers which degrade on roasting while the caffeine content remains virtually unchanged [31]. The fermentation and drying process of cocoa also alters the content and composition of polyphenolic compounds so the anthocyanins of unfermented purple beans are hydrolyzed to anthocyanidins, giving fully fermented beans their brown color, and the low-molecular-weight phenolics, such as epicatechin, are replaced with an enhanced content of tannins [32].

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3' 2' 1 8 A

1'

O

7 C

6

2

4' B 5' 6'

3 5

4

FIGURE 25.1 Basic skeleton structure of ﬂavonoids. (Adapted from Zhang, J., Evaluation of Natural Oxidants, Ph.D. thesis, University of Auckland, 2004.)

Many herbs and spices used to ﬂavor food are a source of dietary phenolic compounds, although the quantities consumed in this way are generally quite small. Among the various culinary herbs, some species are of particular interest because they may be used for the production of raw materials or preparations with putative health beneﬁts as dietary supplements [33]. Many culinary herb species, especially those belonging to the Lamiaceae family, such as sage, oregano, and thyme, show strong antioxidant activity [34]. Rosmarinic acid is one such polyphenolic substance contributing to the antioxidant activity of rosemary, sage, mint, basil, and thyme [35]. Culinary herbs and spices also contain many of the polyphenolics found in fruits and vegetables; for example, laurel and juniper contain quercetin glycosides, fennel contains kaempferol, and cardamom contains caffeic acid and p-coumaric acid [36].

TEA Although green tea is discussed in another chapter, mention should be made of tea here, as some of the polyphenols present in tea are also found in fruits and vegetables [37,38]. Green tea is one of the most popular beverages consumed worldwide. Phenolic compounds constitute up to 35% of the dry weight of tea. The major constituents are ﬂavanols, such as epigallocatechin gallate (EGCG), epigallocatechin (EGC), and catechin; ﬂavonols, such as quercetin, kaempferol, and their glycosides; ﬂavones, such as vitexin and isovitexin; and phenolic acids, such as gallic acid and chlorogenic acid [39]. Fermentation is a critical process for the production of good quality tea, and oxidation of tea phenolics affects the color, ﬂavor, and ﬁnal polyphenolic composition.

MECHANISMS OF ACTION Although large gaps still exist in our understanding of polyphenols and their impact on obesity and related health conditions, the growing body of literature in this area suggests that they may confer a substantial health beneﬁt related to obesity beyond just lowering the energy density of the diet. It has been shown that polyphenols may favorably affect glucose uptake and regulation, adipogenesis and lipolysis, lipid metabolism, and appetite control.

GLUCOSE UPTAKE Glucose, one of the sugars produced by the breakdown of dietary carbohydrate, is central to carbohydrate metabolism and energy control. The regulation of glucose uptake, under the control of insulin, is important for maintaining appropriate blood glucose levels in times of feeding and fasting. A number of ﬂavonoids present in fruits and vegetables have been reported to be competitive inhibitors of glucose uptake by a variety of cell types [40,41]. Phloridzin, a dietary ﬂavonoid common in apples, consists of a glucose moiety and two aromatic rings joined by an alkyl spacer; it has long been known to produce renal glucosuria and block intestinal absorption of glucose [42]. Phloridzin

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does this through inhibition of sodium-dependant glucose transporters (SLGTs), primarily located in the proximal renal tubule and in the mucosa of the small intestine [43]. The SLGTs, two of which (SLGT1 and SLGT2) have been fully characterized, carry glucose against a concentration gradient into cells by coupling with the extrusion of sodium. Phloridzin competitively inhibits both SLGT1, which transports two molecules of glucose for every one of sodium, and SLGT2, which transports one molecule of each. Phloridzin is able to improve insulin sensitivity on its own simply by lowering blood sugar [44]. Thus, the ability to block intestinal glucose absorption and renal glucose absorption, with consequent caloric loss presumably resulting in weight loss, makes phloridzin a potential therapy for obesity. The green tea polyphenol EGC has also been shown to markedly inhibit SLGT1 and can also be considered as a potential therapeutic for weight management [45]. The facilitative glucose transporters (GLUTs), which transport glucose down a concentration gradient, are expressed on virtually all cells and are not affected by phloridzin; however, removal of the glucose moiety from phloridzin to yield phloretin, also found in apples, produces a compound that can block GLUT-mediated glucose transport [46]. Glucose uptake by GLUT is inhibited by many of the polyphenols present in fruits and vegetables. Genistein, quercetin, myricetin, morin, rhamnetin, and isorhamnetin inhibit GLUT-1-mediated glucose transport through direct interaction with the membrane protein in a variety of cell types, and evidence suggests that quercetin and myricetin inhibit GLUT-3 activity as well [47]. GLUT-4 mediates insulin-stimulated glucose uptake speciﬁcally in muscle and adipocytes, and glucose transport in adipocytes plays a critical role in glucose homeostasis. Some ﬂavanoids, including quercetin, myricetin [47], and naringenin [48], have been shown to inhibit this type of glucose transport. Although many ﬂavonoids can act as tyrosine kinase inhibitors, including quercetin, these ﬂavonoids do not appear to inhibit glucose transport by inhibiting tyrosine kinase activity as they do not affect insulin receptor substrate 1 (IRS1) [47]. Naringenin has been shown to act by inhibiting the activity of a key regulator of insulin-induced GLUT-4 translocation, phosphoinositide 3-kinase (PI3K), in 3T3-L1 preadipocytes. By inhibiting PI3K, naringenin may also inhibit proliferation. It is interesting to note that naringenin is able to inhibit insulin-stimulated glucose uptake by 20% in adipocytes at physiologically attainable doses of 6 µM [48]. Inhibition of glucose uptake in the gut and into adipocytes will have beneﬁcial effects on weight management and obesity, but similar inhibition into muscle could potentially lead to the blood glucose effects associated with diabetes.

GLUCONEOGENESIS

AND

GLYCOLYSIS

The process of energy storage and transfer relies on the storage of glucose as glycogen in the liver. Glucose can also be oxidized via the Kreb’s cycle or can undergo glycolysis for the synthesis of fatty acids. Amino acids arising from protein are converted to glucose via the Kreb’s cycle in a process known as gluconeogenesis. Effects of quercetin on both glycolysis and gluconeogenesis have been reported [49] using perfused rat liver. It was concluded that quercetin can inhibit both glucose degradation and production with suggestions that reduction of oxidative phosphorylation, inhibition of Na+–K+–ATPase, and inhibition of glucokinase and glucose-6-phosphatase could all contribute to the overall effect. Oral administration of quercetin to diabetic rats resulted in a decrease in the levels of blood glucose and ameliorated diabetes-induced changes in oxidative stress [50]. Quercetin has also been shown to effectively reduce postprandial hyperglycemia in diabetic rats, reﬂecting its ability to increase carbohydrate metabolism in the small intestine [51]. The major green tea polyphenolic constituent, EGCG, has been shown to mimic some of the effects of insulin in a cell culture system by reducing gene expression of rate-limiting gluconeogenic enzymes [52], and more recently this has been demonstrated in vivo [53]. Similarly, red wine polyphenolic extracts [54] and grapeseed-derived procyanidins [55] have been shown to exert antidiabetic effects in streptozotocin-induced diabetic rats. Grapeseed procyanidin extracts have recently been shown to have insulinomimetic properties in the 3T3-L1 adipocyte cell line, activating both glycogen and lipid synthesis [56].

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Adipocyte dysfunction is strongly associated with the development of obesity and insulin resistance. Adipocytes synthesize and secrete biologically active molecules called adipokines (e.g., leptin), which reduce food intake and increase energy expenditure. Drugs that target regulation of adipocyte function, in particular the peroxisome proliferator-activated receptor γ (PPARγ), have effects on adipocyte differentiation, cause an increase in fatty acid oxidation, and ameliorate hyperglycemia without stimulating insulin secretion. They are used as a therapy for obesity-related metabolic disease. There are fewer studies on the effects of ﬂavonoids in adipocytes than on other cell types, but some interesting results are emerging. Quercetin and ﬁsetin have been shown to potentiate epinephrine-induced lipolysis in isolated rat adipocytes and appear to increase membrane phospholipid methylation, which correlates with cellular accumulation of cyclic AMP [57]. Shisheva and Shechter [58] found that quercetin blocked insulin-mediated lipogenesis by preventing the insulin receptor tyrosine kinase from phosphorylating substrate. These potentially lipolytic and antilipogenic effects in rat adipocytes, coupled with antiproliferative activity in a number of cell lines, suggest that ﬂavonoids may decrease adipose tissue mass or inhibit the signals that promote adipogenesis. Recently, Harmon and Harp [59] showed using 3T3-L1 cells that both genistein and naringenin inhibited proliferation of preconﬂuent preadipocyte cells, but only genistein was able to inhibit proliferation of postconﬂuent preadipocytes at the induction of differentiation and their subsequent differentiation into mature adipocytes. In mature adipocytes, again genistein, but not naringenin, was shown to strongly induce lipolysis, both alone and in combination with epinephrine [59]. These ﬁndings in cultured adipose cells suggest that dietary ﬂavonoids, particularly genistein, may have inhibitory effects on adipose tissue enlargement. The few animal studies that have evaluated the effects of genistein treatment on lipid metabolism or body weight support the ﬁndings with isolated cells [60]. Genistein holds promise for nutrient-mediated regulation of body fat through its effects on preadipocyte replication, differentiation, and lipolysis. The study of gene expression, particularly using microarrays of RNA from adipocytes, has revealed some additional interesting effects of polyphenols. Comparison of obese and lean human omental adipose tissue has demonstrated a general tendency in obese tissue to blunt lipolysis inducer genes and a global downregulation of genes encoding growth factors. Downregulation of growth factors and upregulation of mitogen-activated protein kinases (MAPKs) may indicate an attempt to restrain adipocyte proliferation and differentiation [61]. Dietary anthocyanins have been shown to normalize hypertrophy of adipocytes in epididymal white adipose tissue, ameliorate hyperglycemia induced by a high-fat diet, and suppress development of obesity in mice [62]. In isolated rat adipocytes, anthocyanins have been shown to upregulate adipokine-speciﬁc gene expression and secretion without activation of PPARγ [63]. It has just recently been shown that they also upregulate genes involved in lipid metabolism and signal transduction, leading to upregulation of hormonesensitive lipase and enhancement of lipolytic activity [64]. The anthocyanins used in the latter study were cyanidin-3-glucoside and cyanidin, and the general conclusions regarding responsive genes whose function is important in obesity and diabetes were similar for both studies.

LIPID ABSORPTION

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METABOLISM

Lipase inhibitors are good candidates for the treatment of obesity, and one of the latest drugs for obesity, XENICAL® (orlistat), belongs to this class of compounds. They inhibit the key enzyme that breaks down fat in the gut, resulting in lower fat absorption. Some natural products are lipase inhibitors (for example, ﬂavanol extracts from Cassia nomame [65]), and recently some of the major polyphenols of tea (e.g., EGCG and oolong tea polymerized polyphenols) have been shown to inhibit pancreatic lipase. Catechin, however, was shown to be ineffective in this study [66]. Lipase-inhibiting substances in fruits, related to their condensed tannins, have also been reported [67]. In an in vitro experiment, Moreno et al. [68] showed that a grapeseed extract rich in polyphenol

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compounds inhibited the fat-metabolizing enzymes pancreatic lipase, lipoprotein lipase, and hormone-sensitive lipase, and consequently the authors described it as a safe, natural, and cost-effective weight control treatment. The regulation of cholesterol absorption and metabolism is important in obesity, as enhanced intake may lead to cardiovascular disease. Green tea catechins have hypocholesterolemic effects [67,70] and suppress the intestinal absorption of cholesterol [70,71]. Moreover, the tea polyphenol EGCG has been shown to have an inhibitory effect on acetyl-CoA carboxylase, which is essential for fatty acid biosynthesis in vitro [72], and anti-obesity effects at high doses in rats [73,74]. On analyzing the effect of catechin on intestinal lipid metabolism, Valsa et al. [75] detected an increase in the concentration of cholesterol in the duodenum and jejunum along with an increase in the hydroxy-3-methyl glutaryl CoA (HMGCoA) reductase activity. The authors suggested that this increase in enzyme activity could be due to the binding of catechin to cholesterol in the lumen. De-alcoholized red wine contains resveratrol (a stilbene, with estrogen-like activity); the ﬂavonoids catechin, epicatechin, and quercetin; and phenolic acids, such as gallic acid, which have been shown to increase HMGCoA reductase mRNA and low-density lipoprotein (LDL) receptor binding activity relative to controls in the HepG2 liver cell line. De-alcoholized red wine also increased LDL receptor gene expression, suggesting that red wine polyphenolics regulate major pathways involved in lipoprotein metabolism [76]. By using de-alcoholized wine, the confounding effects of alcohol were removed. In a human trial, it was demonstrated that there was a signiﬁcant delay in fat absorption after the consumption of red wine phenolics [76]. Green tea extracts, rich in catechins, have been shown to have thermogenic properties, increasing 24-hour energy expenditure and fat oxidation in people beyond that expected by their caffeine content [38]. In a trial on Japanese females, oolong tea was shown to increase energy consumption, whereas green tea did not have a signiﬁcant effect. The effect of the oolong tea may have been due to polymerized polyphenols; in comparison with green tea, oolong tea contained approximately half the caffeine and EGCG, while polymerized polyphenols were double [77]. Tea also contains caffeine and theanine, which can have effects on weight management. Zheng et al. [78] showed that, although caffeine and theanine were the constituents of green tea powder responsible for a suppressive effect on body weight increase and fat accumulation, they also demonstrated that catechin and caffeine were synergistic in anti-obesity activities.

APPETITE CONTROL Appetite can be viewed as a bridge between energy intake and expenditure that should aid in coupling the two. Several studies indicate that incorporating cayenne pepper into the diet may help people to lose weight by reducing hunger after meals and calories consumed during subsequent meals. Capsaicin and a closely related compound, dihydrocapsaicin, are responsible for many of the red pepper effects. They have the ability to bind to the capsaicin (or vanilloid) receptors in a subpopulation of primary afferent sensory neurons. Oregano, cinnamon, and cilantro also contain this type of compound but at much lower concentrations. Red pepper and coffee consumption can signiﬁcantly reduce cumulative ad libitum energy intake and increase energy expenditure [79], indicating that their consumption can induce a considerable change in energy balance when individuals are given free access to foods. It was suggested that these effects are mediated by an increase in the ratio of sympathetic nervous system vs. parasympathetic nervous system activity as measured by power spectral analysis of heart rate. Previously, the same group had conducted two studies to investigate the effects of red pepper on feeding behavior and energy intake [80]. The results indicated that the ingestion of red pepper decreases appetite and subsequent protein and fat intakes in Japanese women and energy intake in Caucasian men. Moreover, this effect might be related to an increase in sympathetic nervous system activity in Caucasian men. The maximum tolerable dose of red pepper was found to be necessary to have a suppressive effect on fat intake [81]. In another study, the effects of dietary hot red pepper on energy metabolism at rest and during exercise were examined

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in long-distance male runners [82]. Signiﬁcantly higher plasma epinephrine and norepinephrine levels in those that were fed red hot pepper were found. These results suggested that hot red pepper ingestion stimulates carbohydrate oxidation at rest and during exercise.

DIETARY PHYTOESTROGENS Phytoestrogens are a group of biologically active plant substances with chemical structures related to that of estradiol, the principal endogenous estrogen in humans. These structural elements account for the ability of phytoestrogens to bind to estrogen receptors in various cells [83,84] and exert estrogenic or antiestrogenic effects.

FOOD SOURCES Phytoestrogens are found in various plants consumed by humans, including legumes, seeds, and whole grains. The three major classes of phytoestrogens are isoﬂavones, lignans, and coumestans. The most abundant food sources of isoﬂavones (genistein and daidzein) are soybean and soybean products. Other beans, lentils, and peas contain a small quantity of isoﬂavones. Common food sources of lignans include seeds, whole grains, legumes, and vegetables. Major sources of plant lignans include cereals, cereal brans, oil seeds, and fruit. Coumestrol is the most important coumestan consumed by humans, with the major food sources being alfalfa sprouts, dry round split peas, and other legumes.

ROLE

IN

WEIGHT MANAGEMENT

Substantial data from epidemiological surveys and nutritional intervention studies in humans and animals suggest that the consumption of plant-based foods rich in phytoestrogens may beneﬁt human health. They have been shown to have beneﬁts in protection against menopausal symptoms and in a variety of disorders, including cardiovascular disease, cancer, hyperlipidemia, osteoporosis, and various forms of chronic renal disease [85–88]. Evidence is emerging that consumption of foods rich in phytoestrogens may have a beneﬁcial effect on obesity and diabetes [89]. Nutritional intervention studies performed in animals and humans suggest that the ingestion of isoﬂavones associated with soy protein and ﬂaxseed rich in lignans improves glucose control and insulin resistance. Phytoestrogens have been shown to have a beneﬁcial effect by improving serum lipids and modifying LDL oxidation, the basal metabolic rate, and insulin-stimulated glucose oxidation. Several lines of evidence suggest that phytoestrogens may favorably affect glucose homeostasis, insulin secretion, and lipid metabolism [60,90–92]. Thus, phytoestrogens appear to have favorable biological effects of beneﬁt in weight control, obesity, and diabetes.

EXOTIC FRUITS, VEGETABLES, AND HERBS The activity of ﬂavonoids and tannins in exotic fruits, vegetables, and herbs and their seeds, leaves, stems, and roots have been exploited in many traditional medicines. They will not be dealt with in detail in this chapter, but a few interesting examples are mentioned. In Brazil, a phytomedicine obtained from the fruits of Solanum lycocarpum St. Hill (Solanaceae) has been widely employed for the management of diabetes and obesity and to decrease cholesterol levels. The presence of ﬂavonoids [93] and tannins [94] was found to be responsible for such activity. Polyphenol fractions prepared from the leaves of Salix matsudana were shown to reduce the elevation of rat plasma triacylglycerol and hepatic total cholesterol content after oral administration of a high-fat diet alone [95]. Furthermore, three ﬂavonoid glucosides enhanced norepinephrine-induced lipolysis in fat cells [96]. In his herbal handbook The Green Pharmacy, Duke [97] quotes Russian researchers as having found that the weight-loss effect of plantain is related to polyphenols in this plant. Some tentative evidence supports a potential role for plantago in reducing short-term appetite, fat, and energy intake [98–101].

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St. John’s wort (Hypericum perforatum) is a ﬂowering plant indigenous to much of Europe, the Americas, New Zealand, and Australia. It is reported by some that these extracts have serotonergic activity [102]. Due to its presumed serotonergic action, St. John’s wort is thought to have the potential to suppress appetite and cause weight loss, but animal studies to support this claim are lacking. An open-label study that used a combination of Ma huang and St. John’s wort has been published only in abstract form [103]. In a patent application, Haveson [104] cited three additional studies of St. John’s wort and Ma huang used in combination for controlling weight loss. Herbal preparations known as “YGD” contain yerba maté (leaves of Ilex paraguayensis), guarana (seeds of Paullinia cupana), and damiana (leaves of Turnera diffusa var. aphrodisiaca); they have long been used in South American folk medicines for weight management. Tannins are the major polyphenolics present in this preparation, plus it also contains caffeine. In one doubleblind, placebo-controlled parallel trial, the YGD preparation signiﬁcantly delayed gastric emptying, reduced the time to perceived gastric fullness, and induced signiﬁcant weight loss over 45 days in overweight patients treated in a primary healthcare context [105]. The maintenance treatment given in an uncontrolled context resulted in no further weight loss; however, the mechanisms involved have yet to be published.

HEALTH BENEFITS FOR CONDITIONS ASSOCIATED WITH OBESITY Over the last decade, researchers and food manufacturers have become increasingly interested in polyphenols, due to their antioxidant properties and their potential health beneﬁts with regard to diabetes, cancer, and cardiovascular and neurodegenerative diseases [21,106], some of which are associated with obesity. Epidemiological data are beginning to support the association between a high intake of fruits and vegetables and a low risk of chronic diseases [107]. The total dietary intake of polyphenols can be as high as 1 g/day, which is much higher than any other class of phytochemicals and known dietary antioxidants. Despite their wide distribution in plants, the health effects of dietary polyphenols have come to the attention of nutritionists only rather recently. The main factor that has delayed research on polyphenols is the considerable diversity and complexity of their chemical structures. Current evidence is beginning to support a contribution of polyphenols to the prevention of cardiovascular diseases, cancers, and osteoporosis and suggests a role in the prevention of neurodegenerative diseases and diabetes mellitus [17]. Obesity is clearly associated with some of these diseases and is the dominant modiﬁable risk factor for type 2 diabetes. Some evidence suggests that adequate fruit and vegetable consumption may lower the risk of developing diabetes [108–111]. Despite the presence of dietary ﬁber and minerals in fruits and vegetables, some research suggests that antioxidant compounds such as carotenoids, ﬂavonoids, vitamins, phenolic acids, and indoles could have favorable effects on the pathogenesis of diabetes [112–115]. Treatment of rats, rendered diabetic with streptozotocin, with ethanol-free polyphenols from white wine has been shown to reduce the plasma antioxidant capacity associated with the diabetic state [116]. As insulin resistance and diabetes are associated with increased oxidative stress [117], these beneﬁcial effects of fruit and vegetable polyphenolics could result from their antioxidant properties as well as the other effects that these compounds have on glucose transport, fat absorption, and carbohydrate and fat metabolism. Our knowledge, however, still appears too limited for formulation of recommendations for general population or for particular populations at risk of speciﬁc diseases. Evidence for a reduction of disease risk by ﬂavonoids was considered “possible” for cardiovascular disease and “insufﬁcient” for cancers in a recent report from the World Health Organization [118]. Signiﬁcant progress has been made in the ﬁeld of cardiovascular disease, and today it is well established that some polyphenols, administered as supplements or with food, do improve health status, as indicated by several biomarkers closely associated with cardiovascular risk [119–121]. Limited epidemiologic

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studies tend to conﬁrm the protective effects of polyphenol consumption against cardiovascular diseases [122]. In contrast, evidence for the protective effects of polyphenols against cancers, neurodegenerative diseases, and brain function deterioration is still largely derived from animal experiments and in vitro studies [123,124]. We have to wait for the discovery of predictive biomarkers for such diseases or large intervention studies, similar to those performed with nonphenolic antioxidants [125].

CONCLUSION The majority of the world’s population relies on plants as their source of medicines. Crude botanical drugs or plant extracts are utilized primarily by lay persons as a form of alternative therapy for the treatment of disease states, often of a chronic nature, or to attain or maintain a state of improved health. The ﬁrst documented dietary prescription in the treatment of presumed diabetes appeared in the Papyrus Ebers, written around 1500 B.C., and the use of wheat grains, grapes, honey, and berries has been advocated for this disease more recently [126]. To understand whether the effect of consumption of fruits and vegetables on obesity and weight control is simply due to a substitution of high-calorie foods with those of low-calorie and high-ﬁber content or whether phytochemical constituents such as polyphenols are involved in the observed effects requires carefully planned and controlled feeding trials, which have yet to be carried out. Although the effects of the polyphenolic compounds present in fruits and vegetables on cellular and biochemical mechanisms related to energy control and weight management are beginning to be understood, a better understanding of their interactions with the cell membrane and of their uptake and metabolism is necessary to understand the effects of these compounds in the various cell types and tissues [127]. As evidence emerges that fruit and vegetable constituents aid in weight management and obesity control, the opportunity arises to develop functional foods in this area. These may include food products that help in the management of hunger or increase the satiety or foods that contribute to more inefﬁcient use of ingested energy (i.e., foods that stimulate energy expenditure more than would be expected from their energy content). As the concept of insulin sensitivity becomes generally more accepted by healthcare professionals and the public, foods may be targeted toward maximizing insulin sensitivity and the prevention of diabetes. Foods that have an impact on body weight may include foods that affect the glucose or insulin levels that are seen either following the ingestion of food or later in the day. As synergistic interactions between different food constituents are discovered [128], it may be possible to develop foods that target one or more of the physiological processes involved in weight control in a way that is better than having them on their own. The current evidence for protective effects of polyphenols against diseases has generated new expectations for improvements in health, with great interest from the food and nutritional supplement industry regarding the promotion and development of polyphenol-rich products; however, it is still impossible to evaluate individual needs and recommendations of foods tailored for an individual genotype. Nutrigenomics will lead to the development of new foods for individualized health and nutritional beneﬁt. As we begin to understand the genetic components of weight management and obesity, it should be possible to apply personalized nutrition in this area. In the future, we can look forward to novel functional foods containing fruits and vegetables as wellness foods that may assist in weight management and have associated health beneﬁts that keep obesity at bay.

ACKNOWLEDGMENTS Thanks to Bob Elliott, Daryl Rowen, Steve Skinner, Jingli Zhang, and David Stevenson for critically reading the manuscript.

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Paolisso, G. et al., Evidence for a relationship between free radicals and insulin action in the elderly, Metabolism, 42, 659, 1993. Wolff, S.P., Diabetes mellitus and free radicals, Br. Med. Bull., 49, 642, 1993. Ford, E.S. et al., Diabetes mellitus and serum carotenoids: ﬁndings from a national population-based survey, Am. J. Epidemiol., 149, 168, 1999. Landrault, N. et al., Effect of a polyphenols-enriched chardonnay white wine in diabetic-rats, J. Agric. Food Chem., 51, 311, 2003. Peters, E.M. et al., Vitamin C supplementation attenuates the increases in circulating cortisol, adrenaline and anti-inﬂammatory polypeptides following ultramarathon running, Int. J. Sports Med., 22, 537, 2001. WHO/FAO., Diet, Nutrition, and the Prevention of Chronic Diseases, World Health Organization, Geneva, Switzerland, 2003. Keen, C.L. et al., Cocoa antioxidants and cardiovascular health, Am. J. Clin. Nutr., 81, 298S, 2005. Sies, H. et al., Cocoa polyphenols and inﬂammatory mediators, Am. J. Clin. Nutr., 81, 304S, 2005. Vita, J.A., Polyphenols and cardiovascular disease: effects on endothelial and platelet function, Am. J. Clin. Nutr., 81, 292S, 2005. Arts, I.C.W. and Hollman, P.C.H., Polyphenols and disease risk in epidemiologic studies, Am. J. Clin. Nutr., 81, 317S, 2005. Joseph, J.A., Shukitt-Hale, B., and Casadesus, G., Reversing the deleterious effects of aging on neuronal communication and behavior: beneﬁcial properties of fruit polyphenolic compounds, Am. J. Clin. Nutr., 81, 313S, 2005. Lambert, J.D. et al., Inhibition of carcinogenesis by polyphenols: evidence from laboratory investigations, Am. J. Clin. Nutr., 81, 284S, 2005. Hercberg, S., The history of β-carotene and cancers: from observational to intervention studies. What lessons can be drawn for future research on polyphenols?, Am. J. Clin. Nutr, 81, 223S, 2005. Leeds, A.R., The dietary management of diabetes in adults, Proc. Nutr. Soc., 38, 365, 1979. Spencer, J.P., Abd-el-Mohsen, M.M., and Rice-Evans, C., Cellular uptake and metabolism of ﬂavonoids and their metabolites: implications for their bioactivity, Arch. Biochem. Biophys., 423, 148, 2004. Lila, M.A. and Raskin, I., Health-related interactions of phytochemicals, J. Food Sci., 70, R20, 2005.

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(III) in 26 Chromium Promoting Weight Loss and Lean Body Mass Manashi Bagchi, Harry G. Preuss, Shirley Zafra-Stone, and Debasis Bagchi CONTENTS Introduction ....................................................................................................................................339 Consequences of Chromium (III) Deﬁciency ...............................................................................339 Dietary Sources of Chromium (III) and Recommended Dietary Intake ......................................340 Glucose Tolerance Factor...............................................................................................................340 Bioavailability of Chromium (III) Complexes ..............................................................................341 Chromium (III) Supplementation, Metabolic Syndrome, and Weight Loss.................................341 Safety of Chromium (III) Complexes ...........................................................................................344 Conclusion......................................................................................................................................345 References ......................................................................................................................................345

INTRODUCTION A large number of biochemical, pharmacological, and toxicological studies have established selected chromium (III) complexes as novel micronutrients for ameliorating the components of the metabolic syndrome via enhancing glucose–insulin sensitivity [1–6]. Early studies showed that the biologically active form of chromium (III) in Brewer’s yeast forms a glucose tolerance factor (GTF) that prevents diabetes in experimental animals by impeding the action of insulin and modulating protein, fat, and carbohydrate metabolism, resulting in signiﬁcantly reduced plasma glucose levels in diabetic animals [1–7].

CONSEQUENCES OF CHROMIUM (III) DEFICIENCY A strong association exists between chromium deﬁciency, high blood insulin, atherosclerosis, and elevated blood cholesterol levels. In rats, chromium deﬁciency has been reported to increase serum cholesterol levels and formation of aortic plaques [4]. In humans, it has been well demonstrated that chromium deﬁciency can lead to impaired insulin function, obesity, and cardiovascular dysfunction [4]. This is unfortunate, because many elderly people, diabetics, and pregnant women suffer from chromium deﬁciency. Athletes, too, suffer from chromium deﬁciency, as a major cause of chromium loss is strenuous exercise [1,2]. On the positive side, chromium (III) supplementation has been shown to prevent the formation of aortic plaques and the rise of serum cholesterol [2].

339

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DIETARY SOURCES OF CHROMIUM (III) AND RECOMMENDED DIETARY INTAKE Chromium (III) is available in various food sources, including whole-grain products, high-bran breakfast cereals, egg yolks, coffee, nuts, green beans, broccoli, meat, Brewer’s yeast, and selected brands of beer and wine. Chromium (III) complexes are also found in many mineral or multivitamin supplements. According to the National Research Council (NRC), the Estimated Safe and Adequate Daily Dietary Intake (ESADDI) for chromium (III) is 50 to 200 µg/day, corresponding to 0.83 to 3.33 µg/kg/day for an adult weighing 60 kg [8]. The U.S. Food and Drug Administration (FDA) has selected a Reference Daily Intake (RDI) of 120 µg/day for chromium (III).

GLUCOSE TOLERANCE FACTOR Chromium (III), in the form of the naturally occurring dinicotinic acid–glutathione complex, or glucose tolerance factor (GTF), signiﬁcantly enhances the effect of exogenous insulin on glucose metabolism [2,3]. GTF inﬂuences the action of insulin and potentiates the actions of protein, fat, and carbohydrate metabolism [2,3]. GTF is safe, absorbable, and known to stabilize blood glucose levels; furthermore, GTF has access to biologically important chromium storage depots in the fetus and placenta [2–4]. The most abundant and naturally occurring form of GTF is found in Brewer’s yeast [2–4]. The O-coordinated chromium (III)–dinicotinic acid complex is biologically active, which suggests that a trans conﬁguration of pyridine nitrogen atoms resembles that part of the GTF structure that is recognized by the receptors or enzymes and is involved in the expression of the biological effect [2,3]. The body’s ability to convert simple chromium (III) compounds into the GTF form declines with advancing age and is impaired in diabetes and probably in hyperlipidemic and atherosclerotic patients as well [2,3,9–11]. Unfortunately, naturally occurring GTF represents less than 2% of the available chromium in Brewer’s yeast [2,3]. Several studies demonstrate that the biologically active form of chromium (III) in Brewer’s yeast promotes GTF and prevents diabetes in experimental animals by impeding the action of insulin to enhance protein, fat, and carbohydrate metabolism and signiﬁcantly reduces plasma glucose levels in diabetic mice [2,3,9–11]. A clinical investigation on diabetic patients showed a highly favorable response (i.e., increased insulin sensitivity) to chromium supplementation via Brewer’s yeast. Twenty-two participants (8 males and 14 females; mean age, 51 years) with fasting values of total cholesterol and glucose from 3.21 to 6.90 and 4.3 to 6.2 mmol/L, respectively, were evaluated. After a 9-hr fast, an oral glucose load (75 g) was administered before chromium (III) supplementation, and blood was drawn before and at 30, 60, 90, and 120 min after the glucose load [11,12]. Subjects were given either Brewer’s yeast or torula yeast (10 g yeast powder) daily for 12 weeks. Brewer’s yeast demonstrated a beneﬁcial effect by decreasing serum triacylglycerol values in subjects. In an oral glucose tolerance test, an increment at 0 min and signiﬁcant decreases at 60 and 90 min were shown. In subjects given torula yeast, glucose values increased at both 0 and 30 min after glucose load and 12-week supplementation. Brewer’s yeast and torula yeast signiﬁcantly altered glucose concentrations at 60 min after glucose dosage. Brewer’s yeast had signiﬁcant decreasing effects on insulin output both at 90 and 120 min after glucose load; likewise, in subjects given torula yeast, serum insulin contents decreased at 90 min. Brewer’s yeast supplementation had beneﬁcial effects both on serum triacylglycerol and on the 60- and 90-min glucose values of oral glucose tolerance test [11,12]. A complex of chromium (III) and nicotinic acid was demonstrated to facilitate insulin binding similar to the GTF found in Brewer’s yeast. Urberg et al. [11] showed that humans’ inability to respond to chromium (III) supplementation resulted from suboptimal levels of dietary nicotinic acid to serve as a substrate for GTF synthesis. In a controlled clinical trial, 16 healthy elderly volunteers were given 200 µg chromium (III), 100 mg nicotinic acid, or 200 µg chromium (III) + 100 mg nicotinic acid daily for 28 days and evaluated on days 0 and 28. Fasting glucose and glucose tolerance

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were unaffected by either chromium (III) or nicotinic acid alone. In contrast, the combined chromium–nicotinic acid supplement caused a 15% decrease in a glucose area integrated total (p < 0.025) and a 7% decrease in fasting glucose.

BIOAVAILABILITY OF CHROMIUM (III) COMPLEXES The mechanism of trivalent chromium absorption and action has been studied extensively. After absorption in the gastrointestinal tract, chromium is transported to cells bound to the plasma protein transferrin. Insulin initiates chromium (III) transport into the cells, where it is bound to the oligopeptide apochromodulin. Apochromodulin, combined in a tetra-nuclear assembly of four chromium (III) atoms, forms the low-molecular-weight oligopeptide chromodulin (MW, ~1500 Da), which is important in amplifying the insulin signaling effect. After binding to insulin-activated receptor, chromodulin increases tyrosine kinase activity and forms a part of the intracellular portion of insulin receptor [13]. In a study conducted by Clodfelder et al. [14], the biomimetic cation [Cr3O(O2CCH2CH3)6(H2O)3]+ was found to imitate the ability of oligopeptide chromodulin to stimulate the tyrosine kinase activity of insulin receptor, to increase insulin sensitivity, and to decrease plasma total concentrations, lowdensity lipoprotein (LDL) concentrations, and triglycerides concentrations, as shown in healthy and type 2 diabetic rat models. In addition, due to the stability and solubility of the biomimetic cation, a greater magnitude of absorbability was demonstrated [14]. Olin et al. [15] investigated the absorption and retention of CrCl3, niacin-bound chromium (NBC), and chromium picolinate over a 12-hr period. Male rats (150 to 170 g) were gavaged with 44 µCi (1 mL each or 2.7 nmol) chromium as CrCl3, NBC, or chromium picolinate. At 1, 3, 6, and 12 hr post gavage, rats were anesthetized and killed. Cardiac blood and urine (at 6 and 12 hr) were collected, and liver, kidneys, pancreas, testes, and gastrocnemius were removed, weighed, and assayed to calculate the chromium absorbed/retained. Results reveal that the highest percent of absorbed/retained counts was observed in urine, followed by the muscle, blood, and liver. The average percent chromium (III) retained in the tissues was higher in NBC-gavaged rats than in CrCl3– or chromium-picolinate-gavaged rats for the majority of the time points. One hour post gavage, NBC rats had retention percentages 3.2- to 8.4-fold higher in the tissues collected compared to the chromium picolinate and CrCl3 groups. Three hours post gavage, NBC-treated rats had blood, muscle, and pancreatic chromium retentions that were 2.4 to 8 times higher compared to chromium-picolinate-gavaged rats. By 6 and 12 hr post gavage, the levels of absorbed/retained chromium in tissues were 1.8 to 3.8 times higher in the NBC-treated group compared to rats receiving chromium picolinate. These results demonstrate signiﬁcant differences in the bioavailability of the different chromium compounds, with NBC exhibiting superior bioavailability (see Table 26.1 and Table 26.2).

CHROMIUM (III) SUPPLEMENTATION, METABOLIC SYNDROME, AND WEIGHT LOSS Obesity is a highly prevalent health problem in the United States and around the world [16,17]. Obesity is associated with a broad spectrum of degenerative diseases, including certain forms of cancer. Existing elements of insulin resistance, lipid disturbances, glucose intolerance, obesity, and hypertension have been characterized by the term metabolic syndrome [16–18]. Suboptimal chromium (III) intake, common in the global scenario, can contribute to these metabolic disorders [17,18]. Studies have shown that novel chromium (III) complexes are efﬁcacious in maintaining proper carbohydrate and lipid metabolism in both humans and animals. The insulin signaling potential of trivalent chromium has demonstrated its effects on body composition, including reduction of fat mass and enhancement of lean body mass. Previous studies have focused on the use of the dietary chromium (III), especially niacin-bound chromium, due to its increased absorption and retention [15].

NBC

CrPic

51

51

0.295± 0.082a 1.869± 0.433b 0.250± 0.046a

1 hr

0.769± 0.210 0.668± 0.116 0.345± 0.068

3 hr 0.724± 0.473 0.353± 0.101 0.201± 0.032

6 hr 0.231± 0.039ab 0.378± 0.086a 0.155± 0.029b

12 hr 0.077± 0.057ab 0.309± 0.158a 0.021± 0.008b

1 hr 0.085± 0.044 0.265± 0.231 0.031± 0.016

3 hr 6 hr 0.014± 0.005a 0.030± 0.007b 0.008± 0.002a

Pancreas

0.029± 0.022 0.028± 0.010 0.013± 0.002

12 hr 0.153± 0.034a 0.696± 0.144b 0.146± 0.025a

1 hr 0.459± 0.079 0.441± 0.107 0.571± 0.338

3 hr

NBC

CrPic

51

51

1 hr

1.53± 0.42 12.62± 6.67 4.01± 1.81

3 hr

1.910± 0.857 2.158± 0.948 0.855± 0.325

6 hr 1.879± 1.227 1.910± 0.618 0.591± 0.157

12 hr 0.801± 0.134 1.503± 0.474 0.594± 0.083

1 hr 0.346± 0.085a 2.575± 0.756b 0.450± 0.115a

3 hr 0.681± 0.134ab 1.180± 0.346b 0.497± 0.103a

Blood 6 hr 0.338± 0.052a 0.629± 0.187b 0.347± 0.080a

12 hr 0.229± 0.037a 0.381± 0.070b 0.183± 0.036a

—

—

—

1 hr

—

—

—

3 hr

a,bEach data point represents mean ± SEM at 1, 3, 6, and 12 hr post gavage. Values with non-identical superscripts are signiﬁcantly different (p ≤ 0.05).

CrCl3

51

Muscle (Gastrocnemius)

TABLE 26.2 Percent of 51Cr Dose Absorbed/Retained in the Muscle, Blood, and Urine Urine

Kidney

3.05± 0.67a 8.91± 2.54b 2.95± 0.83a

6 hr

0.209± 0.039a 0.476± 0.133b 0.156± 0.034a

6 hr

4.35± 0.86ab 6.25± 1.36a 3.00± 0.54b

12 hr

0.179± 0.033a 0.355± 0.090b 0.137± 0.029a

12 hr

342

a,b Each data point represents mean ± SEM at 1, 3, 6, and 12 hr post gavage. Values with non-identical superscripts are signiﬁcantly different (p ≤ 0.05).

CrCl3

51

Liver

TABLE 26.1 Percent of 51Cr Dose Absorbed/Retained in the Liver, Pancreas, and Kidney Tissues

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Clinical studies have consistently reported that chromium supplementation in overweight people induces loss of fat mass and/or increases lean body mass. Crawford et al. [19] reported that supplementation of 600 µg per day of elemental chromium (III) as NBC over a period of 2 months by African-American women, combined with a moderate diet and exercise regimen, favorably inﬂuenced weight loss and body composition. In a randomized, double-blinded, placebo-controlled, crossover study, 20 overweight African-American women received placebo t.i.d. during the control period and 200 µg NBC t.i.d. during the verum period and engaged in a modest diet and exercise regimen for 2 months. Group 1 subjects (n = 10) received placebo ﬁrst then NBC; group 2 subjects (n = 10) received NBC ﬁrst then placebo later. Body weights and blood chemistries were measured by routine clinical methodology. Fat and non-fat body masses were estimated using bioelectrical impedance (electrolipography). In women receiving NBC after the placebo period (group 1), body weight loss was essentially the same, but fat loss was signiﬁcantly greater and non-fat body mass loss was signiﬁcantly less with chromium (III) intake. There was a signiﬁcantly greater loss of fat in the placebo period compared to the verum period of group 1; however, the ability of chromium supplementation to augment fat loss and decrease lean body mass loss was carried over into the placebo period even after a 1-month wash-out period. No changes in blood chemistries were observed in either group. To summarize, results conﬁrmed that NBC given to African-American women in conjunction with moderate diet and exercise caused a signiﬁcant loss of fat and spared muscle compared to placebo, and this effect can be carried over for months [19]. Grant et al. [20] studied the effects of chromium (III) supplementation (400 µg elemental chromium per day) as NBC and chromium picolinate, with or without exercise training, in young, obese women. Exercise training combined with NBC supplementation resulted in signiﬁcant weight loss and lowered the insulin response to an oral glucose load. In contrast, chromium picolinate supplementation was associated with a signiﬁcant weight gain. Accordingly, exercise training with NBC supplementation is beneﬁcial for weight loss and lowers the risk of diabetes. Recently, NBC in combination with HCA-SX and a standardized Gymnema sylvestre extract was evaluated in a weight loss study of moderately obese subjects [21–23]. A randomized, doubleblind, placebo-controlled human study was conducted in 60 moderately obese subjects (ages 21 to 50 yr, body mass index [BMI] > 26 kg/m2) for 8 weeks. One group was administered a combination of 4 mg NBC, 4667 mg HCA-SX, and 400 mg Gymnema sylvestre extract, while another group was given placebo daily in three equally divided doses 30 to 60 min before meals [22,23]. All subjects received a diet of 2000 kcal per day and participated in a supervised walking program. At the end of 8 weeks, body weight and BMI decreased by 5 to 6%. Food intake as well as total cholesterol, LDL, triglycerides, and serum leptin levels were signiﬁcantly reduced, while highdensity lipoprotein (HDL) levels and excretion of urinary fat metabolites increased [22,23]. In another related study, 30 moderately obese subjects received the same combination of NBC, Gymnema sylvestra extract, and HCA-SX or placebo daily in 3 equally divided doses 30 to 60 min before each meal for 8 weeks [22,23]. Subjects also received a diet of 2000 kcal day and underwent a 30-min/day supervised walking program, 5 days a week, as in the previous study. Results demonstrated that, at the end of 8 weeks, the chromium-combination-supplemented group had reductions in body weight and BMI of 7.8 and 7.9%, respectively. Food intake was reduced by 14.1%. Total cholesterol, LDL, and triglyceride levels were reduced by 9.1, 17.9, and 18.1%, respectively, while HDL and serotonin levels increased by 20.7% and 50%, respectively. Serum leptin levels decreased by 40.5%, and enhanced excretion of urinary fat metabolites increased by 146 to 281%. No signiﬁcant changes were observed in the placebo group [22,23]. In another study, moderately obese women participated in a 12-week exercise program that investigated the effect of chromium picolinate supplementation on body composition, resting metabolic rate, and selected biochemical parameters [24]. In this double-blind study, 44 women (ages 27 to 51 years) received either 400 µg/day of elemental chromium (III) as chromium picolinate or a placebo and participated in a supervised weight-training and walking program 2 days per week for 12 weeks. Body composition and resting metabolic rate were measured at baseline and at 6

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and 12 weeks. Body composition and resting metabolic rate were not signiﬁcantly changed by chromium picolinate supplementation. Overall results demonstrated that 12 weeks of chromium picolinate supplementation (400 µg elemental chromium (III) per day) did not signiﬁcantly affect body composition, resting metabolic rate, plasma glucose, serum insulin, plasma glucagon, serum C-peptide, or serum lipid concentrations. The effects of daily chromium supplementation (200 µg elemental chromium as chromium picolinate) were investigated in football players during spring training for 9 weeks in a doubleblind study [25]. Subjects receiving chromium picolinate demonstrated urinary chromium losses ﬁve times greater than those in the placebo group, and the chromium picolinate supplementation was ineffective in bringing about changes in body composition or strength during a program of intensive weight-lifting training. Another double-blind, randomized, placebo-controlled study assessed the effects of 14 weeks of chromium picolinate supplementation, during a preseason resistance and conditioning program, on body composition and neuromuscular performance in NCAA Division I wrestlers [26]. Twenty wrestlers from the University of Oklahoma were assigned to a treatment group (n = 7; 20.4 yr ± 0.1) receiving 200 µg elemental chromium (III) as chromium picolinate daily, a placebo group (n = 7; 19.9 yr ± 0.2), or a control group (n = 6; 20.2 yr ± 0.1) using a stratiﬁed random sampling technique based on weight classiﬁcation. Body composition, neuromuscular performance, metabolic performance, and serum insulin and glucose were measured before and immediately following the supplementation and training period. Repeat measures by ANOVA indicated no signiﬁcant changes in body composition for any of the groups. Aerobic power increased signiﬁcantly (p < 0.002) in all groups, independent of supplementation. The results from the above two studies demonstrated that chromium picolinate supplementation coupled with typical preseason training programs does not enhance body composition or performance variables beyond improvements seen with training alone, at least at the relatively low doses used. In another double-blind, placebo-controlled study, the efﬁcacy of chromium picolinate as a fatreduction aid for obese individuals enrolled in a physical exercise program was investigated for 16 weeks [27]. Participants were healthy, active-duty Navy personnel who exceeded the Navy’s percent body fat standards of 22% fat for men and 30% for women. Mean age was 30.3 years, and comparisons between the subjects who completed the study (n = 95; 79 men, 16 women) and dropouts (n = 109) revealed no signiﬁcant differences in demographics or baseline percent body fat. The physical conditioning programs were held a minimum of 3 times per week for at least 30 minutes of aerobic exercise. On a daily basis, subjects were given either 400 µg elemental chromium (III) as chromium picolinate or a placebo. At the end of 16 weeks, the group as a whole had lost a small amount of weight and body fat; however, the chromium-picolinate-supplemented group failed to show a signiﬁcantly greater reduction in either percent body fat or body weight or a greater increase in lean body mass compared to the placebo group. Livolsi et al. [28] examined the effect of chromium picolinate supplementation on muscular strength, body composition, and urinary excretion in women softball athletes. Fifteen women softball athletes were randomly divided into two groups: chromium picolinate (500 µg elemental chromium per day; n = 8) and placebo control (n = 7). Results demonstrated that no signiﬁcant (p < 0.05) differences in muscular strength or body composition were found after 6 weeks of resistance training. A 16-month, longitudinal, double-blind, randomly assigned intervention study of 33 female obese subjects combined supplementation of 200 µg elemental chromium (III) as chromium picolinate with a very low energy diet (VLED) during the ﬁrst 2 months. Results showed that chromium picolinate intake did not result in signiﬁcant changes in blood parameters and body composition [29].

SAFETY OF CHROMIUM (III) COMPLEXES Numerous studies have been conducted to evaluate the safety of chromium (III) complexes available in the marketplace. In a comparative evaluation, the toxicities of chromium chloride, chromium picolinate, and NBC were examined. At equal and physiological relevant doses, chromium picolinate

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demonstrated mutagenic potential at the hypoxanthine (guanine) phosphoribosyltransferase locus in Chinese hamster ovary cells, while chromium chloride and NBC exhibited no mutagenicity [30]. In a separate study, chromium picolinate was again found to produce chromosome damage in Chinese hamster ovary cells, but no chromosome damage was observed following treatment with similar doses of NBC or nicotinic acid [31]. This damage was concluded to be due to the picolinate ligand, as picolinic acid alone resulted in some chromosomal damage, nephrotoxicity, and clastogenicity [30–32]. A number of published studies demonstrated the neurological effects (both beneﬁcial and deleterious) associated with chromium picolinate supplementation [33–35]; however, chromium picolinate has recently received self-afﬁrmed Generally Recognized as Safe (GRAS) status [36]. Based on the results of extensive safety studies (acute oral, acute dermal, primary dermal, and eye irritation studies; 90-day subchronic toxicity; Ames’ bacterial reverse mutation assay; and mouse lymphoma mutagenicity assay), NBC also has received self-afﬁrmed GRAS status [37,38]. No signiﬁcant toxic effect of chromium chloride has been reported. No detailed safety studies have been reported on other trivalent chromium complexes.

CONCLUSION The novel chromium (III) micronutrients have been demonstrated to help insulin metabolize fat, favorably inﬂuence glucose and insulin metabolism, maintain healthy lipid proﬁles and blood sugar levels, turn protein into muscle. and convert sugar into energy [1–5,39]. Also, novel chromium (III) complexes may play a role in regulating appetite, reducing sugar cravings, and increasing lean body mass [1–5,39]. Trivalent chromium levels are known to decrease with advancing age and pregnancy, and marginal chromium deﬁciencies appear to be widespread [1–5,39–41]. In summary, based on extensive scientiﬁc research on chromium (III), it may be concluded that supplementation of well-researched, safe, novel chromium (III) complexes may promote lean body mass and regulate obesity. Research studies have demonstrated the superior safety, bioavailability, and efﬁcacy of NBC over other chromium (III) complexes.

REFERENCES [1]

[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]

Preuss, H.G., Bagchi, D., and Bagchi, M., Protective effects of a novel niacin-bound chromium complex and a grape seed proanthocyanidin extract on advancing age and various aspects of syndrome X, Ann. N.Y. Acad. Sci., 957, 250, 2002. Mertz, W., Chromium research from a distance: from 1959 to 1980, J. Am. Coll. Nutr., 17, 544, 1998. Mertz, W., Effects and metabolism of glucose tolerance factor, in Nutrition Reviews: Present Knowledge in Nutrition, Nutrition Foundation, Washington, D.C., 1976, p. 365. Shapcott, D. and Hubert, J., Chromium in Nutrition and Metabolism, Elsevier, Amsterdam, 1979. Anderson, R.A. and Kozlovsky, A.S., Chromium intake, absorption and excretion of subjects consuming self-selected diets, Am. J. Clin. Nutr., 41, 1177, 1985. Lefavi, R.G., Anderson, R.A., Keith, R.E., Wilson, D., McMillan, J.L., and Stone, M.H., Efﬁcacy of chromium supplementation in athletes: emphasis on anabolism, Int. J. Sports Nutr., 2, 111, 1992. Stohs, S.J. and Bagchi, D., Oxidative mechanisms in the toxicity of metal ions, Free Radic. Biol. Med., 18, 321, 1995. National Research Council, Chromium, in Recommended Dietary Allowances, 10th ed., National Academy Press, Washington, D.C., 1989, pp. 241, 243, 284. Cooper, J.A., Anderson, B.F., and Buckley, P.D., Structure and biological activity of nitrogen and oxygen coordinated nicotinic acid complexes of chromium, Inorg. Chim. Acta, 91, 1, 1984. Glinsmann, W.H. and Mertz, W., Effect of trivalent chromium on glucose tolerance, Metabolism, 15, 510, 1966. Urberg, M. and Zemel, M.B., Evidence for synergism between chromium and nicotinic acid in the control of glucose tolerance in elderly humans, Metabolism, 36, 896, 1987. Li, Y.C., Effects of brewer’s yeast on glucose tolerance and serum lipids in Chinese adults, Biol. Trace Elem. Res., 41, 341, 1994.

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Obesity: Epidemiology, Pathophysiology, and Prevention Clodfelder, B.J., Emamaullee, J., Hepburn, D.D., Chakov, N.E., Nettles, H.S., and Vincent, J.B., The trail of chromium (III) in vivo from the blood to the urine: the roles of transferrin and chromodulin, J. Biol. Inorg. Chem., 6, 608, 2001. Clodfelder, B.J., Chang, C., and Vincent, J.B., Absorption of the biomimetic chromium cation triaquamu3-oxo-mu-hexapropionatotrichromium(III) in rats, Biol. Trace Elem. Res., 98, 159, 2004. Olin, K.L., Stearns, D.M., Armstrong, W.H., and Keen C.L., Comparative retention/absorption of 51chromium (51Cr) from 51Cr chloride, 51Cr nicotinate and 51Cr picolinate in a rat model, Trace Elem. Electrolytes, 11, 182, 1994. Reaven, G.M., Syndrome X, Curr. Treat. Options Cardiovasc. Med., 3, 323, 2001. Behn, A. and Ur, E., The obesity epidemic and its cardiovascular consequences, Curr. Opin. Cardiol., 21, 353, 2006. Reaven, G.M., The metabolic syndrome: is this diagnosis necessary?, Am. J. Clin. Nutr., 83, 1237, 2006. Crawford, V., Scheckenbach, R., and Preuss, H.G., Effects of niacin-bound chromium supplementation on body composition in overweight African-American women, Diab. Obes. Metab., 1, 331, 1999. Grant, K.E., Chandler, R.M., Castle, A.L., and Ivy, J.L., Chromium and exercise training: effect on obese women, Med. Sci. Sports Exer., 29, 992, 1997. Talpur, N., Echard, B.W., Yasmin, T., Bagchi, D., and Preuss, H.G., Effects of niacin-bound chromium, Maitake mushroom fraction SX and (–)-hydroxycitric acid on the metabolic syndrome in aged diabetic Zucker fatty rats, Mol. Cell. Biochem., 252, 369, 2003. Preuss, H.G., Bagchi, D., Bagchi, M., Rao, C.V., Dey, D.K., and Satyanarayana, S., Effects of a natural extract of (–)-hydroxycitric acid (HCA-SX) and a combination of HCA-SX plus niacin-bound chromium and Gymnema sylvestre extract on weight loss, Diab. Obes. Metab., 6, 171, 2004. Preuss, H.G., Bagchi, D., Bagchi, M., Sanyasi Rao, C.V., Satyanarayana S., and Dey, D.K., Efﬁcacy of a novel, natural extract of (–)-hydroxycitric acid (HCA-SX) and a combination of HCA-SX, niacinbound chromium and Gymnema sylvestre extract in weight management in human volunteers, Nutr. Res., 24, 45, 2004. Volpe, S.L., Huang, H.W., Larpadisorn, K., and Lesser, I.I., Effect of chromium supplementation and exercise on body composition, resting metabolic rate and selected biochemical parameters in moderately obese women following an exercise program, J. Am. Coll. Nutr., 20, 293, 2001. Clancy, S.P., Clarkson, P.M., DeCheke, M.E., Nosaka, K., Freedson, P.S. et al., Effects of chromium picolinate supplementation on body composition, strength, and urinary chromium loss in football players, Int. J. Sports Nutr., 4, 142, 1994. Walker, L.S., Bemben, M.G., Bemben, D.A., and Knehans, A.W., Chromium picolinate effects on body composition and muscular performance in wrestlers, Med. Sci. Sports Exer., 30, 1730, 1998. Trent, L.K. and Thieding-Cancel, D., Effects of chromium picolinate on body composition, J. Sports Med. Phys. Fitness, 35, 273, 1995. Livolsi, J.M., Adams, G.M., and Laguna, P.L., The effect of chromium picolinate on muscular strength and body composition in women athletes, J. Strength Conditioning Res., 15, 161, 2001. Pasman, W.J., Westerterp-Plantenga, M.S., and Saris, W.H., The effectiveness of long-term supplementation of carbohydrate, chromium, ﬁbre and caffeine on weight maintenance, Int. J. Obes. Relat. Metab. Disord., 21, 1143, 1997. Stearns, D.M., Silveira, S.M., Wolf, K.K., and Luke, AM., Chromium(III) tris(picolinate) is mutagenic at the hypoxanthine (guanine) phosphoribosyltransferase locus in Chinese hamster ovary cells, Mutat. Res., 513, 135, 2002. Stearns, D.M., Wise, Sr., J.P., Patierno, S.R., and Wetterhahn, K.E., Chromium(III) picolinate produces chromosome damage in Chinese hamster ovary cells, FASEB J., 9, 1643, 1995. Beskid, M., Jachimowicz, J., Taraszewska, A., and Kukulska, D., Histological and ultrastructural changes in the rat brain following systemic administration of picolinic acid, Exper. Toxicol. Path., 47, 25, 1995. Speetjens, J.K., Collins, R.A., Vincent, J.B., and Woski, S.A., The nutritional supplement chromium(III) tris(picolinate) cleaves DNA, Chem. Res. Toxicol., 12, 483, 1999. Bagchi, D., Stohs, S.J., Downs, B.W., Bagchi, M., and Preuss, H.G., Cytotoxicity and oxidative mechanisms of different forms of chromium, Toxicology, 180, 5, 2002.

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Chromium (III) in Promoting Weight Loss and Lean Body Mass [35] [36] [37] [38] [39] [40]

[41]

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Vincent, J.B., The potential value and toxicity of chromium picolinate as a nutritional supplement, weight loss agent and muscle development agent, Sports Med., 33, 213, 2003. Berner, T.O., Murphy, M.M., and Slesinski, R., Determining the safety of chromium tripicolinate for addition to foods as a nutrient supplement, Food Chem. Toxicol., 42, 1029, 2004. Shara, M., Bagchi, M., Yasmin, T., Chatterjee, A., and Bagchi D., Safety and toxicological evaluation of a novel niacin-bound chromium (III) complex, J. Inorg. Biochem., 99, 2161, 2005. Personal communication from Burdock Group, Washington, D.C., June 8, 2005. Preuss, H.G. and Anderson, R.A., Chromium update: examining recent literature, Curr. Opin. Clin. Nutr. Metab. Care, 6, 509, 1998. Jeejeebhoy, K.N., Chu, R.C., Marliss, E.B., Greenberg, G.R., and Bruce-Robertson, A., Chromium deﬁciency, glucose intolerance, and neuropathy reversed by chromium supplementation, in a patient receiving long-term total parenteral nutrition, Am. J. Clin. Nutr., 30, 531, 1977. Tyson, D.A., Talpur, N.A., Echard, B.W., Bagchi, D., and Preuss, H.G., Acute effects of grape seed extract and niacin-bound chromium on cardiovascular parameters of normotensive and hypertensive rats, Res. Comm. Mol. Pathol. Pharmacol., 5, 91, 2000.

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Overview on 27 An (–)-Hydroxycitric Acid in Obesity Regulation Shirley Zafra-Stone, Manashi Bagchi, Harry G. Preuss, Gary J. Grover, and Debasis Bagchi CONTENTS Introduction ....................................................................................................................................349 (–)-Hydroxycitric Acid, a Natural Extract from Garcinia cambogia (Family Guttiferae) ..........350 Pharmacognosy .......................................................................................................................351 Chemistry ................................................................................................................................351 Isolation Techniques and Physicochemical Properties...........................................................352 Structural Characterization of a Calcium/Potassium Salt of (–)-Hydroxycitric Acid...........352 Bioavailability of (–)-Hydroxycitric Acid ..............................................................................353 Safety of (–)-Hydroxycitric Acid...................................................................................................354 Animal Studies...............................................................................................................................355 Clinical Studies ..............................................................................................................................360 Beneﬁts of Ca2+ and K+ in HCA-SX in Weight Management......................................................364 Molecular Mechanisms of Serotonin and Neuropeptide Y in Appetite Suppression...................365 Regulation of Genes by HCA-SX .................................................................................................365 Conclusion......................................................................................................................................366 References ......................................................................................................................................367

INTRODUCTION Obesity has become a worldwide epidemic and a major challenge to health professionals. In fact, a new term, globesity, has been coined to describe the recent upsurge of overweight and obesity in the global population. Today, obesity rates in the United States have reached epidemic proportions — 58 million Americans are overweight with a body mass index (BMI) of 25 or greater, 40 million are obese, and 3 million are morbidly obese (BMI ≥ 30); 8 out of 10 U.S. adults over 25 years of age are overweight [1,2]. These changes in rates of overweight and obesity are primarily attributed to overeating and a sedentary lifestyle. A recent survey found that 25% of Americans lead sedentary lifestyles, while 78% of Americans do not meet basic activity level recommendations. A 76% increase in type 2 diabetes in adults 30 to 40 years old has occurred since 1990 [1,2]. According to the World Health Organization (WHO), more than 1 billion adults are overweight and at least 300 millions are clinically obese worldwide. The International Obesity Task Force estimated that 22 million of the world’s children under 5 are overweight or obese [1,2]. Obesity has been shown to be associated with a broad spectrum of degenerative diseases, including metabolic disorders and

349

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certain forms of cancer. It has been reported that 80% of the cases of type 2 diabetes, 70% of cardiovascular diseases, and certain forms of cancer such as breast and colon (42%) are related to obesity [1,2]. Also, obesity is the major cause of 30% of gallbladder surgery, and 26% of obese people have high blood pressure. Among children diagnosed with type 2 diabetes, 85% are obese [2]. Globesity has generated an unlimited array of weight-loss strategies [1,2]. Fundamental changes have been made to the Food Guide Pyramid, and new strategies to readdress the consequences of excessive reﬁned-carbohydrate consumption are emerging. In addition to drug therapy, numerous procedures suggested to promote weight loss include reduced caloric intake (such as meal-replacement products), special weight-loss diets (e.g., grapefruit diet or cabbage soup diet), increased caloric expenditure (via exercise or stimulants), reduced-fat diets, increased water consumption, increased ﬁber consumption, reduced carbohydrate consumption and glycemic indexing (e.g., Atkins’ Diet, South Beach Diet, The Zone Diet, Cave Man Diet), appetite suppression, fat blockers, fat burners, starch/sugar blockers, bariatric and other surgeries (e.g., liposuction or stomach reduction), acupuncture, hypnotism, support groups, and body wraps, all of which are supported by products, programs, and services designed to help the consumer achieve desired results. Rapidweight-loss products and programs dominate the focus of marketers and consumers alike; however, rapid weight loss is potentially unhealthy and disturbs metabolic setpoint homeostasis, inducing undesirable rebound weight-gain consequences. Several synthetic drugs and phytopharmaceuticals have been demonstrated to help in weight management; however, concerns about exaggerated unsubstantiated beneﬁt claims, undesirable side effects, and federal regulatory intervention regarding dietary supplements are increasing. Consequently, the search has intensiﬁed for products backed by credible scientiﬁc research that promote healthy body composition and body mass redistribution but do not stimulate the central nervous system, elevate blood pressure, cause nervousness, interfere with sleep, or block nutrient absorption (e.g., fat, starch, and sugar blockers). Outside of signiﬁcant and permanent lifestyle changes, previously acceptable conventional methods alone or in combination have not resulted in sustained success. In some cases, these regimens resulted in undesirable side effects or serious consequences, such as the use of ephedrine and phenylpropanolamine (PPA), which have prompted regulatory scrutiny and intervention. At the same time, adverse side effects have been demonstrated for synthetic drugs. Thus, it is very important to develop a strategic therapeutic intervention using safe, novel natural supplements supported by credible research. This chapter demonstrates the role of (–)-hydroxycitric acid derived from the fruit rind of Garcinia cambogia in weight loss.

(–)-HYDROXYCITRIC ACID, A NATURAL EXTRACT FROM GARCINIA CAMBOGIA (FAMILY GUTTIFERAE) The fruit of Garcinia cambogia is valued for its dried rind, which is used extensively in Southern India for culinary purposes and particularly as a condiment, in place of tamarind or lemon, for ﬂavoring curries and meat and seafood dishes. The fruit extract also serves as a unique ﬂavor enhancer for beverages, as a gourmet spice, and as a postprandial carminative. The fruit has also been used for centuries to make meals more ﬁlling [3,4]. The dried rind of G. cambogia, which contains (–)-hydroxycitric acid (HCA), is also used in pickling ﬁsh [5,6]; the commercial pickling of ﬁsh is called Colombo curing [5,7]. The organic acids present in the fruit are responsible for the bacteriostatic effect of the pickling medium by a simple lowering of the pH. In addition to the ﬂavoring and preservative effects of the fruit extract, in the traditional system of herbal medicine in India (Ayurveda), Garcinia is considered to be a prime herb beneﬁcial for health. A decoction of the fruit rind is given for rheumatism and bowel complaints. In veterinary medicine, the extract is employed as a rinse for some diseases of the mouth in cattle [8]. HCA, the organoleptically characterizing ingredient of G. cambogia, is a popular component of several dietary supplements marketed under various trade names. It has been reported that the calcium salts of HCA, which

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An Overview on (–)-Hydroxycitric Acid in Obesity Regulation COOH HO – C – H HO – C – COOH H– C – COOH H

a. (–)-Hydroxycitric acid COOH HO – C – H HOOC – C – OH H– C – COOH H

c. (+)-allo-Hydroxycitric acid

351

COOH H – C – OH HOOC – C – OH H– C – COOH H

b. (+)-Hydroxycitric acid COOH H – C – OH HO – C – COOH H– C – COOH H

d. (–)-allo-Hydroxycitric acid

FIGURE 27.1 Chemical structures of the stereoisomers of hydroxycitric acid.

are typically less than 50% soluble, are less bioavailable compared to the readily soluble calcium/ potassium salts of HCA. As a dietary supplement in the United States, HCA is regulated under the Dietary Supplement Health and Education Act (DSHEA) of 1994 [9].

PHARMACOGNOSY Garcinia is a large genus of approximately 180 species of polygamous trees or shrubs distributed in tropical Asia, Africa, and Polynesia. Approximately 30 species of Garcinia are found in India and Southeast Asia. One of the species, G. cambogia, found commonly in the evergreen forests of southwest India, is a small or medium-sized tree with a rounded crown and horizontal or drooping branches. The leaves are dark green and shiny, elliptic obovate, 5 to 12 cm long, and 2 to 7 cm broad. The tree ﬂowers during the hot season, and fruits ripen during the rainy season. The fruit, which is the source of HCA, is ovoid and 5 cm in diameter; it ranges in color from yellow to orange or red when ripe and has six to eight grooves. The fruit has six to eight seeds surrounded by a succulent aril. The G. cambogia fruit is included in the U.S. Department of Agriculture’s inventory of perennial edible fruits of the tropics [10]. The fruit contains approximately 10 to 30% acid calculated as citric acid on a dry-weight basis [7]. In some early studies, the organic acids present in the fruits were mistakenly identiﬁed as tartaric and citric acids. In subsequent studies, the major acid in the fruit of G. cambogia was identiﬁed as HCA [11,12]. HCA-SX, derived by a novel patented process from the dried fruit rind of G. cambogia, contains approximately 95% calcium/potassium salt of (–)-hydroxycitric acid. The calcium/potassium salt contains approximately 60% HCA, as characterized by high-performance liquid chromatography (HPLC).

CHEMISTRY Hydroxycitric acid (1,2-dihydroxypropane-1,2,3-tricarboxylic acid) has two asymmetric centers; hence two pairs of distereoisomers or four different isomers are possible (Figure 27.1). All four isomers, (–)-HCA, (+)-HCA, (–)-allo-HCA, and (+)-allo-HCA, have been chemically synthesized

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starting from trans-aconitic acid [12,13]. Of these isomers, (–)-HCA is the principal constituent of HCA-SX, occurring in Garcinia (Figure 27.1a), while the (+)-HCA isomer is found in Hibiscus species (Figure 27.1b) [12,13]. (–)-HCA is the principal acid in the highly acidic fruit of G. cambogia. The absolute conﬁguration of (–)-HCA was determined from Hudson’s lactone rule, optical rotatory dispersion curves, circular dichromism curves, and calculation of partial molar rotations [14]. By employing x-ray crystallography, Glusker et al. [15,16] determined the structure and absolute conﬁguration of calcium hydroxycitrate and HCA lactone. The acid is present at a level of 10 to 30% in the dried fruit rind of G. cambogia. The acid can be isolated in its free form, as a mineral salt (Ca2+ salt, Na+ salt, K+ salt, Mg2+ salt, Ca2+/K+ double salt, Mg2+/K+ double salt, and others formed after extraction), or as a lactone by various methods. Lowenstein and Brunengraber [17] estimated the hydroxycitrate content of the fruit of G. cambogia by gas chromatography (GC). During concentration and evaporation, free HCA leads to the formation of HCA lactone. Based on information submitted to the U.S. Patent Ofﬁce, several investigators have reported the preparation of HCA concentrate from Garcinia rinds with 23 to 54% HCA and 6 to 20% lactone [18,19]. Recently, Jayaprakasha and Sakariah [20,21] developed HPLC methods for the estimation of organic acids in the fruits of G. cambogia and commercial samples of G. cambogia extracts. Using these methods, dilute extracts can be quantiﬁed without concentration, drying, or derivatization. An additional advantage of these methods is that the HCA and its lactone can be quantiﬁed separately. Loe et al. [22] reported a gas chromatography/mass spectrophotometry (GC/MS) method for quantitative determination of blood hydroxycitrate levels.

ISOLATION TECHNIQUES

AND

PHYSICOCHEMICAL PROPERTIES

Lewis and Neelakantan [11] reported a method for the large-scale isolation of HCA from the dried rinds of G. cambogia. In this method, the acid was extracted by heating the raw material with water under pressure. The extract was then concentrated and pectin was removed by precipitation with alcohol. The clear ﬁltrate was neutralized and the acid was recovered after passing through cationexchange resin. The recovered acid was concentrated, dried, and recrystalized to small, needleshaped crystals of lactone. Using another method, Lewis [12] isolated HCA from dried Garcinia fruit rinds using acetone. The acetone extract was concentrated, and the acid was extracted in water. The water extract was evaporated to yield lactone. In yet another process, aqueous extract of HCA was passed through an anion-exchange column for adsorption of HCA. The adsorbed HCA was eluted with sodium/potassium hydroxide. The free acid was prepared by passing it through a cationexchange column. In recent years, several manufacturers have employed different procedures (patented) to prepare salts of HCA with improved solubility and bioavailability. Among the number of HCA salts available in the marketplace are Ca2+ salt, Na+ salt, K+ salt, Mg2+ salt, Ca2+/K+ double salt, and Mg2+/K+ double salt. The solubility of these HCA salts, which can affect bioavailability, ranges from less than 50 to 100%. Furthermore, different salts have different physicochemical characteristics, including color, taste, and odor. Extensive research has been conducted on a novel, patented calcium/potassium salt of 60% HCA extract (HCA-SX, known commercially as Super CitriMax®), which is tasteless and odorless as well as 100% water soluble.

STRUCTURAL CHARACTERIZATION OF SALT OF (–)-HYDROXYCITRIC ACID

A

CALCIUM/POTASSIUM

A typical compositional analysis of HCA-SX reveals that it contains 60% (–)-hydroxycitric acid in its free form, 1.0% (–)-hydroxycitric acid in its lactone form, 10% calcium, 15% potassium, 0.5% sodium, 0.05% total phytosterols, 0.3% total protein, 4.5% moisture, and 8.5% soluble dietary ﬁber (by difference). It also contains 0.1% magnesium, 0.03% iron, and trace amounts of manganese, copper, zinc, selenium, total fat, and total sugar. HCA-SX provides approximately 150 calories per 100 g and exhibits an optical rotation [α]D20 = –17.55 (c = 1.0 H2O), as measured in a Rudolph AUTOPOL II Polarimeter (Hackettstown, NJ) using a 10-cm cell at 589 nm.

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353

Using HPLC, HCA-SX was detected by injecting a 20 µL solution of HCA-SX (sample concentration 1.6 mg/mL) in water (pH 2.1, adjusted with sulfuric acid) on a Shimadzu HPLC (Tokyo, Japan) equipped with LC-10AT pumps, SCL-10A system controller, SIL-10A auto injector, SPD-M10AVP detector (detector was set at 210 nm), CLASS-M10A software, and a 5-µ Altima C18 column (250 mm × 4.6 mm) (Alltech Associates, Inc.; Deerﬁeld, IL) at a ﬂow rate of 1 mL/min in an isocratic mode using a mobile phase of 0.05-M sodium sulfate in water (pH 2.3, adjusted with sulfuric acid) at 25 ± 2°C. The retention time for HCA was noted at 4.78 min, which was reconﬁrmed by spiking with an authentic standard of HCA (Wako, Japan). When the ultraviolet (UV) spectra of HCA-SX were recorded on a Varian Cary 50 UV–VIS spectrometer (Mulgrave, Victoria, Australia), the UV spectra (H2O) exhibited a shoulder at λmax 210 nm. The infrared (IR) spectra of HCA-SX were recorded on a PerkinElmer Spectrum BX FT-IR spectrometer (Norwalk, CT) with the following results: IR (KBr pellet, cm–1) 3403.20 (OH), 1599.39 (asymmetric C=O stretching band), 1397 (symmetric C=O stretching band), 1295.93 (C–O stretch), 1099.74, 1061.98 (alcoholic C–O absorption), 905.99, 837.40 (C–C stretching), and 627.11 (C–C bending). The proton nuclear magnetic resonance (NMR) spectrum (300 MHz, D2O) was recorded on a JEOL JNM-LA (Lambda) NMR spectrometer (Tokyo, Japan), and the chemical shift values were expressed in ppm. 1H NMR data of HCA-SX showed H-2 at δ 3.98 s, H-4a at δ 2.53 d (J = 16.5 Hz), and H-4b at δ 2.69 d (J = 16.5 Hz). The 13C NMR spectrum (75 MHz, D2O) was recorded on a JEOL JNM-LA (Lambda) NMR spectrometer (Tokyo, Japan), and the chemical shift values were expressed in ppm. The 13C NMR spectrum of HCA-SX exhibited C-1, C-5, and C-6 at δ 181.0, 179.7, and 178.7 ppm, and C-2, C-3, and C-4 at δ 42.4, 79.8, and 77.1, respectively. The mass spectrum was recorded on an Agilent 1100 Series liquid chromatograph (LC)/mass selective detector (MSD) (Palo Alto, CA) under electrospray ionization (ESI), negative ion mode conditions. In electrospray ionization, the mass spectrum contains abundant pseudomolecular ions (M+1, M+23, etc. in positive-ion mode and M–1 in negative-ion mode). These ions were used to conﬁrm the molecular weight of the compounds. The peak at m/z 207 (M–1) in the mass spectrum of HCA-SX corresponds to the pseudomolecular ion of HCA (molecular weight 208) [22].

BIOAVAILABILITY

OF

(–)-HYDROXYCITRIC ACID

Loe et al. [23] conducted a study utilizing a simple method that requires minimal sample preparation and is able to measure trace amounts of HCA with accuracy and precision using [U-13C] citrate (CA*) as the internal standard to account for losses associated with the isolation, derivatization, and measurement of HCA. These authors developed a new GC/MS method to measure HCA levels in blood. HCA and CA* were derivatized with BSTFA + 10% TMCS and analyzed using positive chemical ionization (PCI) GC/MS (HCA, m/z 553; CA*, m/z 471). Plasma HCA concentration was measured over a 3.5-hr period in four subjects who had ingested 2 g of HCA-SX. Their plasma HCA concentrations were 0.8 and 8.4 µg/mL 30 min and 2 hr after ingestion, respectively. These results demonstrated that, when taken acutely, HCA is absorbed yet present in small quantities in human plasma. In a separate study, these authors assessed the bioavailability of HCA-SX in both fasting and fed states in humans [24]. HCA-SX concentrations peaked 2 hr after administration and were not completely cleared after 9 hr (Figure 27.2). Feeding appeared to hinder HCA-SX absorption, as the peak concentration was approximately 60% lower than for absorption in the fasting state. HCA-SX absorption was detectable in the urine and was used to determine relative HCA-SX absorption [23,24]. A recent pharmacokinetics study was conducted on HCA-SX in Sprague–Dawley rats. HCA-SX was given orally at 912 mg/kg by gavage. Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hr, and plasma concentrations of HCA-SX were measured. HCA-SX was absorbed in a time-dependent manner, and the Tmax value (1 hr) suggests fairly rapid absorption of HCA-SX. After achieving Cmax, the HCA-SX levels rapidly declined, suggesting that this compound is rapidly metabolized. By 8 to 24 hr, it had disappeared from the plasma. The plasma half-life was between 1 and 2 hr. Key pharmacokinetic proﬁles are shown in Table 27.1.

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9 Fasting (n=3)

8 Plasma HCA Concentration (µg/mL)

Fed (n=3) 7 6 5 4 3 2 1 0 1

2

3

4

5

6

7

8

9

Time (hr)

FIGURE 27.2 Plasma HCA (mg/mL) concentrations in fasted and fed human subjects over a period of 9 hr following a single oral administration of HCA-SX (2.0 g).

SAFETY OF (–)-HYDROXYCITRIC ACID An extensive safety evaluation was conducted on HCA-SX. Acute oral, acute dermal, primary dermal irritation, and primary eye irritation toxicity studies have demonstrated the safety of HCA-SX [25]. The LD50 of HCA-SX was found to be greater than 5000 mg/kg body weight when administered once orally via gastric intubation to fasted male and female Albino rats. No gross toxicological ﬁndings were observed under the experimental conditions. The dermal LD50 of HCA-SX was found to be greater than 2000 mg/kg body weight when applied once for 24 hr to the shaved, intact skin of male and female albino rabbits. No evidence of acute systemic toxicity was observed among rabbits that were dermally administered HCA-SX at 2000 mg/kg body weight. In the dermal irritation study, no deaths or signiﬁcant body weight changes were observed during the study period. HCA-SX induced very slight erythema on one animal [25]. No edema or other dermal ﬁndings were noted, and all irritation was reversible and had completely subsided by the end of day 1. The primary dermal irritation index (PDII) was calculated to be 0.0. Based on these observations, HCA-SX received a descriptive rating classiﬁcation of nonirritating. In the eye irritation study, no deaths or remarkable changes in body weights occurred during the study period. The results indicate that HCA-SX causes ocular irritation with the production of inﬂammatory exudate in some animals. Positive iridal and conjuctival reactions were present in all animals and subsided within 48 hr. A total maximum score of 110 is possible, and a score of 15 was obtained in the study, indicating mild irritation [25]. Sprague–Dawley rats were used to assess the dose- and time-dependent effects of HCA-SX on body weight, selected organ weights, hepatic lipid peroxidation and DNA fragmentation, hematology, and clinical chemistry over a period of 90 days (subchronic study) [26,27]. Furthermore, a 90-day histopathological evaluation was conducted. The animals were treated with 0, 0.2, 2.0, and 5.0% HCA-SX of feed intake and were sacriﬁced at 30, 60, or 90 days of treatment. The body weights and selected organ weights were assessed and correlated as a percentage of body weight and brain weight at 90 days of treatment. A signiﬁcant reduction in body weight was observed in treated rats as compared to control animals. An advancing age-induced marginal increase in hepatic

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TABLE 27.1 Key Pharmacokinetic Values for HCA-SX in Rats Pharmacokinetic Estimate Half-life (hr) Tmax (hr)

Value 1.3 1

Cmax (µg/mL)

384.0

AUC0-t (hr*µg/mL)

1336

Volume of distribution (mL/kg)

1286

Clearance (mL/hr/kg)

683

lipid peroxidation was observed in both male and female rats, while no such difference in hepatic DNA fragmentation was observed as compared to the control animals. Furthermore, selected organ weights individually and as a percentage of body and brain weights at 90 days of treatment exhibited no signiﬁcant difference between the groups. No difference was observed in hematology and clinical chemistry or the histopathological evaluation. Taken together, these results show that 90-day treatment of HCA-SX results in a reduction in body weight and does not cause any changes in major organs or in hematology, clinical chemistry, and histopathology [26,27]. Ames’ bacterial reverse mutation studies and mouse lymphoma tests have shown that HCA-SX does not induce mutagenicity [27]. Five histidine-dependent strains of Salmonella typhimurium (TA98, TA100, TA1535, TA 1537, and TA102) were used to evaluate the mutagenic potential of HCA-SX (up to 5000 µg/plate) in both the presence and absence of metabolic activation (±S9). No mutagenic potential of HCA-SX was observed. The mutagenic potential of HCA-SX (up to the recommended dose level of 5000 µg/plate) was assessed in the mouse lymphoma assay using L5178Y mouse lymphoma cells, clone –3.7.2C (ATCC #CRL-9518, American Type Culture Collection; Manassas, VA). HCA-SX did not induce mutagenic effects in the mammalian cell gene mutation test on L5178Y mouse lymphoma cells TK+/–, with or without metabolic activation [27]. In an independent study, Saito et al. [28] demonstrated that diets containing 51 mmol HCA per kg diet (389 mg HCA per kg body weight per day) or less did not cause any adverse effects. Accordingly, 51 mmol HCA per kg diet (389 mg HCA per kg body weight per day) was deemed to be the no-observed adverse effect level (NOAEL) [28]. The structure, mechanism of action, long history of use of HCA, and other toxicity studies indicate that HCA-SX is unlikely to cause reproductive or developmental effects. In several placebocontrolled, double-blind trials employing up to 2800 mg/day HCA, no treatment-related adverse effects were reported. Sufﬁcient qualitative and quantitative scientiﬁc evidence, including animal and human data, suggest that the intake of HCA at levels up to 2800 mg/day is safe for humans [29].

ANIMAL STUDIES Since 1970, a number of animal studies conducted with hydroxycitrate, singly and in combination with other ingredients, have demonstrated beneﬁcial effects for weight and fat loss. Early studies showed that (–)-hydroxycitrate is a potent competitive inhibitor of ATP citrate lyase, the extramitochondrial enzyme that supplies most of the acetyl coenzyme A for lipid synthesis [30,31]. Hydroxycitrate was also shown to inhibit the conversion of carbohydrate and its metabolites into lipid by reducing the acetyl coenzyme A pool, the substrate for fatty acids and cholesterol. Studies in the 1970s on HCA supplementation in rats demonstrated evidence of decreased lipogenesis levels

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and appetite suppression. Lowenstein [32] demonstrated that (–)-hydroxycitrate is a highly effective inhibitor of fatty acid synthesis by rat liver in vivo. Hepatic fatty acid synthesis was inhibited strongly by sodium (–)-hydroxycitrate. An i.p. dose of as little as 0.1 mmol per kg body weight inhibited fatty acid synthesis by 25 to 30% (equivalent to about 2.9 mg of (–)-hydroxycitrate per 150 g rat). Inhibition of 50% and 75% was obtained with an i.p. dose of 0.28 and 1 mmol per kg of body weight, respectively. The results also demonstrated that inhibition of fatty acid synthesis remained strong between 50 and 95 min after administration of hydroxycitrate. Additional experiments showed that inhibition of fatty acid synthesis remained strong up to 2 to 3 hr after administration of hydroxycitrate [32]. Sullivan et al. [33] determined the effect of the hydroxycitrate stereoisomers on the rate of lipogenesis in rat liver. Inhibition of lipogenesis by administration of (–)-hydroxycitrate, (+)hydroxycitrate, (–)-allo-hydroxycitrate, and (+)-allo-hydroxycitrate stereoisomers i.v. or i.p demonstrated that only (–)-hydroxycitrate signiﬁcantly decreased the rates of lipid synthesis in both studies. The in vivo rate of lipogenesis was markedly decreased for 150 minutes following the administration of (–)-hydroxycitrate. Fatty acid and cholesterol synthesis was also signiﬁcantly inhibited by the oral administration of (–)-hydroxycitrate when the compound was given before the feeding period [33]. In another study, oral administration of (–)-hydroxycitrate in female rats was shown to depress the in vivo lipogenic rates in a dose-dependent manner in the liver, adipose tissue, and small intestine [33]. Hepatic lipogenesis was signiﬁcantly inhibited during the 8 hr period in the (–)-hydroxycitrate treated animals and was 11% less than controls. Rats receiving (–)-hydroxycitrate also consumed less food than the untreated controls [34]. Although this decreased caloric intake was not responsible for the drug-induced depression of hepatic lipogenesis (as shown by studies in pair-fed rats), a separate pair-feeding study demonstrated that the reduction in food intake accounted for a decrease in weight gain and body lipid observed with (–)-hydroxycitrate treatment [34,35]. In this study, a signiﬁcant reduction in body weight gain, food consumption, and total body lipid was observed in female rats with a chronic oral administration of (–)-hydroxycitrate for a period of 11 to 30 days. An equal amount of citrate administration did not have any effects. Pair-feeding studies demonstrated that these effects on weight and body lipids were due to the decreased caloric intake produced by (–)-hydroxycitrate [35]. In another in vivo study, Sullivan et al. [36] examined the inﬂuence of (–)-hydroxycitrate on weight gain, appetite, and body composition in several obese rodent model systems: mature normal rat, the goldthioglucose obese mouse, and the ventromedial-hypothalamic-lesioned obese rat. In all models, food intake and body weight gain were reduced signiﬁcantly by the chronic oral administration of (–)-hydroxycitrate (52.6 mmol/kg of diet, a dose approximately equivalent to 2.74 mmol/kg body weight) as part of the dietary admixture. The dietary admixture was a G-70 diet that consisted of 70% glucose, 23% vitamin-free casein, 5% Phillips and Hart salt mixture, and 40 g/kg of cellulose [36]. Hamilton et al. [37] investigated the inﬂuence of (–)-hydroxycitrate on serum triglyceride and cholesterol levels, as well as the in vitro and in vivo rates of hepatic fatty acid and cholesterol synthesis in normal and hyperlipidemic rat model systems. (–)-Hydroxycitrate reduced equivalently the biosynthesis of triglycerides, phospholipids, cholesterol, diglycerides, cholesteryl esters, and free fatty acids in isolated liver cells. In vivo hepatic rates of fatty acid and cholesterol synthesis determined in meal-fed normolipidemic rats were suppressed signiﬁcantly by the oral administration of (–)-hydroxycitrate for 6 hr, when control animals exhibited maximal rates of lipid synthesis. Results also demonstrated that serum triglyceride and cholesterol levels were signiﬁcantly reduced. In two hypertriglyceridemic models — the genetically obese Zucker rat and the fructose-treated rat — elevated triglyceride levels were due, in part, to enhanced hepatic rates of fatty acid synthesis. (–)-Hydroxycitrate signiﬁcantly reduced the hypertriglyceridemia and hyperlipogenesis in both models. The marked hypertriglyceridemia exhibited by the triton-treated rat was only minimally due to increased hepatic lipogenesis. This study showed that (–)-hydroxycitrate signiﬁcantly inhibited both serum triglyceride levels and lipogenesis in this model [37].

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In another in vivo study conducted by Greenwood et al. [38], (–)-hydroxycitrate treatment in growing lean Zucker rats resulted in a decrease in the percent of body fat in the carcass and a signiﬁcant decrease in fat cell size. Young Zucker lean (Fa/–) and obese (fa/fa) female rats were fed the fatty acid synthesis inhibitor (–)-hydroxycitrate as a dietary admixture for 39 days. In the lean rats, (–)-hydroxycitrate treatment decreased body weight, food intake, percent of body fat, and fat cell size. In the obese rat, food intake and body weight were reduced, but the percent of body fat remained unchanged. Throughout the treatment period, obese rats maintained a fat cell size equivalent to their obese controls. Although a reduction in fat cell number in the obese rats occurred during the treatment period, marked hyperplasia was observed during the post-treatment period. The results of this study indicate that the obese rat, despite a substantial reduction in body weight produced by (–)-hydroxycitrate, still defends its obese body composition [38]. Rao et al. [39] evaluated the effects of (–)-hydroxycitric acid in male albino Winstar rats fed a lipogenic diet for a period of 15 days. A control group was fed a lipogenic diet without HCA. Analysis results from blood, liver, and epididymal fat demonstrated that inclusion of (–)-hydroxycitrate in the diet signiﬁcantly reduced food intake, body weight, epididymal fat, and serum triglyceride in animals. A decrease in the feed efﬁciency ratio was also observed. The effect of HCA was dose dependent [39]. In another study, body weight gain was decreased and fat deposition was inhibited by (–)hydroxycitrate, but no difference in cumulative food intake was observed [40]. In a study conducted by Vasselli et al. [40], growing male Sprague–Dawley rats (n = 5) were fed (–)-hydroxycitrate ad libitum as a dietary admixture for 28 days. A separate experiment tested the ability of (–)-hydroxycitrate to alter 24-hr energy expenditure (EE) in rats (n = 6) fed a mixed high-carbohydrate diet (75% CHO, 3.90 kcal/g) known to stimulate lipogenesis in humans. EE was measured in whole body respirometers during days 1 through 5 of a 28-day test period, and the ﬁnal weights of 3 fat depositions were determined. Results of the ﬁrst experiment demonstrated that (–)-hydroxycitrate inhibited body weight gain (–48.9 g, p < 0.01) and cumulative food intake (control, 675.7 ± 23.5 g; (–)-hydroxycitrate, 622.5 ± 44.6 g; p < 0.05). The second experiment showed that (–)-hydroxycitrate increased 24-hr EE by 12.6% (no change in respiratory quotient was observed). Results in the (–)-hydroxycitrate group included the following: body weight gain, 73.8 ± 7.1 g (p < 0.02); EE (kcal/24 hr), 62.59 ± 5.41 (p < 0.02); cumulative food intake, 614.7 ± 27.8 g; and total pad weight, 16.04 ± 1.28 g (p < 0.01). The results for the control group included the following: body weight gain, 91.5 ± 12.7 g; EE (kcal/24 hr), 55.67 ± 2.43; cumulative food intake, 629.1 ± 8.8 g; and total pad weight, 21.45 ± 2.57 g [40]. Ishihara et al. [41] conducted a study on hydroxycitrate and male Std ddY mice. Mice were divided into three groups (n = 60, 54, and 12) of equal body weights. The ﬁrst group of mice (n = 60) were placed in metabolic chambers to measure respiratory gas. Diet and water were prohibited from 0930 hr; at 1000 hr, they were administered orally 10 or 30 mg of a 0.48 mol/L hydroxycitrate solution or water, and the respiratory gas was analyzed. The same procedures were applied in the second mice group (n = 54). Blood was collected 30 or 100 min after administration of the hydroxycitrate to measure serum variables. The effect of hydroxycitrate on glycogen accumulation was evaluated in the gastrocnemius muscle and liver tissue in the ﬁnal mice group (n = 12). In a separate experiment, mice (n = 18) were forced to swim to exhaustion at a ﬂow rate of 8 L/min twice a day for a preliminary period of 1 week. They were then divided into three groups and orally administered 10 or 30 mg of 0.48 mol/L hydroxycitrate or 10 mg water (control); also, they were given free access to commercial diet and water. Following the treatment, the mice swam until fatigue every day at the same ﬂow rate, and the maximum swimming time was measured. The mice were administered hydroxycitrate orally every day after swimming. Finally, in another experiment, mice (n = 18) were divided into two groups of equal mean body weights. They were orally administered 10 mg of 0.48 mol/L hydroxycitrate or water (control) twice a day for 25 days. At day 26, each mouse was placed in a treadmill chamber and allowed to rest for 1 hr, followed by a 1-hr run at a speed of 15 m/min while respiratory gas

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was monitored. Body weight and food intake were taken every day until termination. The authors demonstrated that oral administration of 10 mg hydroxycitrate elevated serum free fatty acid concentration and increased muscle glycogen concentration in mice at rest. Mice that were chronically (twice daily for 25 days) administered hydroxycitrate had a signiﬁcantly reduced respiratory exchange ratio (RER) at rest and during running exercise. Lipid oxidation was increased and carbohydrate utilization was less in the early stages of the running exercise. These results indicated that the enhancement of exercise endurance by orally administered hydroxycitrate in mice might have occurred by attenuation of glycogen consumption caused by the promotion of lipid oxidation during the running exercise [41]. In a series of experiments, 24 male rats were fed restrictively (10 g/day) for 10 days and then given ad libitum access to one of four different diets: high sucrose (HI-Suc), high glucose (HIGlu), grounded standard rat chow (Chow), and high glucose + fat (HI-Glu+fat), which varied in the content of fat and low-molecular-weight carbohydrates for 10 days. In the other rats (n = 12), the ad libitum diet was supplemented with 3% (w/w) HCA. HCA reduced body weight regain with all diets except Chow. HCA also reduced food intake temporarily with three of the four tested diets. The suppressive effect of HCA on food intake was particularly strong in the HI-Glu+fat diet group (fat = 24% of energy). For the HI-Glu and HI-Glu+Fat diets, HCA reduced the feed conversion efﬁciency (cumulative body weight regain [g]/cumulative food intake [MJ]) during the 10 ad libitum days, suggesting that it also increased energy expenditure. This effect seemed to be positively related to the glucose content of the diet [41]. Two experiments were performed in 23 and 24 adult male Sprague–Dawley rats [42,43]. Initial body weights for experiment 1 and 2 were 663 ± 12 g and 616 ± 7 g, respectively. Both groups were fed only 10 g powdered standard rodent chow for 10 days before being divided into groups. Rats were divided into two groups (n = 11 or 12) for each experiment and matched for body weight loss and given one of two diets ad libitum for 22 days. The diet of one group was always supplemented with 3 g/100 g hydroxycitrate (85 mmol/kg diet). In experiment 1, rats in both groups were given a 1% (g/100 g) fat diet = 81% carbohydrate, 10% protein, and 1% fat. In experiment 2, rats in both groups were given a 12% (g/100 g) fat diet = 76% carbohydrate, 9% protein, and 12% fat. Rats lost 72 ± 3 g and 75 ± 2 g body weight, respectively, during the 10-day restrictive feeding in experiments 1 and 2. Hydroxycitrate reduced body weight regain in rats fed both diets throughout the period of ad libitum consumption. In experiment 1 (1% fat diet group), the cumulative body weight regain in rats fed hydroxycitrate was signiﬁcantly less than in controls on ad libitum day 2 (control, 17 ± 1 g; hydroxycitrate, 12 ± 1 g). On day 22, the control rats had regained 70 ± 6 g body weight, and the hydroxycitrate rats had regained 48 ± 3 g body weight (overall p < 0.01). Thus, the hydroxycitrate-fed rats regained only 68 ± 4% of the control group’s body weight regain. HCA did not affect any metabolic variables examined. In experiment 2 (12% fat diet group), after day 22 the control group and had regained 81 ± 7 g while the hydroxycitrate group had regained 49 ± 6 g (overall p < 0.01). The latter was 61 ± 8% of the control group’s body weight regain. As in experiment 1, the control group had compensated the body weight loss on ad libitum day 22 (body weight loss, 75 ± 3g; body weight regain, 81 ± 3g), whereas the hydroxycitrate group had not (body weight loss, 75 ± 3g; body weight regain, 49 ± 6 g; p < 0.01). Hydroxycitrate had no effect on plasma β-hydroxybutyrate but reduced plasma triacylglycerol and increased liver fat concentration. The suppressive effect of hydroxycitrate on body weight regain, which was maintained for at least 3 weeks, appears to be independent of the dietary fat content; yet, the fat content of the diet seemed to be important for the long-term suppressive effect of hydroxycitrate on feeding [42,43]. Hayamizu et al. [44] evaluated the effects of 3.3% Garcinia cambogia extract on 10% sucrose loading in mice for 4 weeks. The authors demonstrated that G. cambogia extract efﬁciently improved glucose metabolism and displayed leptin-like activity. The dose- and time-dependent effects in rats of HCA-SX (Super CitriMax®, 60% calcium/potassium salt of HCA) were evaluated with regard to body weight, selected organ weights, hepatic lipid peroxidation and DNA fragmentation, hematology and clinical chemistry, and histopathological

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evaluation [45]. Male and female Sprague–Dawley rats (male rats, 251 to 320 g; female rats, 154 to 241 g) were treated with HCA-SX at 0, 0.2, 2.0, and 5.0% of feed intake and were sacriﬁced on 30, 60, or 90 days of treatment. The body weight and selected organ weights were assessed and correlated as a percentage of body weight and brain weight at 90 days of treatment. A 90-day histopathological evaluation was also conducted. A signiﬁcant reduction in body weight was observed in treated rats as compared to control animals. An advancing age-induced marginal increase in hepatic lipid peroxidation was observed in both male and female rats, but no such difference in hepatic DNA fragmentation was observed as compared to the control animals. Selected organ weights individually and as a percentage of body weight and brain weight at 90 days of treatment exhibited no signiﬁcant differences between the groups. No differences were observed in hematology and clinical chemistry or the histopathological evaluation. Taken together, these results show that 90-day treatment of HCA-SX results in a reduction in body weight and does not cause any changes in major organs or in hematology, clinical chemistry, and histopathology [26,27]. Roy et al. [45] determined the effects of low-dose oral HCA-SX on the body weight and abdominal fat gene expression proﬁle of Sprague–Dawley rats. At doses relevant for human consumption, dietary HCA-SX signiﬁcantly reduced body weight growth. This response was associated with lowered abdominal fat leptin expression. Other genes, including vital genes transcribing for mitochondrial/nuclear proteins which are necessary for fundamental support of the tissue, were not affected by HCA-SX. Under the current experimental conditions, HCA-SX proved to be effective in restricting body weight gain in adult rats. Functional characterization of HCA-SXsensitive genes revealed that upregulation of genes encoding serotonin receptors, as well as fat and carbohydrate metabolism, represent a distinct effect of dietary HCA-SX supplementation. In another study, 24 male Sprague–Dawley rats were fed restrictively (10 g/day) for 10 days and then given ad libitum access to a high-glucose diet supplemented with 3% hydroxycitrate for 6 days [46]. Controls received the same diet without the supplement. The respiratory quotient (RQ) and energy expenditure (EE) were measured during ad libitum days 1, 2, and 6. An oral glucose tolerance test was performed on ad libitum day 4 or 5. Hydroxycitrate decreased RQ and EE during ad libitum days 1 and 2. In all probability, these ﬁndings reﬂect a decrease in de novo lipogenesis. On ad libitum day 6, RQ and EE did not differ between treatment groups. Hydroxycitrate suppressed food intake during the ﬁrst 3 days ad libitum, but overall body weight regain was not decreased in the hydroxycitrate group. The oral glucose tolerance test showed that hydroxycitrate signiﬁcantly decreased the increase in plasma glucose from baseline and tended to decrease the area under the curve for glucose. The area under the curve for insulin did not differ between the groups. These results indicate that, in this animal model, hydroxycitrate suppressed de novo lipogenesis and may improve glucose tolerance. Leonhardt et al. [47] conducted a study in which a total of 63 male Sprague–Dawley rats were fed restrictively for 10 days. Animals were then divided into seven groups (n = 9 per group) and switched to ad libitum consumption. The diet contained 70% (w/w) carbohydrates, 9% protein, and 12% fat. Results demonstrated that hydroxycitrate (3%) signiﬁcantly suppressed food intake and body weight regain and neither conjugated linolein acid (CLA) (1%) nor guar gum (3%) increased the effect of hydroxycitrate on these parameters. Also, CLA and guar gum alone had no effect on food intake and body weight regain. The liver fat content of the combined hydroxycitrate + CLA groups was signiﬁcantly lower compared to that of the control group. This study conﬁrms the effectiveness of hydroxycitrate to reduce food intake and body weight regain after a period of restrictive feeding. Wielinga et al. [48] investigated whether HCA reduces the postprandial glucose response by affecting gastric emptying or intestinal glucose absorption in rats [48]. They compared the effect of regulator HCA (310 mg/kg) and vehicle (control) on the glucose response after an intragastric or intraduodenal glucose load to investigate the role of altered gastric emptying. Hydroxycitrate treatment delays the intestinal absorption of enterally administered glucose at the level of the small intestinal mucosa in rats. Hydroxycitrate strongly attenuated postprandial blood glucose levels after

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both intragastric (p < 0.01) and intraduodenal (p < 0.001) glucose administration, excluding a major effect of hydroxycitrate on gastric emptying. Hydroxycitrate delayed the systemic appearance of exogenous glucose but did not affect the total fraction of glucose absorbed over the study period of 150 min. This study supports a possible role for hydroxycitrate as a food supplement for lowering postprandial glucose proﬁles. The most recent study by Ono et al. [49] shows that the calcium salt of hydroxycitric acid does not induce chromosomal aberration. Chromosomal aberration and micronucleus tests were conducted in cultured Chinese hamster lung cells and in mice. The extract did not increase the number of cells with structural aberration or numerical aberrations, nor did it increase the frequency of micronucleated polychromatic erythrocytes.

CLINICAL STUDIES Numerous clinical trials have been performed to assess the weight management potential of various (–)-hydroxycitric acid preparations. Following are summaries of the human clinical studies conducted with different forms of HCA and formulations. A randomized, placebo-controlled, double-blind study was conducted in 54 male and female subjects (ages, 21 to 55 years; degree of obesity, 15 to 45% overweight) [50]. This 8-week study consisted of group A (n = 30) given Lipodex-2™ (500 mg rind of Garcinia indica and 100 µg elemental chromium as chromium nicotinate) 3 times a day, and group B (n = 24), who received placebo. All subjects were given the same dietary instructions, consisting of a low-fat, low-sugar, low-sodium, and high-ﬁber diet plan (1200 kcal diet/day), and were encouraged to drink 64 oz of water each day. Twenty-two subjects in group A and 17 subjects in group B completed the study. The average weight loss per subject (n = 23) in group A was 5.06 kg (11.14 lb); under the identical clinical conditions, group B subjects (n = 17) had an average weight loss of 1.91 kg (4.2 lb). One subject in group A who had multiple allergies and experienced itching around the mouth was advised to discontinue the study. Ramos et al. [51] conducted a randomized, double-blind, placebo-controlled trial on 35 healthy subjects for 8 weeks. Of the 40 subjects who started the program, 35 completed the study. Three subjects dropped out due to inﬂuenza, and two subjects in the placebo group dropped out due to a lack of positive results. The subjects were randomly divided into a placebo group (n = 17, 4 males and 13 females; ages, 38.7 ± 12.3 years; percent overweight, 52.4 ± 20.5%; BMI, 33.2 ± 4.4 kg/m2) and a Garcinia cambogia extract group (n = 18, 5 males, 13 females; ages, 35.3 ± 11.8 years; percent overweight, 50.7 ± 20.8%; BMI, 32.6 ± 4.3 kg/m2). The placebo group received 500 mg capsule of placebo before each meal, and the second group received 500 mg lyophilized extract of Garcinia cambogia (GCE) in a similar form daily for 8 weeks. At the beginning of study and every two weeks throughout the study, all subjects underwent a physical examination and blood chemistry analysis. Both groups were placed on recommended diets providing 1000, 1200, or 1500 kcal depending on their theoretical ideal weight (TIW). At the end of the study, total cholesterol signiﬁcantly decreased by 18%, and triglyceride levels signiﬁcantly decreased by 26% in the GCE group as compared to the control group. Average weight loss after 8 weeks was 1.3 ± 0.9 kg in the placebo group and 4.1 ± 1.8 kg (p < 0.001) in the GCE group. The GCE group also experienced reduced appetite starting from the ﬁrst day of administration. Two subjects treated with GCE stated that they experienced slight headaches and nausea, and one subject in the control group experienced similar symptoms. No other adverse reactions were observed. A randomized, placebo-controlled, double-blind study was conducted in 60 obese subjects (44 females and 16 males) [52]. All subjects were on a low-fat diet of 1200 kcal/day and were instructed to exercise 3 times a week for 8 weeks. Subjects were given either placebo (n = 30) or HCA (n = 30) t.i.d. (30 minutes before meals). The dose of hydroxycitrate was 1320 mg/day. The HCA group signiﬁcantly lost an average body weight of 6.4 kg (p < 0.001), and the placebo group lost an average body weight of 3.8 kg. The difference in weight reduction is highly signiﬁcant. The

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composition of the weight loss, determined with a near-infrared (NIR) technique, showed that 87% of the weight loss in the HCA group was due to fat loss compared to 80% in the placebo group. Blood pressure, total cholesterol, and hip and waist circumferences were signiﬁcantly reduced in both groups. A statistically signiﬁcant difference between the groups in favor of the HCA group was seen in all of these parameters (p < 0.001). Appetite scores during the study, using visual analog scales, were signiﬁcantly reduced in the HCA group but not in the placebo group (p < 0.001). The tolerability of the treatments was excellent. Two subjects stopped the treatment due to stomach pain, one in the HCA group and one in the placebo group. Girola et al. [53] conducted a randomized, double-blind, placebo-controlled trial in 150 obese subjects for four weeks. Group 1 (n = 50) received a hypocaloric diet plus 1 capsule per day of dietary integrator (capsules containing chitosan 240 mg, Garcinia cambogia extract 55 mg, and chromium 19 µg); group 2 (n = 50) received a hypocaloric diet and 2 capsules per day; and group 3 (n = 50) received a hypocaloric diet and a placebo. Following completion of the study, group 1 demonstrated a weight loss of 7.9%, total cholesterol reduction of 19.8%, LDL cholesterol reduction of 22.9%, triglyceride reduction of 18.3%, and HDL cholesterol augmentation of 9.0%. Group 2 exhibited a weight loss of 12.5%, total cholesterol reduction of 28.7%, LDL cholesterol reduction of 35.1%, triglyceride reduction of 26.6%, and HDL cholesterol augmentation of 14.1%. In the placebo group (group 3), weight reduction was 4.3%, total cholesterol reduction was 10.7%, LDL cholesterol reduction was 15.2%, triglyceride reduction was 13.2%, and HDL cholesterol augmentation was 6.3%. Adverse events were reported in 6.4% of subjects in the placebo group (nausea and/or constipation), 6.1% of the subjects in group 1 (nausea), and 2.1% of the subjects in group 2 (headache), without any statistically signiﬁcant difference between these three groups. No pathologic or clinically signiﬁcant changes in blood chemistry or hematological assay were observed. Rothacker and Waitman [54] evaluated the effectiveness of a combination of HCA and natural caffeine in weight loss in a randomized, placebo-controlled, double-blind study for 6 weeks. Of the 50 obese subjects (BMI, 27 to 33) enrolled in the study, 48 completed the study. Subjects were randomized to treatment with a proprietary combination containing 400 mg Garcinia cambogia extract (50% HCA), 25 mg natural caffeine (guarana and green tea), and 20 µg elemental chromium as chromium polynicotinate or an identical-appearing placebo caplet. Subjects (mostly females) were instructed to take 2 caplets three times per day, 30 to 60 minutes before meals. All subjects were instructed to follow the same 1200 kcal high-ﬁber diet. The herbal supplement group (n = 25) exhibited a mean weight change of –4.0 ± 3.5 kg, and the placebo group (n = 23) exhibited a mean weight change of –3.0 ± 3.1 kg. The endpoint revealed directional differences between treatment groups in favor of the HCA group (p = 0.30). No serious adverse events were reported. Heymsﬁeld et al. [55] conducted a randomized, placebo-controlled, double-blind study to evaluate the antiobesity potential of a Garcinia cambogia extract (GCE). Of the 135 overweight men and women (BMI, approximately 32 kg/m2) who enrolled in the study, 84 subjects completed the study. Subjects were randomized to receive either GCE (n = 66; 1500 mg of HCA/day) or placebo (n = 69), and both groups were prescribed a high-ﬁber, low-energy (1200 kcal) diet. The treatment period was 12 weeks. Body weight was evaluated every other week and fat mass was measured at week 0 and 12. Both the placebo and GCE groups lost weight; however, no signiﬁcant differences were observed. No signiﬁcant adverse effects were reported. Unfortunately, the sources or physicochemical characteristics of the HCA used in this study were not identiﬁed, which raises questions about the proper dosing and bioavailability of the HCA in the test substance. Kriketos et al. [56] conducted a double-blind, placebo-controlled, randomized, crossover study involving 3 days of HCA (3.0 g/day) or placebo supplementation in sedentary adult male subjects (n = 10; ages, 22 to 38 years; BMI, 22.4 to 37.6 kg/m2). The effect of HCA supplementation on metabolic parameters with or without moderately intense exercise was studied over four laboratory visits. Two of the four visits involved no exercise (Protocol A) with and without HCA treatment, while the remaining two visits included a moderately intense exercise regimen (Protocol B; 30 min at 40% maximal aerobic ﬁtness [VO2max] and 15 min at 60% VO2max) with and without HCA

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treatment. Energy expenditure (measured by indirect calorimetry) and respiratory quotient were measured for 150 min following an overnight fast. Blood samples were collected for the determination of glucose, insulin, glucagon, lactate, and β-hydroxybutyrate concentrations. In a fasted state and following 3 days of HCA treatment, the RQ was not signiﬁcantly lowered during rest (Protocol A) nor during exercise (Protocol B) compared with the placebo treatment. Treatment with HCA did not affect EE, either during rest or during moderately intense exercise. Furthermore, the blood substrates measured were not signiﬁcantly different between treatment groups under the fasting conditions of this study. These results do not support the hypothesis that HCA alters the short-term rate of fat oxidation in the fasting state during rest or moderate exercise at doses likely to be achieved in humans while subjects maintain a typical Western diet (approximately 30 to 35% total calories as fat). Mattes and Bormann [4] assessed the effects of HCA on appetitive variables in a randomized, placebo-controlled, double-blind, parallel group study in 89 mildly overweight female subjects (18 to 65 years old). Forty-two subjects were given 400-mg caplets of Garcinia cambogia extract (GCE) 30 to 60 min before each meal, three times a day (total dose, 2.4 g/day; total dose of HCA, 1.2 g/day); 47 subjects were given placebo for 12 weeks. Weight and body composition were assessed at baseline and every other week. Participants were counseled to adhere to a 1200-kcal exchange diet that contained 30% of energy from fat. Although both groups lost body weight, the active group (Garcinia cambogia group) achieved a signiﬁcantly greater reduction (7.0 ± 3.1 vs. 2.4 ± 2.9 kg). No adverse events were reported. No effects of the HCA were observed on appetitive variables. In a study conducted by van Loon et al. [57], the effects of acute HCA supplementation on substrate metabolism were assessed at rest and during exercise in a randomized controlled trial in humans. Ten cyclists (ages, 24 ± 2 years; weight, 73 ± 2 kg; maximal oxygen uptake, 4.95 ± 0.11 L/min; maximal work output [W:max], 408 ± 8 W). Subjects were studied at rest and during 2 hr of exercise at 50% W:max on 2 occasions. Both 45 and 15 min before exercise and 30 and 60 min after the start of exercise, 3.1 mL/kg body weight of an HCA solution (19 g/L) or placebo was ingested. Total fat and carbohydrate oxidation rates were assessed. Blood samples were collected at 15-min intervals at rest and every 30 min during exercise. Plasma HCA concentrations increased after HCA ingestion up to 0.39 ± 0.02 mmol/L (82.0 ± 4.8 mg/L); however, no signiﬁcant differences in total fat and carbohydrate oxidation rates were observed between trials. Accordingly, plasma glucose, glycerol, and fatty acid concentrations did not differ between trials. Plasma lactate concentrations were signiﬁcantly lower in the HCA than in the placebo trial after 30 min of exercise, but at the end of the exercise period they did not differ between trials. In conclusion, HCA, even when provided in large quantities, does not increase total fat oxidation in vivo in endurance-trained humans. Kovacs et al. [58] assessed the effects of 2-week ingestion of HCA combined with mediumchain triglycerides (MCTs) on satiety and food intake in 21 normal to moderately obese subjects (7 males and 14 females; ages, 43 ± 10 years; BMI, 27.6 ± 2.0 kg/m2). The study consisted of three intervention periods of 2 weeks separated by wash-out periods of 2 or 6 weeks in a randomized, crossover, placebo-controlled, double-blind study. Subjects consumed three self-selected meals and four isoenergetic snacks daily with either no supplementation (placebo), with 500 mg HCA, or with 500 mg HCA + 3 g MCT. Each intervention period ended with a test day consisting of a standardized breakfast and ad libitum lunch and dinner. There was signiﬁcant body weight loss during the 2 weeks of intervention (placebo, –0.5 ± 0.3 kg, p < 0.05; HCA, –0.4 ± 0.2 kg, p < 0.05; HCA+MCT, –0.7 ± 0.2 kg, p < 0.01), but the reduction was not different between the treatments. No adverse events were reported. Hayamizu et al. [59] assessed the effects of long-term administration of Garcinia cambogia extract on visceral fat accumulation in humans. A randomized, double-blind, placebo-controlled trial was conducted in 40 subjects (BMI, 25 to 35 kg/m2) for 8 weeks. Subjects were randomized to either a GCE group (n = 20, 1000 mg HCA per day) or a placebo group (n = 20). Each was subjected to a computed tomography (CT) scan at the umbilical level before and after the treatment period, and blood samples were taken to measure the clinical laboratory data every 4 weeks. As

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for a higher visceral fat area (VFA) in the subjects (who had initial VFAs over 90 cm2), both the VFA and the ratio of VFA to subcutaneous fat area (SFA) ratio were measured. In the GCE group, both the VFA and VFA/SFA signiﬁcantly decreased compared to the placebo group (p < 0.01 and p < 0.05, respectively). Triacylglycerol was also reduced signiﬁcantly in higher VFA subjects in the GCE group, compared to the initial levels (p < 0.05), but no signiﬁcant difference was found between the groups with regard to the loss of body weight and waist-to-hip ratio. Thus, GCE is useful in reducing body fat accumulation, especially visceral fat accumulation. No adverse effects were noted. Westerterp-Plantenga and Kovacs [60] evaluated the effect of HCA on energy intake and satiety in a randomized, placebo-controlled, single-blind study in 24 overweight, healthy, dietary-unrestrained subjects (12 males and 12 females; BMI, 27.5 ± 2.0 kg/m2; ages, 37 ± 10 years). In this 6-week trial, subjects consumed three times a day for 2 weeks 100 mL tomato juice (placebo) and, separated by a 2-week wash-out period, 100 mL tomato juice with 300 mg HCA (HCA-SX). After 2 weeks, 24-hr energy intake, appetite proﬁle, hedonics, mood, and possible change in dietary restraint were assessed. Prevention of degradation and bioavailability were documented. The 24-hr energy intake was decreased by 15 to 30% (p < 0.05) with HCA treatment compared to placebo. No changes were observed in the appetite proﬁle, dietary restraint, mood, taste perception, and hedonics; body weight tended to decrease, and satiety was sustained. Lim et al. [61] conducted a randomized, placebo-controlled study to determine whether shortterm HCA ingestion increases fat oxidation during exercise in athletic human volunteers. Subjects were administered 250 mg of HCA or placebo for 5 days, after each time performing cycle ergometer exercise at 60% VO2max for 60 min followed by 80% VO2max until exhaustion. Blood was collected and expired gas samples were analyzed at rest and every 15 min. The respiratory exchange ratio was signiﬁcantly lower in the HCA trial than in the control trial (p < 0.05). Fat oxidation was signiﬁcantly increased by short-term administration of HCA, and carbohydrate oxidation was signiﬁcantly decreased (p < 0.05) during exercise, presumably resulting in an increase in the cycle ergometer exercise time to exhaustion after 1 hr of 60% VO2max performance with increasing fat oxidation, which spares glycogen utilization during moderate-intensity exercise in athletes. In another randomized, double-blind, placebo-controlled study, Lim et al. [62] assessed whether or not HCA ingestion increases fat utilization during exercise in six untrained female subjects. Subjects ingested 250 mg HCA or placebo capsule for 5 days and then participated in a cycle ergometer exercise. Subjects cycled at 40% VO2max for 1 hr, and then the exercise intensity was increased to 60% VO2max until exhaustion on day 5 of each experiment. HCA decreased the respiratory exchange ratio and carbohydrate oxidation during 1 hr of exercise. In addition, exercise time to exhaustion was signiﬁcantly enhanced (p < 0.05). These results suggest that HCA increases fat metabolism, which may be associated with a decrease in glycogen utilization during the same intensity exercise and enhanced exercise performance. Preuss et al. [63] conducted a randomized, placebo-controlled, double-blind pilot study to determine the efﬁcacy of HCA-SX and a combination of HCA-SX, niacin-bound chromium, and Gymnema sylvestre extract (GSE) in weight management in 30 obese subjects (ages, 21 to 50 years; BMI, >26 kg/m2). Subjects were randomly divided into three groups (10 subjects per group): Group A was given 4667 mg HCA-SX (60% Ca2+/K+ salt of HCA as HCA-SX). Group B was given a combination of 4667 mg HCA-SX, 400 µg elemental chromium as niacin-bound chromium (NBC), and 400 mg Gymnema sylvestre extract (GSE). Group C was given a placebo. Each group received treatment daily in three equally divided doses 30 to 60 min before meals. In addition, subjects received a 2000-kcal/day diet and underwent a 30-min/day supervised walking program 5 days a week for 8 weeks. In group A, body weight and BMI decreased by 6.3%; food intake was reduced by 4%; total cholesterol, LDL, and triglycerides levels were reduced by 6.3%, 12.3%, and 8.3%, respectively; and HDL and serotonin levels increased by 10.7% and 40%, respectively. Serum leptin levels were decreased by 36.6%, and the enhanced excretion of urinary fat metabolites, including malondialdehyde (MDA), acetaldehyde (ACT), formaldehyde (FA), and acetone (ACON), increased

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by 125 to 258%. Under identical conditions, group B reduced body weight and BMI by 7.8% and 7.9%, respectively; food intake was reduced by 14.1%; total cholesterol, LDL, and triglyceride levels were reduced by 9.1%, 17.9%, and 18.1%, respectively; and HDL and serotonin levels increased by 20.7% and 50%, respectively. Serum leptin levels decreased by 40.5% and enhanced excretion of urinary fat metabolites increased by 146 to 281%. Group C (placebo) reduced body weight and BMI by only 1.6% and 1.7%, respectively. No other signiﬁcant changes were observed in the placebo group. In a subsequent randomized, placebo-controlled, double-blind study, Preuss et al. [64] evaluated the effects of HCA-SX and a combination of HCA-SX plus NBC and GSE in 60 obese subjects (ages, 21 to 50; BMI, >26 kg/m2). Subjects were randomly divided into three groups. Group A was administered 4667 mg HCA-SX. Group B was administered a combination of 4667 mg HCA-SX, 400 µg elemental chromium as NBC, and 400 mg GSE. Group C was given a placebo. All three groups received treatment daily in three equally divided doses 30 to 60 min before meals. All subjects received a 2000-kcal/day diet and participated in a supervised walking program for 8 weeks. At the end of 8 weeks, body weight and BMI decreased by 5 to 6% in both treatment groups A and B. Food intake, total cholesterol, LDL, triglyceride, and serum leptin levels were signiﬁcantly reduced in both groups, while HDL levels and excretion of urinary fat metabolites increased in both groups. A marginal or nonsigniﬁcant effect was observed in all parameters in group C (placebo). Results demonstrate that HCA-SX, and to a greater degree the combination of HCA-SX, NBC, and GSE, are effective in reducing body weight and promoting healthy cholesterol levels. No adverse effects were observed.

BENEFITS OF Ca2+ AND K+ IN HCA-SX IN WEIGHT MANAGEMENT Calcium (Ca2+) and potassium (K+) are important cations for regulating a number of metabolic pathways inﬂuencing energy expenditure, leptin metabolism, and weight control. K+ is a major mineral in the body, and the recommended daily intake is 3500 mg. Severe K+ deﬁciency causes cardiac arrhythmias, muscle weakness, and glucose intolerance; a moderate deﬁciency leads to increased blood pressure and salt sensitivity, an increased risk of kidney stones, and increased bone turnover. Inadequate K+ intake may also increase the risk of cardiovascular disease, particularly stroke, and may disturb intracellular pH homeostasis. K+ and Ca2+ ﬂux may play important roles in coupling intracellular energy production to leptin secretion [65,66]. Restriction of Na+ intake is a common dietary recommendation in the treatment of syndrome X disorders; however, metaanalyses indicate that increased Ca2+ and K+ intake should be the focus of dietary recommendations, rather than restriction of Na+, in the management of such disorders as hypertension. Evidence demonstrates that diets rich in Ca+ and K+ produce a potent antihypertensive effect [65]. Angelos et al. [66] reported that rat hearts perfused with glucose, insulin, and K+ had signiﬁcantly higher adenosine triphosphate (ATP), creatine phosphate, and nicotinamide adenine dinucleotide phosphate (NADP+) and lower adenosine monophosphate (AMP) and inosine levels compared to controls after 30 min of reperfusion. Reperfusion improved post-ischemic recovery of contractile function and the myocardial bioenergetic state. Dietary Ca2+ also plays a crucial role in regulating energy metabolism. High Ca2+ diets have been shown to inhibit fat synthesis and storage in adipocytes and reduce weight gain during overconsumption of an energy-rich diet. High Ca2+ intake was shown to increase lipolysis and preserve thermogenesis during caloric restriction, accelerating weight loss. In contrast, low Ca2+ diets have been shown to inhibit body fat loss [67,68]. Several clinical studies of Ca2+ intake were found to be associated with reduced weight in all groups. The Ca2+-treated subjects in a controlled trial exhibited signiﬁcant weight loss across nearly 4 years of observation [69]. In addition, other data from six observational studies and three controlled trials were evaluated to determine the

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relationship between Ca2+ intake and body fat. Analysis reveals that higher intake of Ca2+ is consistently associated with body weight loss and reduced weight gain. Heaney et al. [70] demonstrated that a 300-mg increment of regular Ca2+ intake is associated with 1 kg less body fat loss in children and 2.5 to 3.0 kg lower body weight in adults. Furthermore, Heaney et al. [70,71] estimated that, although Ca2+ intake explains only a fraction of the variability in weight gains, increased Ca2+ intake could reduce the prevalence of overweight and obesity signiﬁcantly. A related review by Teegarden [72] reports that Ca2+ may play a key role in reducing the incidence of obesity and prevalence of insulin resistance syndrome. The most obvious reason for adequate Ca2+ intake by postmenopausal women during a weight-loss regimen is to reduce the risk of bone demineralization disorders, such as osteoporosis [73]. This evidence supports the notion that adequate intake of dietary K+ and Ca2+ enhances energy production, leptin, and insulin metabolism and satisﬁes particular nutrient needs of important pathways required for healthy sustained weight loss and maintenance. In addition to 60% HCA, 4500 mg of HCA-SX supplies approximately 495 mg of Ca2+ (49.5% of RDI) and 720 mg of K+ (15% of the Reference Daily Intake [RDI]) bound to HCA. The Ca2+ and K+ ions in this novel preparation contribute an important role in achieving signiﬁcant improvements in body composition and the weight distribution effects by multiple synergistic pathways.

MOLECULAR MECHANISMS OF SEROTONIN AND NEUROPEPTIDE Y IN APPETITE SUPPRESSION Earlier in vitro studies in our laboratories have demonstrated that HCA-SX can induce increased serotonin (5-hydroxytryptamine, or 5-HT) release and serve as a mild serotonin receptor reuptake inhibitor (SRRI) [25,74]. The effect of HCA on basal and potassium-chloride-depolarization-evoked increases in radiolabeled serotonin ([3H]-5-HT) release from rat brain cortex slices in vitro was investigated. Results demonstrated that HCA (10 µM to 1 mM) altered the baseline of spontaneous tritium efﬂux, reaching a maximum at 300 µM, but had no signiﬁcant effect on the potassiumevoked release of [3H]-5-HT. HCA-SX can inhibit [3H]-5-HT uptake (and also increase 5-HT availability) in isolated rat brain cortical slices in a manner similar to that of SRRIs and thus may prove beneﬁcial in controlling appetite, as well as treatment of depression, insomnia, migraine headaches, and other serotonin-deﬁcient conditions [81,82]. In subsequent in vivo studies, we found elevated serotonin levels in the brain tissues of male and female rats (unpublished data). These ﬁndings were further corroborated in the human clinical trials and the cDNA oligonucleotide microarray studies conducted by Preuss et al. [56,57] and Roy et al. [45], respectively. Thus, serotonin regulation may be a major mechanism of appetite suppression by HCA-SX. In a very recent study, HCA-SX caused a signiﬁcant reduction of basal neuropeptide Y (NPY) concentrations in the hypothalamic tissues, further establishing a role for HCA-SX as an appetite suppressant (unpublished data).

REGULATION OF GENES BY HCA-SX Obesity is an energy-balance disorder in which certain genes that are programmed to resist loss of body fat prevail [75,76]. This programmed genetic predisposition is responsible for downregulating the resting metabolic rate in response to dietary and caloric restriction, which is significantly disrupted following rapid-weight-loss regimens [77]. Overconsumption of food (excess energy intake) is a normal consequence that contributes to weight gain and obesity. A resistance to the hormone leptin also characterizes common obesity. Insulin has been shown to increase leptin secretion by 25% [78]. Ample evidence demonstrates that insulin resistance is also a primary contributor to obesity, suggesting that insulin-resistance-induced hyperinsulinemia can provoke leptin-resistant hyperleptinemia with a consequential increase in fat synthesis and storage

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in adipocytes, a characteristic sequel of syndrome X. Furthermore, adipocytes from fatter animals secrete more leptin, and a correlation between intracellular ATP concentration and the rate of leptin secretion appears to exist [78]. As such, the leptin concentration correlates positively with percent body fat. A low resting metabolic rate for a given body size and composition, a low rate of fat oxidation, and low levels of physical activity are risk factors for weight gain and common traits of obese individuals [79]. The effects of low-dose oral HCA-SX were investigated on the body weight and abdominal fat transcriptome in rats [45]. HCA-SX restricted body weight gain in rats and lowered abdominal fat leptin expression. High-density microarray analysis of 9960 genes and expressed sequence tags (ESTs) present in the fat tissue identiﬁed a speciﬁc set of genes sensitive to dietary HCA-SX [45]. Functional characterization of HCA-SX-sensitive genes revealed that upregulation of genes encoding serotonin receptors represents a distinct effect of HCA-SX on appetite suppression [45]. HCA-SX upregulated a signiﬁcant number of genes associated with serotonin receptor and neuropeptide signaling, which demonstrate its appetite suppression ability [45]. Serotonin is believed to be a mood-enhancing chemical in the brain. High levels of serotonin are important for emotional well-being as serotonin provides a feeling of satiation and a calming effect. Serotonin also plays a role in appetite suppression and reduces cravings for carbohydrates and foods with a high glycemic index [78]. Appetite control involves an integration of the drive signals arising from energy stores in the body with the satiety signals generated by periodic episodes of food consumption. Serotonin (i.e., 5-HT1B and 5-HT2C postsynaptic receptors) has been implicated in the processes of withinmeal satiation and post-meal satiety, which are affected by the signals arising from the pattern of food intake. Stimulation of serotonergic receptors reduces feeding and perhaps enhances the satiating effect of food. Furthermore, regulation of the 5-HT2A gene plays an essential role in body weight management through the regulation of cortisol secretion [79]. Also, polymorphism of the 5-HT2A genes causes abdominal obesity in humans [79]. These ﬁndings corroborate with our previously conducted in vitro and in vivo studies demonstrating the ability of HCA-SX to enhance serotonin release and availability in the brain vicinity and act as a mild serotonin receptor reuptake inhibitor [25,56,57,74]. HCA-SX has also been shown to modulate a signiﬁcant number of genes, including prostaglandin D synthase (PGDS), aldolase B, lipocalin 2, fructose-1,6-biphosphatase 1, and low-density lipoprotein (LDL) receptor-related protein 2, which play prominent roles in lipid metabolism, carbohydrate metabolism, glycolysis, and cell communication [45]. It is worthwhile to mention that PGDS serves as a ligand for the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), and PPARγ signaling causes metabolic changes that ultimately lead to obesity [80,81]. These ﬁndings agree with our clinical studies, which have demonstrated the inﬂuence of HCA-SX on reductions in LDL, triglycerides, and total cholesterol; on the enhanced excretion of urinary fat metabolites, including malondialdehyde, acetaldehyde, formaldehyde, and acetone; and on marginal increases in HDL levels, in conjunction with body weight loss and BMI reduction [56,57]. The mitochondrial/nuclear proteins necessary for fundamental support of the tissue were not affected by HCA-SX, thus demonstrating the safety of HCA-SX [45]. These ﬁndings further emphasize that HCA-SX is safe, efﬁcacious, and capable of regulating a signiﬁcant number of obesity regulatory genes.

CONCLUSION Garcinia cambogia preparations are quite popular and have been used in India and Southeast Asia for the last several centuries. In the practice of Ayurveda medicine, several G. cambogia preparations are recommended for diverse therapeutic applications. In the Western world, a signiﬁcant number of scientists have conducted in vitro, in vivo, and mechanistic research on G. cambogia since the late 1960s. A number of patents and manufacturing process have been developed, and several (–)hydroxycitric acid preparations are commercially available in the marketplace. Extensive safety,

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mechanistic, and efﬁcacy studies have been conducted on a novel calcium/potassium salt of HCA (HCA-SX). Literature shows that the solubility, taste, and odor of HCA salts, as well as the structural integrity, bioavailability, and stability of the HCA preparations, depend largely on the binding cations and novel manufacturing technology. It is worthwhile to mention that these physicochemical characteristics are very important to demonstrating the safety and efﬁcacy of HCA salts in weight management. A signiﬁcant number of studies have shown that HCA-SX is safe and efﬁcacious in obesity management, as evidenced by the lowering of body weight and BMI in clinical studies. HCA-SX also exhibits discrete mechanisms for appetite suppression through serotonin and hypothalamic neuropeptide Y regulation. HCA-SX has also been shown to promote fat oxidation, as demonstrated by enhanced excretion of urinary fat metabolites, and to reduce serum leptin levels in human subjects. HCA-SX also was found to promote healthy blood lipid proﬁles in a clinical study, and no signiﬁcant adverse effects were observed. Effective dose, bioavailability, balanced diet, and moderate exercise, coupled with the synergistic inﬂuences of calcium and potassium, can signiﬁcantly enhance the therapeutic efﬁcacy of HCA-SX in obesity regulation. These studies were further substantiated by an unbiased cDNA oligonucleotide microarray study, which demonstrated the regulatory role of HCA-SX on obesity genes, without compromising the levels of mitochondrial and nuclear proteins essential for optimal biochemical and physiological functions in cellular system.

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Review of the Safety and 28 AEfficacy of Citrus aurantium in Weight Management Sidney J. Stohs and Michael Shara CONTENTS Introduction ....................................................................................................................................371 Historical Perspective.....................................................................................................................372 Chemistry .......................................................................................................................................372 Review Articles ..............................................................................................................................373 Animal Studies...............................................................................................................................374 Clinical Studies ..............................................................................................................................375 Case Reports ..................................................................................................................................377 Other Safety Considerations ..........................................................................................................378 Summary and Conclusions ............................................................................................................380 References ......................................................................................................................................381

INTRODUCTION Citrus aurantium extract and its primary alkaloidal constituent, synephrine, are widely used in weight management products and as thermogenic agents. Citrus aurantium extract is also known as bitter orange extract, a product that is derived from the unripe (green) fruits. In traditional Chinese medicine, it is known as “Chih-shi” or “Zhi shi.” Synephrine is a phenylethylamine derivative, also known as oxedrine or p-synephrine due to the hydroxy group in the para position on the benzene ring. In recent years, bitter orange extract has been used in weight management products due to its putative stimulant effects on metabolic processes, including increased lipolysis and thermogenesis as well as its mild appetite suppressant effects. Controversy exists regarding the safety and efﬁcacy of bitter orange extract. This controversy exists for a number of reasons. Little research is extant in which synephrine and extracts of bitter orange have been studied without the addition of various other ingredients and herbal products. The issues of safety and efﬁcacy are clearly clouded by the structural similarity of synephrine to ephedrine, notwithstanding that the pharmacokinetics of the two compounds and the receptor binding speciﬁcities are vastly different due to signiﬁcant structural differences. Risk-to-beneﬁt ratios have not been determined, and much of the information published that relates to risk has been questionable. Other issues have also clouded the picture with respect to the safety and efﬁcacy of bitter orange extract. Many of the extracts that are used are either nonstandardized or poorly standardized, making it exceedingly difﬁcult to establish reproducibility. Lack of knowledge of the chemical composition of the extracts being used precludes meaningful comparisons. Products containing bitter orange extract almost invariably contain a variety of other herbal extracts, many of which 371

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contain caffeine. Issues exist regarding the appropriate use of products containing bitter orange extract, and, in some cases, what might be considered high or excessive levels have been incorporated into some products. Warnings about not using products containing bitter orange extract or bitter orange extract in combination with caffeine if one has a history of high blood pressure, cardiovascular disease, diabetes, or thyroid disease are largely ignored by the consuming public. A ﬁnal serious issue that has added greatly to the overall confusion by the public and scientiﬁc community has been the release of erroneous adverse events information by governmental agencies. Statements implying that large numbers of adverse events and even deaths due to the use of products containing bitter orange extract have been shown to be incorrect and misleading but are still widely parroted by the popular press. Compounding the problem are pronouncements made by governmental ofﬁcials, lawmakers, and public ﬁgures based on information that is now known to be clearly in error. The questions to be asked are “What information can be obtained from studies that have been conducted on bitter orange extract?” and “Is bitter orange extract safe and effective for weight management when used as directed in appropriate amounts?” This review will cover published data associated with animal studies, human studies, and unpublished clinical studies, as well as case reports.

HISTORICAL PERSPECTIVE According to traditional Chinese medicine [8], Zhi shi (immature bitter orange) “is one of the best herbs to treat gastrointestinal disorders characterized by stagnation and accumulation” and “is one of the best herbs to relieve distention and hardness of the epigastric area caused by cholecystitis.” Pharmacologically, this compendium reports that Zhi shi does not affect heart rate or respiration and has minimal toxicity. Based on studies in mice, the estimated LD50 is approximately 175 mg/kg for synephrine. Youngken [31] described the collection and preparation of bitter orange peel USP and its uses as an aromatic bitter and ﬂavoring agent with an average dose of 1 g for the dried material and 4 mL for the bitter orange peel tincture USP. Trease and Evans [29] described the history of bitter orange trees, noting that they were ﬁrst brought to Europe about 1200 AD from Northern India via Africa. At the time this book was published, the peel of the bitter orange was ofﬁcially in the British Pharmocopoeia. Bitter orange peel has been used in South America in folk medicine for anxiety, insomnia, and epilepsy, and the oil from the peel has been shown to possess anxiolytic, sedative, and anticonvulsant properties [7]. The current use of Citrus aurantium can be arguably traced to the work of Arch and Ainsworth [3] which suggested that this product has the potential to augment thermogenesis and increase calorie consumption while at the same time producing fewer cardiovascular perturbations than ephedrine due to its lack of penetration of the central nervous system. As a result of the ban of ephedrine in 2004, bitter orange extract rapidly replaced ephedra, although the use of bitter orange extract had gradually increased as a thermogenic agent over the past 10 years.

CHEMISTRY A number of studies have assessed the chemical components in bitter orange extract responsible for the effects on weight management as well as other physiological effects. Hashimoto et al. [16] developed a high-performance liquid chromatographic (HPLC) method for determining synephrine content in Chinese medicinal drugs and concluded that synephrine was present at levels of 0.174 to 0.566% in these crude drug preparations. Pellati et al. [24] determined the alkaloidal content of fresh fruit as well as two dried extracts and three herbal products. The synephrine content of fresh fruit was approximately 0.02%, and it increased to about 0.35% in dried fruit. Two dried extracts contained about 3% synephrine and three herbal products had yields of 0.25%, 0.66%, and 0.99%. Dried extracts contained approximately 0.25% and 0.06% octopamine and tyramine, respectively.

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The question regarding which synephrine alkaloids are present in Citrus aurantium has been addressed by Allison et al. [1]. These investigators developed an isocratic reserve-phase liquid chromatographic system coupled with mass spectroscopy, enabling them to separate and identify the possible isomers of synephrine. They were able to differentiate p-synephrine (parahydroxy) from m-synephrine (metahydroxy). The m-synephrine is also known as phenylephrine. Both isomers are naturally present in small amounts in the body. The m-synephrine (phenylephrine) is available as an over-the-counter nasal decongestant and as an ophthalmic product for mydriasis [30]. Allison et al. [1] determined that both isomers were present in an over-the-counter weight-loss product they had obtained. Confusion exists regarding whether both isomers are naturally present in bitter orange extracts, whether environmental and extraction conditions inﬂuence the relative composition of the two alkaloids, and whether some extracts may be adulterated with the m-isomer. The question regarding which isomer is present is relevant to the effects and side effects of any given product. Both meta and para isomers of synephrine are phenylethanolamine derivatives; however, the p-isomer is believed to be primarily a β3-adrenergic receptor agonist that may be responsible for inducing a thermogenic response [2,10]. m-Synephrine (phenylephrine) is believed to exert more α-receptor activity as well as some β1 and β2 receptor activity, resulting in pressor as well as cardiac effects. Chemically, although ephedrine is structurally related to p-synephrine, it differs in that it is a phenylpropanolamine derivative rather than a phenylethanolamine, and ephedrine does not contain a parasubstituted hydroxy group. These chemical differences can greatly alter pharmacokinetic properties, particularly transport across the blood–brain barrier. The parahydroxy group of synephrine can predictably decrease lipophilicity and therefore transport into the central nervous system [19]. In addition to synephrine, Citrus aurantium contains a family of related phenylethylamines including N-methyltyramine, tyramine, hordenine, and octopamine. For example, a product used in a clinical trial by Gougeon et al. [13] was reported to contain an extract of C. aurantium such that each capsule contained 26 mg synephrine, 4 mg octopamine, 3.5 mg N-methyltyramine, and hordenine. Unfortunately, the entire alkaloidal proﬁle of extracts is usually not determined [16,24,25]. The net result is that as long as the chemical composition of any given dietary supplement containing a bitter orange extract is not known, one cannot make informed comparisons between different research studies nor can one make generalized statements regarding the safety and efﬁcacy of products containing a bitter orange extract.

REVIEW ARTICLES Preuss et al. [26] reviewed the effects of Citrus aurantium as a thermogenic, weight reduction replacement for ephedra. Based on the literature available at that time, these authors concluded that C. aurantium might be a possible thermogenic substitute for ephedra. They also concluded that more studies and widespread use of this natural product would reveal the efﬁcacy and relative safety of C. aurantium compared to ephedra. A review of Citrus aurantium as an ingredient in dietary supplements marketed for weight loss was published by Fugh-Berman and Myers [12]. This study is frequently cited as evidence for the lack of safety of C. aurantium extracts and their use in dietary supplements associated with weight management. Much of the evidence cited for the lack of safety related to increased blood pressure due to synephrine. Unfortunately, essentially all of the data supporting the ability of synephrine to increase blood pressure are related to studies involving the intravenous administration thereof, not the oral consumption of extracts containing synephrine. These authors concluded that, although no adverse events have been reported in conjunction with ingestion of C. aurantium products orally to date, products containing synephrine have the potential to increase cardiovascular events in humans, disregarding the route of administration. These investigators further concluded that little evidence supports the use of products containing C. aurantium as effective aids to weight loss and weight management [12]. It must be concluded that the warning about safety is hypothetical and not based on scientiﬁc evidence or actual data involving oral product use.

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The safety and efﬁcacy of Citrus aurantium for weight loss were also reviewed by Bent et al. [4]. These authors identiﬁed 157 titles of articles referring to C. aurantium, of which 7 were randomized controlled trials; 6 studies were excluded because the products also contained ephedrine. Only one study satisﬁed all of the inclusion criteria and was a 6-week, randomized, placebocontrolled trial reported by Colker et al. [9]. This study is described in greater detail under the Clinical Studies section. Although a small but signiﬁcant weight loss was reported by Colker et al., Bent et al. [4] concluded that a systematic review failed to produce evidence that C. aurantium was effective for weight loss. These authors also concluded that safety information is extremely limited, but, because C. aurantium contains synephrine, use of the herb may pose risks of adverse cardiovascular events, although no evidence to support this contention was presented.

ANIMAL STUDIES Relatively few studies have been conducted concerning the efﬁcacy and safety of Citrus aurantium extracts in animals. One of the most widely cited studies is the work of Calapai et al. [6], who examined the effects of repeatedly administering orally 2.5 to 20 mg/kg of two C. aurantium fruit extracts that had been standardized to 4 and 6% synephrine. These investigators examined the effects of these extracts on food intake, body weight gain, arterial blood pressure, electrocardiogram (ECG), and mortality in male rats. Animals were treated for 7 consecutive days, and the various measurements were recorded for 15 consecutive days. Signiﬁcant dose-dependent decreases in food intake as well as body weight were observed. No signiﬁcant changes were observed in blood pressure, but ECG alterations were signiﬁcant after 10 days of treatment. Some deaths were noted in the treated animals, although the difference was not statistically signiﬁcant. Several questions exist with respect to the study of Calapai et al. [6]. Parra et al. [23] have examined the LD50 of various plant extracts including Citrus aurantium in mice. Of interest was the observation that their calculated LD50 for a C. aurantium extract was approximately 477 mg/kg in mice as compared to a maximum of 140 mg/kg in rats in the study of Calapai et al. [6]. The reason for the large disparity in the apparent toxicity is unclear. Differences in the methods of preparing the respective extracts may have contributed to the discrepancies. The concentration of synephrine was not reported by Parra et al. [23]. One would not expect to see large differences in response between mice and rats with respect to this extract. In an earlier study, Huang et al. [18] investigated the effects of a Citrus aurantium extract on portal hypertensive rats. In vitro contractile studies as well as hemodynamic effects were performed after partial portal vein ligation. The C. aurantium extract was infused into the femoral vein. Synephrine at up to 0.38 mg/kg/min was similarly infused. The results demonstrated a dose-dependent decrease in portal venous pressure and heart rate with a dose-dependent increase in mean arterial pressure. Most notable is the fact that the extract and synephrine were administered intravenously as opposed to orally. As a consequence, it is difﬁcult to meaningfully extrapolate the data obtained to the typical situation where C. aurantium extract is used orally in dietary supplements for appetite control and weight management. The concentrations of synephrine and related alkaloids used in dietary supplements would not be expected to achieve the blood levels produced following intravenous administration. Several other studies have examined the properties of preparations from Citrus aurantium. Carvalho-Freitas and Costa [7] demonstrated a sedative effect of an essential oil product from peel and a hydroethanolic (70% w/v) extract from leaves. No toxicological studies were conducted, and the product was not known to contain phenylethylamine alkaloids. Hosseinimehr et al. [17] demonstrated that a hydroethanolic extract of the dried peels of ripe fruit provided a radioprotective effect against gamma radiation in mice. The citrus extract was given by intraperitoneal injection at doses up to 1000 mg/kg body weight. No toxicological studies were reported, and the studies were not repeated following oral administration. The authors concluded that ﬂavonoids were responsible for the radioprotective effects. In general, few well-deﬁned and deﬁnitive studies have been conducted in animals on the safety of C. aurantium extracts as related to weight management and thermogenesis.

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CLINICAL STUDIES As is the case with animal studies, relatively few well-designed, controlled studies have been conducted with Citrus aurantium extracts to assess their efﬁcacy and safety. Most studies have been conducted using products that contain not only an extract of C. aurantium but also other ingredients, including caffeine, ephedrine, ginkgo, ginseng, and St. John’s wort. The fact that C. aurantium extract is almost invariably incorporated into products containing other potentially active ingredients makes comparative analyses exceedingly difﬁcult, if not impossible. It is also difﬁcult to gather information on the safety and efﬁcacy of C. aurantium extract alone. Because Citrus aurantium extract is generally incorporated with other ingredients, it is appropriate to conduct studies on these combinations to assess not only their efﬁcacy but also the safety of these diverse preparations. One of the earliest studies to be conducted on the effects of C. aurantium extract on body fat loss, lipid levels, and mood in overweight adult subjects was conducted by Colker et al. [9]. The product used in this study contained 975 mg C. aurantium extract (6% synephrine alkaloids), 528 mg caffeine, and 900 mg St. John’s wort on a daily basis. Twenty subjects completed the study. The subjects followed an 1800-kcal/day American Heart Association Step One diet and performed a circuit-training exercise program 3 days a week. The study reported that, after 6 weeks of the study, the treated group lost a small but signiﬁcant amount of body weight (1.4 kg) and a signiﬁcant amount of body fat (2.9%). No signiﬁcant changes in blood pressure, heart rate, electrocardiographic ﬁndings, serum chemistry, or urinalysis were noted, and no signiﬁcant changes were noted in the results of the Proﬁle of Mood States Questionnaire for fatigue or vigor. The treated group also experienced a signiﬁcant increase in basal metabolic rate as compared to the placebo rate, which experienced a signiﬁcant decrease in this indicator [9]. Several observations can be made regarding this study. St. John’s wort (Hypericum perforatum) is an antidepressant, and depression is associated with overeating and obesity; however, no change in mood was noted in the study. The amount of caffeine consumed daily in conjunction with the product (528 mg) is equivalent to approximately 4 cups of coffee, which is a well-known thermogenic agent [11]. Whether the weight loss and increase in basal metabolic rate were due to the caffeine, the Citrus aurantium extract, or a combination thereof is not clear; however, the net result is that a small but signiﬁcant loss in body weight as well as body fat was observed. The authors concluded that the combination of C. aurantium extract, caffeine, and St. John’s wort was effective and safe when used in combination with exercise and mild caloric restriction for promoting fat and body weight loss in healthy, overweight adults. It should be noted that the total daily intake of phenylethylamine-related alkaloids was approximately 58.5 mg. Kalman et al. [20] reported the results of a 14-day clinical trial using a commercial weightloss product (Xenadrine EFX™) and involving 16 overweight or obese healthy subjects in combination with exercise. The product contained a proprietary blend of extracts from Citrus aurantium, yerba maté, grapeseed, green tea, and ginger root in conjunction with several vitamins and amino acids. The amount of phenylethylamine alkaloids from various sources was not reported nor was the amount of caffeine and other methylxanthines. Over the 14 days of the study, no signiﬁcant effects of the product were noted as compared to the placebo group with respect to blood pressure, heart rate, electrocardiographic data, fasting blood glucose, renal function, hepatic function, or complete blood count with differentials. Sleep quality was negatively impacted in the treated group, but this same group experienced a signiﬁcant reduction in fatigue levels. The treated group experienced a reduction in diastolic blood pressure as compared to the placebo group (–8.0 vs. ±4.2 mmHg). No serious adverse events were reported. Minor effects including headache, sleep disturbance, dry mouth, and “spotting” were reported among participants of the treated group, while headache, nervousness, and increased sweating were reported by participants of the placebo group. The authors concluded that the product was safe over the course of the study. It should be noted that no weight loss was observed. The study suffers from its short duration and small number of subjects. Furthermore, the fact that no weight loss was observed over the 14 days of the study may

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be surprising to some individuals but an expected outcome among others [20]. Furthermore, based on the proprietary nature of the product, it is not possible to make meaningful comparisons with other studies and other products. Zenk et al. [32] conducted a randomized double-blind study to evaluate the effect of a proprietary weight management product (Lean Source™) on body composition of overweight men and women. Of the 65 adults enrolled, 54 completed the 8-week study. In addition to Citrus aurantium, the product contained extracts of guarana and green tea in conjunction with 7-oxo-dehydroandrostenedione (DHEA), conjugated linoleic acid, and chromium picolinate. The daily consumption of C. aurantium extract was 200 mg. At the completion of the study, the treated group lost an average of 2.9 kg body weight compared to a 1.5-kg body weight loss by the placebo group. The weight loss experienced by the treated group was not large considering the time frame involved and the fact that the subjects were overweight. No signiﬁcant differences were noted between the treatment group and the placebo group with respect to systolic and diastolic blood pressures, heart rate, or temperature. Furthermore, no signiﬁcant differences were observed in chemistry proﬁles and complete blood counts between the two groups. There was also no difference in the reported incidence of adverse events between the two groups, and no serious adverse events were reported. Constipation and back pain were the most prominent adverse events reported among the treated group, and nausea, headache, and peripheral neuropathy were reported by individuals on the placebo [32]. Several conclusions can be drawn. The complex product appeared to be safe when taken as directed. Weight loss was minimal on the product. As with other studies involving complex products, it is impossible to determine the contribution of C. aurantium to the weight loss that was reported, and the net effect may well be due to the combination of ingredients. A study by Zenk et al. [33] involved the use of another commercial weight-loss product (Lean System 7™) and assessed various parameters. The study was a randomized, double-blind placebocontrolled study involving 47 healthy, overweight adults. A total of 35 subjects completed the 8-week study. Each adult received three capsules of the weight-loss product twice daily or an identical placebo in conjunction with a calorie-restricted diet and an exercise program. The commercial product contained 6 mg synephrine per capsule (36 mg/day). The product also contained 3-acetyl-7-oxo-dehydroepiandrosterone (17 mg), Coleus forskohlli extract (50 mg extract, 10 mg forskolin), yerba maté (167 mg), guarana extract (233 mg extract, 51 mg caffeine), piperine (1.67 mg from Piper nigrum), and dandelion leaf and root powder (83 mg). The most signiﬁcant ﬁnding of the study was a 7.2% increase in resting metabolic rate in the treated subjects; however, no signiﬁcant differences were noted between the treated and the placebo-controlled groups with respect to body weight, body fat, or lean tissue [33]. No changes in heart rate or blood pressure were observed, and no serious adverse events were reported. In general, the product was well tolerated over the 8 weeks of the study, but no weight was lost. Seifert et al. [27] conducted a study on the effects of a product containing Citrus aurantium that evaluated the effects of an herbal blend on energy expenditure in mildly obese subjects. The study involved 14 females and 9 males in a placebo-controlled, crossover design. Subjects ingested three treatment capsules on day one, and one more capsule on the morning of the second day. Data were collected 60 min after the last administration of the product. The results demonstrated that from pre-test on day one to post-test on day two, caloric expenditure increased by 8% following ingestion of the product. Oxygen uptake increased from 230 to 250 mL/min following treatment. No differences were observed following treatment with regard to heart rate or blood pressure. The study suffers from a lack of adequate information regarding the amount of phenylethylamine alkaloids ingested, as well as the kinds and amounts of other herbal products present in the product. Furthermore, the study was an acute study and did not provide information on long-term usage, as is characteristic of weight-loss and weight-management products. The thermic effects of food in conjunction with the phenylethylamine alkaloids extracted from Citrus aurantium were investigated in healthy, weight-stable male and female subjects [13]. The thermic effect of food from a 1.7-MJ, 30-g protein meal was determined intermittently for 300 min

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by indirect calorimetry. The C. aurantium extract was provided in capsule form. Five capsules provided 26 mg synephrine and 4 mg or less each of octopamine, N-methyltyramine, tyramine, and hordenine. The thermic effect of food was determined on an initial 30 subjects. A subset of 11 men and 11 women was studied a second time after ingestion of the C. aurantium extract in conjunction with the protein meal, and a subset of 12 women and 8 men was studied a third time following ingestion of capsules containing C. aurantium alone. The study clearly demonstrated that the thermic effect of food was 20% lower in women than men following a meal. When the C. aurantium extract was used in conjunction with the protein meal, an increase in the thermic effect on food was seen only in women, increasing by 29%. In men, the addition of the C. aurantium extract did not signiﬁcantly affect the thermic effect of food, and under these conditions the values did not differ between men and women. A signiﬁcant increase in the respiratory quotient occurred in both sexes in response to the C. aurantium extract alone. Following exposure to the C. aurantium extract, no signiﬁcant changes occurred in pulse rates or systolic and diastolic blood pressures when compared with baseline values. The results of this acute study do not provide information regarding long-term usage as related to safety or efﬁcacy in terms of weight loss; however, the study does indicate a thermogenic effect of a C. aurantium extract in women. The study also demonstrates an increase in resting energy expenditure in both sexes. The signiﬁcance of an increase in urinary epinephrine excretion remains to be determined.

CASE REPORTS Several case reports have been presented in the literature regarding the possible involvement of Citrus aurantium-containing weight-management products with cardiovascular incidents. From these reports, it is difﬁcult to determine whether the occurrence of the event was coincidental with the use of a C. aurantium-containing product or whether there was a causal relationship. The ﬁnger is pointed at C. aurantium in these reports, when in fact all of the products involved were multicomponent, and it is difﬁcult if not impossible to determine the cause of the cardiovascular incident. Furthermore, in most cases, many other compounding factors were involved; therefore, although these case reports should raise the level of consciousness and awareness with regard to the use of complex weight-management products containing extracts of C. aurantium, it is not possible to extrapolate the cause of these cardiovascular effects to the synephrine that may have been present in the products. These case reports are presented below. Nykamp et al. [22] reported what they believed to be a possible incidence of myocardial infarction associated with the use of a Citrus aurantium-containing dietary supplement in a patient with undetected coronary vascular disease. The product in question contained 200 mg of a C. aurantium extract (alkaloidal content unknown), an herbal diuretic complex, extracts of guarana and green tea, 250 mg carnitine, 400 µg chromium, and 300 mg of an extract containing hydroxycitric acid. The authors concluded that the use of Citrus aurantium-containing supplements may pose a risk for cardiovascular toxicity and concluded that the C. aurantium “is probably associated with this cardiovascular event.” It is truly difﬁcult to determine how this conclusion could be reached in light of the numerous confounding factors present, including preexisting heart disease (undetected), a 37-year history of smoking one and a half packs of cigarettes per day, overweight, probable monosodium glutamate ingestion before the onset of symptoms, and high caffeine intake. Furthermore, the product in question contained a relatively low amount of C. aurantium extract (200 mg), and, if one assumes the synephrine content was as high as 6%, then the daily ingestion of this alkaloid would amount to only 12 mg/day. Up to 5 times this amount of total alkaloids daily have been shown to be without adverse events in healthy adults over a 6-week period of time [9]. It should be noted that the combination of all the confounding factors, including the use of this weight-management product, may have led to the myocardial infarction; however, it is not scientiﬁcally or physiologically plausible to assume that the single initiating ingredient or factor was the C. aurantium extract.

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A case of ischemic stroke associated with the use of a dietary supplement containing synephrine has been reported by Bouchard et al. [5]. According to the manufacturer, each capsule contained 6 mg synephrine and 200 mg caffeine alkaloids (kola nut extract). The patient reported having taken one or two capsules per day of the product for one week. The individual presented to the emergency room with recent onset of unsteady gate, dizziness, memory loss, and difﬁculty in concentrating. He had no family history of arterosclerotic disease. The subject was mildly obese with a moderate history of cigarette smoking. The authors concluded that the diagnosis could be consistent with stroke of vascular origin based primarily on the patient’s symptoms and the coincident ingestion of the synephrine and caffeine-containing weight loss product; however, this conclusion was not supported by laboratory analyses. A magnetic resonance angiography of cervical arteries showed normal course and caliber of all vessels. Transthoracic and transesophageal echocardiography and carotid artery Doppler ultrasonography demonstrated no abnormalities. Furthermore, erythrocyte sedimentation rate, hemoglobin A1c levels, serum lipid proﬁles, serum homocysteine, thrombin time and ﬁbrinogen, protein C, protein S, factor II, factor VIII, and factor V were all normal. In addition, no commonly abused drugs were detected in the urine [5]. As a consequence, it is difﬁcult to conclude that the symptoms were related to the synephrine ingestion at a level of not more than 12 mg/day. The authors did not consider the possibility that the symptoms might have been related to the ingestion of the kola nut extract or a combination of ingredients. Furthermore, the subject may have been taking a much higher dose of the product than reported. A case report involving Xenadrine EFX™ was presented by Nasir et al. [21]. Exercise-induced syncope occurred in a healthy 22-year-old woman an hour after taking a dose of the weightmanagement product. Electrocardiography indicated a prolongation of the QT interval, which resolved within 24 hours. Results of an exercise stress test and an echocardiography were normal, and a 9-month follow-up revealed no arrhythmias. The syncope was most probably due to multiple factors. The individual had not run for over a month prior to the incident. She also had not used the product regularly for the past month; she had taken one dose the previous evening and had taken one tablet approximately 45 minutes before running three miles. She had not eaten that day prior to the run. As a consequence, the combination of consuming a product with neuroactive ingredients, the failure to have eaten prior to running, the lack of regular exercise, the distance run, and the consumption of the weight-management product a short time before running may have all contributed to the observed outcome. The discussion by the authors is confusing in that they point to C. aurantium as the hemodynamically most active component; however, the product was reported to contain only 3 mg of synephrine in addition to caffeine and other ingredients. The authors presumed that the synephrine present was the metahydroxy isomer, when, in reality, the parahydroxy isomer was present, which has little cardiovascular activity. Other ingredients in the product, including L-tyrosine, caffeine, tyramine, and other methylxanthines, may have been contributing factors. This case report should not be used as support for removing a product containing C. aurantium extract from the market, but rather should be a case study in how multiple factors can inﬂuence a physiological response and the inappropriate use of a product.

OTHER SAFETY CONSIDERATIONS The cardiovascular effects of Seville (sour) orange juice in normotensive adults was determined by Penzak et al. [25]. The study was conducted because extracts of this orange (Citrus aurantium) contain phenylethylamines. Synephrine concentrations were approximately 57 µg/mL, and octopamine was not detected. Twelve subjects consumed 8 ounces of orange juice and water in a crossover design followed by repeat ingestion 8 hours later. Hemodynamic parameters, including heart rate and blood pressure, did not signiﬁcantly differ between control and treated groups. The authors, however, concluded that individuals with tachyarrhythmias, severe hypertension, and narrow-angle glaucoma, as well as monoamine oxidase inhibitor receptors, should avoid Seville orange juice.

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Haller et al. [15] examined the cardiovascular changes associated with a single oral dose of a Citrus aurantium-containing extract (46.9 mg synephrine) as compared to a multiple-component dietary supplement (Xenadrine EFX™), which contained 5.5 mg synephrine, caffeine, and other ingredients. The protocol consisted of a randomized, double-blind, placebo-controlled crossover study with a one-week wash-out between treatments. The results demonstrated that the dietary supplement but not the synephrine-containing C. aurantium extract increased both systolic and diastolic blood pressures at 2 hr post-treatment. Heart rate increased at 6 hr by 16.7 beats/minute for the dietary supplement and by 11.4 beats/minute for the C. aurantium extract. The authors concluded that the pressure effects were not likely caused by the C. aurantium alone, as no blood pressure effect was observed with an 8-fold higher dose of synephrine. The authors also concluded that the increase in blood pressure may be attributable to caffeine and other stimulants in the dietary supplement. Several other possible explanations exist. The pressor effects could be due to a combination of multiple ingredients exerting an adrenergic effect. Furthermore, based on the study of Allison et al. [1], differences in isomers of synephrine between the two products might at least in part account for the differences in effects on blood pressure. According to a personal communication from the manufacturer of the C. aurantium extract containing 46.9 mg synephrine (Advantra Z™; Nutratech, Wayne, NJ), the synephrine present in the product is the para isomer, which is believed to exert its primary effects on β3-adrenergic receptors, which are predominantly responsible for lipolysis and the removal and oxidation of fat from adipose tissues. The C. aurantium extract associated with the dietary supplement might contain the meta isomer of synephrine (phenylephrine, neosynephrine), which is known to act on β1 and β2 receptors and therefore exert cardiovascular effects. Whether the amount of synephrine (5.5 mg) in this product is sufﬁcient to exert a cardiovascular effect by itself is not clear, but it may contribute in combination with caffeine and other stimulants in the product. The historical and traditional use of extracts of Citrus aurantium in Chinese medicine as well as the fact that literally millions of doses of products containing C. aurantium have been administered in this country during the past several years without the widespread report of serious incidence must be taken into consideration and should aid in putting the safety issue into context. Several minor side effects including nausea, headache, jitters, and dizziness have been reported; however, none of these events is considered serious, and these are common complaints and observations associated with numerous and common over-the-counter drugs as well as with placebos. A major contributor to the concerns regarding the safety of Citrus aurantium extracts has been the federal government. The Food and Drug Administration (FDA) anonymously supplied information to a leading newspaper indicating that 85 adverse reactions and 7 deaths had been associated with C. aurantium. Subsequently, the purported number of adverse events increased to 169 [28]. A dissection of the FDA information on which the reports were based clearly indicated that no credible adverse events could be attributed directly to C. aurantium extracts. Unfortunately, this reality has not prevented scientiﬁcally inastute and politically misguided individuals and newspapers from parroting information clearly known to be untrue and from making statements regarding C. aurantium that are clearly not based on the facts at hand. Are there issues with Citrus aurantium extracts? The answer is clearly yes. Standardization is most assuredly an issue. Furthermore, clear and decisive data regarding the efﬁcacy of Citrus aurantium extracts with respect to weight management and weight loss are currently insufﬁcient and clearly needed. Finally, as with anything we ingest, C. aurantium can be used inappropriately and misused, and its use may be contraindicated for some individuals due to existing sensitivities or physiological conditions. Comparing the current evidence regarding adverse events for Citrus aurantium with widely and commonly used over-the-counter drugs as well as prescription drugs and many food substances, C. aurantium appears to be amazingly safe. We tend to forget the high incidence of adverse events and deaths associated with such common household products as ibuprofen, acetaminophen, aspirin, and other nonsteroidal anti-inﬂammatory agents, not to mention the anti-inﬂammatory agents that have been removed from the market for causing presumably thousands of deaths.

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We also tend to ignore the very high incidence of adverse events among the prescription drugs used for weight management; for example, the drug orlistat (XENICAL®; Roche, Basel, Germany), which is used for weight reduction, has a very high incidence of adverse events. Among users of this drug, one ﬁfth report abdominal pain and/or ﬂatus with discharge, and as many as 15% of patients report nausea and fecal incontinence (Physicians Desk Reference, 2005). One can spend much time arguing risk–beneﬁt ratios and risk management; however, to date, with literally millions of consumers having used Citrus aurantium products and large numbers of anecdotal reports of successful weight management without adverse events, the science does not support the politics regarding C. aurantium. The widespread advice by federal agents, politicians, newspapers, and some experts to avoid Citrus aurantium-containing weight-loss products does not appear to be based on sound science. The assumption that these products may have adverse effects on hemodynamic systems and may cause interactions with many drugs has not been supported by current evidence and usage. For example, the study of Gurley et al. [14] concluded that supplements containing C. aurantium extracts did not appear to signiﬁcantly modulate cytochrome P450 enzyme activities in human subjects, and therefore posed minimal risk for cytochrome P450-mediated herb–drug interactions.

SUMMARY AND CONCLUSIONS It is clear that additional research is necessary in terms of both the safety and efﬁcacy of Citrus aurantium extract. Studies involving the use of standardized products with and without other commonly added ingredients such as caffeine need to be conducted in both animal and human studies based on oral administration. Current confusion regarding the safety and efﬁcacy is clouded by multiple issues, including the lack of standardization of C. aurantium extract with respect to alkaloidal constituents, the isomeric forms of synephrine present, political agendas, and the use of complex mixtures of ingredients, including C. aurantium extract. Furthermore, many of the projected warnings regarding cardiovascular risks are extrapolated from studies involving intravenously administered extracts and synephrine. Based on the current data presented above, what conclusions can be drawn regarding synephrine-containing extracts of Citrus aurantium? It is difﬁcult to predict the number of doses of products containing C. aurantium extract that have been consumed over the past few years. It is equally difﬁcult to estimate the number of individuals who have consumed these products; however, it is clear that many millions of doses of C. aurantium-containing extract have been used, and the number of individuals consuming these products may also be in the millions. In spite of this large amount of consumption of these products, Fugh-Berman and Myers [12] acknowledged that no adverse events have been reported in conjunction with ingestion of C. aurantium-containing products orally to date. Since their review, several case studies have been reported involving cardiovascular incidents in which Citrus aurantium was present as a component of complex products. Interestingly, in each of these cases, the amount of synephrine ingested was very low relative to amounts used in clinical trials involving healthy but obese subjects. In each of these case reports, a variety of other confounding factors were involved, in addition to the fact that the products in question contained multiple ingredients and relatively low amounts of synephrine. The high levels of caffeine and other neuroactive ingredients in these products in combination with synephrine must be taken into consideration, and the mild adverse effects that have been infrequently reported are most probably due to a combination of ingredients. With respect to efﬁcacy in terms of weight loss, the clinical studies that have been conducted to date involve products with multiple ingredients, invariably containing caffeine from various sources in addition to Citrus aurantium extract. The study of Gougeon et al. [13] has demonstrated that an extract of C. aurantium can increase the resting energy expenditure in both sexes and, when used in conjunction with a protein meal, can increase the thermogenic effect of food in women. In

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contrast, however, the vast majority of studies involving products with C. aurantium extract in conjunction with other ingredients have demonstrated, at best, very modest weight loss after 6 to 8 weeks of product usage. Because caffeine is known to have a thermogenic effect, and most studies have involved products containing caffeine in addition to C. aurantium extract, any weight loss cannot be clearly assigned directly and speciﬁcally to the C. aurantium. In summary, based on currently published information, the dire consequences of using bitter orange extract predicted by some have not materialized, and, based on wide product usage, the extract appears to be exceedingly safe when used as directed and in reasonable amounts. Conversely, the efﬁcacy of Citrus aurantium-containing products has also not lived up to the expectations of many with respect to weight loss and weight management. Weight loss from C. aurantiumcontaining products has been modest at best based on a number of controlled studies. As is invariably the case, additional studies in both animals and human subjects are necessary to bring greater clarity to issues concerning both safety and efﬁcacy. Longer term studies than those reported to date are essential. Finally, the facts should be allowed to speak for themselves.

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[19] Jones, D., Citrus and ephedra, Whole Foods, 40, 2004. [20] Kalman, D.S., Rubin, S., and Schwartz, H.I., An acute clinical trial to evaluate the safety and efﬁcacy of a popular commercial weight loss supplement when used with exercise, poster presentation at the Federation of American Societies of Experimental Biology, 2003. [21] Nasir, J.M. et al., Exercise-induced syncope associated with QT prolongation and ephedra-free Xenadrine, Mayo Clin. Proc., 79, 1059, 2004. [22] Nykamp, D.L., Fackih, M.N., and Compton, A.L., Possible association of acute lateral-wall myocardial infarction and bitter orange supplement, Ann. Pharmacother., 38, 812, 2004. [23] Parra, A.L. et al., Comparative study of the assay of Artemia salina L. and the estimate of the medium lethal dose (LD50 value) in mice, to determine oral acute toxicity of plant extracts, Phytomedicine, 8, 395, 2001. [24] Pellati, F., Benvenuti, S., and Melegari, M. High-performance liquid chromatography methods for the analysis of adrenergic amines and ﬂavanones in Citrus aurantium L. var. amara, Phytochem. Anal., 15, 220, 2004. [25] Penzak, S.R. et al., Seville (sour) orange juice: synephrine content and cardiovascular effects in normotensive adults, J. Clin. Pharmacol., 41, 1059, 2001. [26] Preuss, H.G. et al., Citrus aurantium as a thermogenic, weight-reduction replacement for ephedra: an overview, J. Med., 33, 247, 2002. [27] Seifert, J.G. et al., The effects of acute Citrus aurantium ingestion of energy expenditure in mildly obese subjects, 2005 (unpublished). [28] CFSAN examines AER reporting following bitter orange miscalculation, Tan Sheet, 12(38), 11, 2004. [29] Trease, G.E., Aurantii Amari cortex, in A Textbook of Pharmacognosy, 9th ed., Balliere, Tindall & Cassell, London, 1966, p. 467. [30] USP DI®, Vol. 1, Drug Information for the Health Care Professional (electronic version), Micromedex, Inc., Englewood, CO, 2003, p. 2227. [31] Youngken, A.M., Lemon peel USP (Limonis cortex), in A Textbook of Pharmacognosy, 6th ed., McGraw-Hill, New York, 1948, p. 503. [32] Zenk, J.L. et al., A prospective, randomized, double blind study to evaluate the effect of LeanSource™ on body composition in overweight adult men and women, 2005, www.leansource.com. [33] Zenk, J.L. et al., Effect of Lean System 7 on metabolic rate and body composition, Nutrition, 21, 179, 2005.

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Linoleic Acid 29 Conjugated and Weight Control: From the Biomedical Immune Viewpoint Zwe-Ling Kong CONTENTS Introduction ....................................................................................................................................383 Chemical Properties, Sources, Pharmacology, and Safety............................................................384 Chemical Properties, Origin, and Production ........................................................................384 Pharmacology and Dosage .....................................................................................................385 Dietary Safety and Adverse Effects .......................................................................................385 Weight Control and Body Composition in Cultured Cell, Animal, and Human Studies ............386 Diseases Related to Obesity: The Role of Inﬂammation and Adipokines ............................386 Metabolic Syndrome, Adipogenesis, and Neurotrophins.......................................................386 Cell–Cell Interactions, Integrin, and Matrix Metalloproteinase ............................................387 Cell, Animal, and Human Lipid Metabolism Studies............................................................387 Mechanism of CLA Effects: Differentiation, Organelles, Gene Expression, Putative Receptors, and Immune Response...................................................................................388 Adipocyte and Preadipocyte Differentiation and Activation .................................................388 Organelle Functions: Mitochondria and Endoplasmic Reticulum.........................................389 Gene Expression, PPARs, Signal Transduction, and Adipokines..........................................389 Estrogen and Retinoic Acid Receptors...................................................................................390 Inﬂammation and Oxidative Stress ........................................................................................391 Conclusion......................................................................................................................................393 References ......................................................................................................................................393

INTRODUCTION Obesity is an important medical problem worldwide. It is associated with a number of acute and chronic medical complications, including cardiovascular disease, diabetes, arthritis, depression, and respiratory and gastrointestinal problems. Traditional weight-loss treatments, usually involving a reduction of fat intake, have generally had very limited success. In this chapter, we report on recent study results and review updated knowledge on adipocytes with regard to conjugated linoleic acid (CLA) effects, focusing on gene expression, cytokines, and adipokines in various models, including cultured cell, rodent, and human studies. In 1987, Ha et al. [1] found that CLA present in fried ground beef reduced tumor incidence in mice. CLA has attracted much attention over the past several years for the role it might play in the obesity issue. Earlier research has indicated that the intake of CLA might

383

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Dietary lipids (mainly triglycerides)

Hydrolysis

Glycerol

Propionic acid

Free fatty acids

Saturated fatty acid

C18:0

Rumen

C18:3

cis-9C18:0

Unsaturated fatty acids C18:2

Isomerization

Isomerization

cis-9,trans-11,cis-15 CLA cis-9,trans-11 CLA

Hydrogenation trans-11,cis-15 CLA Hydrogenation

Hydrogenation

n

tio

dr

trans-11C18:1

Hy

a en og

1

2 Intestine

C18:0

Tissues

C18:0

trans-11C18:1

trans-11C18:1

Desaturation

cis-9,trans-11 CLA

cis-9,trans-11 CLA

∆9-desaturase

Milk and meat

FIGURE 29.1 Biosynthesis of CLA during its incorporation in meat and milk ruminants. (Adapted from Tanaka, K., Anim. Sci. J., 76, 291–303, 2005. With permission.)

reduce adiposity, providing antioxidant protection for the treatment of diabetes and cardiovascular disease in humans, among other potentially important beneﬁcial effects. CLA-enriched diets have been found to result in a rapid and marked decrease in fat stores in several species, including pig, rat, hamster, chicken, and mouse [2–6], suggesting that CLA might be useful as a weight-loss agent. Unfortunately, however, data regarding the use of CLA supplementation in human subjects have shown marked variations in reports on the health-related outcomes. Additionally, adverse side effects have been recently reported in mice fed a commercial CLA mixture. Thus, the relationship between CLA taken as supplements and the treatment of obesity could be more complex than initially thought.

CHEMICAL PROPERTIES, SOURCES, PHARMACOLOGY, AND SAFETY CHEMICAL PROPERTIES, ORIGIN,

AND

PRODUCTION

The CLA family consists of several different conjugated forms, and many have been identiﬁed [7–9]. Natural forms of CLA can be found predominantly in ruminant products [10,11]. The most common type, cis-9/trans-11 (c9t11)-CLA (also known as rumenic acid [15–19]), is present in milk fat, and CLA isomers can also be found in hydrogenated vegetable oils (see Figure 29.1). Because the CLA content of dairy products is related to the fat content, CLA levels are greater in higher fat than in lower fat products. The two predominant isomers found in foods and commercial preparations are c9t11CLA and t10c12-CLA. Commercial dietary supplements contain the c9t11-CLA and t10c12-CLA isomers in approximately equal amounts. Measurements of c9t11-CLA in human adipose tissue have found that its presence is highly correlated with milk fat intake [20–24]. Anaerobic ruminant bacteria, such as Butyrivibrio ﬁbrisolvens [25], produce predominantly c9t11-CLA through biohydrogenation

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of linoleic acid (LA) and α-linoleic acid obtained from plant material, and pathway of linoleic acid by cis-9,trans-11-octadecadienoate reductase [26]. CLAs found in fried ground beef are heat-altered derivatives of linoleic acid [1]. In the formation of CLA, a hypothetical mechanism is that oxygenderived free radicals might induce a double bond of linoleic acid to shift [27]. In addition to dietary sources, some CLA can be produced endogenously by humans [28]. Several methods are currently available to chemically synthesize CLA [29,30], which is either absorbed or further metabolized to vaccenic acid (trans-11-octadecenoic acid), a predominant transfatty acid in milk fat that can be converted to c9t11-CLA by the enzyme ∆9 stearoyl-CoA desaturase, an alternative route in mammals, including humans [31,32]. Blood levels of CLA in humans may reﬂect both dietary intake of CLA and endogenous synthesis from trans-vaccenic acid. Interestingly, in diabetes, the glycation and subsequent glycoxidation reactions are enhanced by elevated glucose concentrations. Ratios of CLA to linoleic acid are signiﬁcantly increased in diabetic erythrocytes compared with control erythrocytes. This indicates that glycation via chronic hyperglycemia links lipid peroxidation in the erythrocytes of both diabetic and healthy subjects [27]. The conjugated trienoic fatty acids produced from α- and γ-linolenic acid were further saturated by Lactobacillus plantarum to trans-10,cis-15-18:2 and cis-6,trans-10-18:2 [35]. Recently, puriﬁed CLA isomers have become commercially available and are expected to facilitate clariﬁcation of the dietary function paradox and the physiological activity of each isomer.

PHARMACOLOGY

AND

DOSAGE

In vitro and experimental animal studies found a number of potential health beneﬁts for CLA. CLA inhibits the proliferation of some cancer cells such as mammary, colorectal, prostate, and forestomach cancers [36]. Most studies have used synthetic mixtures of CLA at doses from 10 to 25 µM. In human serum, CLA has been reported to be around 7.1 µM. One report indicates that a potent cytotoxic effect on cancer cell line can be exerted at physiological concentration [37,38]. In a study of body composition, the intake of CLA reduced body fat and increased lean body mass in several species of growing animals [39], and it improved glucose utilization and reversed symptoms of diabetes in laboratory animals. CLA may lower total and low-density lipoprotein (LDL) cholesterol, as well as triglyceride levels, and it has been shown to reduce the severity of atherosclerosis in experimental animals [40]. Recent reports also suggest that each CLA isomer has different functions; for example, t10c12-CLA has signiﬁcant anticarcinogenic, anti-obese, and antidiabetic effects, whereas c9t11-CLA seem to exert an anticancer effect. In addition, CLA enhances select immune responses in experimental animals and increases the rate of bone formation by inﬂuencing factors that regulate bone metabolism. Physiological difference between free and triglyceride-type CLA on the immune function of C57BL/6N mice has also been investigated [41]. The typical dosage of CLA ranges from 3 to 5 g daily as a dietary supplement. CLA was found to induce leptinemia and adiponectinemia, followed by hyperinsulinemia, in C57BL/6J female mice fed a 1% isomeric mixture of CLA for various periods of time ranging from 2 to 28 days. Only a few reports have been published and evidence is weak with regard to the anticancer and anti-obese effects of CLA in humans study; therefore, more detailed evaluations (especially double-blind, placebo-controlled studies using pure CLA isomers) of the physiological bioactivities of CLA and how they affect lifestyle- and agerelated diseases in humans and animals would be of great interest in future studies.

DIETARY SAFETY

AND

ADVERSE EFFECTS

The t10c12-CLA isomer has an anti-obese effect that is especially dramatic in the mouse; however, it is noteworthy that a signiﬁcant impairment of insulin sensitivity has been reported in overweight subjects receiving the puriﬁed t10c12-CLA isomer, among whom the isomer is associated with severe hyperinsulinemia, insulin resistance, and massive liver steatosis (referred to as the CLAmediated lipoatrophic syndrome) [42,43]. This ﬁnding questions the safety of dietary supplements

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containing CLA. In general, the usual doses of CLA used in animal studies greatly exceed those used in human studies, which explains why animal studies produce better results than human studies and may also explain the adverse effects of CLA in rats. Collectively, evidence for a putative beneﬁcial effect of CLA supplementation in humans is still inconclusive; perhaps the safety of dietary supplements containing CLA requires more consideration, and additional isomer-speciﬁc clinical trials are clearly necessary.

WEIGHT CONTROL AND BODY COMPOSITION IN CULTURED CELL, ANIMAL, AND HUMAN STUDIES DISEASES RELATED

TO

OBESITY: THE ROLE

OF INFLAMMATION AND

ADIPOKINES

Despite the enormous medical implications of obesity, effective prevention and treatment strategies are still lacking. It is important to distinguish the term obesity, used to describe excess body fat, from other forms of overweight. Obesity results from the hypertrophy and hyperplasia of adipocytes within the organism and is generally thought to be the result of both genetic and environmental inﬂuences. Being overweight or obese has become highly prevalent in Western countries, and the obese population is growing rapidly in the developing world [44]. Obesity-related disorders, such as insulin resistance, hypertension, and diabetes, are also dramatically increasing. Obesity is associated with endothelial dysfunction and arterial stiffness from as early as the ﬁrst decade of life [45]; this is probably mediated in part by low-grade inﬂammation associated with cytokine-like molecules called adipokines. White adipose tissue is a major endocrine/secretory organ that releases a wide range of adipokines. A number of adipokines (e.g., IL-1β, IL-6, MCP-1, MIF, TNFα, leptin, adiponectin, NGF, VEGF, PAI-1) are somehow linked to the inﬂammatory response. Recent research indicates that adipose-tissue-derived factors inﬂuence metabolic and cardiovascular disease. Leptin is now considered to play a key role in obese, hypertensive patients, and decreased secretion of adiponectin appears to be an important predictor of diabetes [46,47]. A high leptin concentration, in particular, is found in obese individuals and is strongly associated with vascular changes related to early atherosclerosis [48,49].

METABOLIC SYNDROME, ADIPOGENESIS,

AND

NEUROTROPHINS

Obese adipose tissue originates from a long-term process of adipogenesis; it is characterized by inﬂammation and the progressive inﬁltration by macrophages as obesity develops [50], both of which point to a link between metabolic and signaling pathways and metabolic disease and immune response that result in diabetes [51]. The elevated production of inﬂammation-related adipokines is considered to be important in the development of diseases linked to obesity, particularly the metabolic syndrome. [52]. Metabolic syndrome, which encompasses diabetes, hypertension, dyslipidemia, coronary artery disease, and obesity, is also known as syndrome X or the insulin resistance syndrome [53–56]. The global epidemic of obesity and diabetes has led to a marked increase in the number of persons with metabolic syndrome. Type 2 diabetes and metabolic syndrome share common features and patients. An increasing number of researchers of the metabolic syndrome assume that many mechanisms are involved in the complex pathophysiology of neurotrophins, such as disorders of the hypothalamic–pituitary–adrenal axis, increased sympathetic activity, chronic subclinical infections, the presence of proinﬂammatory cytokines, the actions of adipocytokines, and psycho-emotional stress [57]. Research in this ﬁeld conﬁrms the role of the neurotrophins and mastocytes in the pathogenesis of inﬂammatory and immune diseases [58]. Ciliary neurotrophic factor, another neurocytokine expressed by glial cells in the nervous system, is generally recognized for its function in survival of non-neuronal and neuronal cell types. It was recently acknowledged for its potential role in the control of obesity [59].

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Triglyceride concentration (mmol/L)

3 c9t11-CLA t10c12-CLA a

2

a a

ab

a

ab c c

1

0 p

M

10

15 20 25 RA TZD Sample (µg/L)

FIGURE 29.2 Effects of c9t11- and t10c12-CLA on triglyceride accumulation in differentiated 3T3-L1 cells. Abbreviations: p, preadipocyte; M, MDI; RA, retinoic acid (5 µM); TZD, thiazolidine (10 µM).

CELL–CELL INTERACTIONS, INTEGRIN,

AND

MATRIX METALLOPROTEINASE

In obesity, changes in fat pad size lead to physical changes in the surrounding area and modiﬁcations of the paracrine function of the adipocyte; for example, adipocytes begin to secrete tumor necrosis factor α (TNFα), which will stimulate preadipocytes to produce monocyte chemoattractant [60–64] and contribute to progressive inﬂammation. The processes of adipogenesis include the migration, adhesion, proliferation, and differentiation of preadipocytes into mature adipocytes. Many of these biological functions are related to cell integrins, such as the triglyceride content and gene expression of peroxisome proliferator-activated receptor γ (PPARγ). Leptin levels have been shown to decrease in response to treatment with disintegrin [65], and an in vivo model found that partial inhibition of gelatinolytic activity is associated with moderate effects on adipose tissue development. Matrix metalloproteinase (MMP) inhibitor decreases adipose conversion of 3T3-L1, and enhancement of MMP expression counteracts the inhibitor in adipose tissue [66]. These ﬁndings suggest a role for the MMP system in the control of proteolytic processes and adipogenesis during obesity-mediated fat mass development [67].

CELL, ANIMAL,

AND

HUMAN LIPID METABOLISM STUDIES

Potential anti-obesity mechanisms of CLA include decreased preadipocyte proliferation and differentiation into mature adipocytes, reduced fatty acid and triglyceride accumulation, and increased energy expenditure, lipolysis, and fatty acid oxidation. CLA intake has consistently been demonstrated to decrease body fat accumulation and increase lean body mass in several experimental animals, including mice, rats, hamsters, and pigs; however, the effect of CLA on overall body weight appears to be variable [68,69]. CLA was shown to accumulate in the white adipose tissue much more than in the serum or liver, and levels of triglycerides in the white adipose tissue and serum nonesteriﬁed fatty acid were reduced in a CLA dose-dependent manner [70]. In animal studies, the most dramatic and desirable effects of CLA on body composition are ascribed to the t10c12 isomer rather than the c9t11 isomer. Recent ﬁndings in mice and hamsters indicate that the t10c12-CLA isomer is largely responsible for the effect of CLA on body composition and adipocyte morphology, as well as for many of the effects of CLA seen in diabetes and obesity [71,72]. As shown in Figure 29.2, we conﬁrmed these earlier ﬁndings and found that t10c12-CLA prevents

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triglyceride accumulation. The t10c12-CLA isomer has been reported to inhibit heparin-releasable lipoprotein lipase activity and leptin secretion from 3T3-L1 adipocytes and to suppress delta 9desaturase activity [73]. Although many mechanisms are presumably involved, how CLA alters body composition is still unclear and remains to be determined. Little direct evidence is available with regard to the effect of CLA on body composition in humans. Recent reports surprisingly suggest that supplementation with the t10c12-CLA isomer or with c9t11-isomer-enriched foods may not contribute to the expected beneﬁcial changes in the risk variables associated with the metabolic syndrome. Because the effects of CLA on adiposity and lipid metabolism are dependent on its isomer speciﬁcity, data on CLA supplementation in humans are conﬂicting because these studies have used different mixtures and dosages of CLA isomers and diverse subject populations [74]. Many published studies in human subjects have reported that CLA does not affect body weight, body composition, or adipose tissue mass [75]; for example, a randomized crossover study on plasma lipoproteins and body composition in men found that CLAenriched butter induced no signiﬁcant change in the cardiovascular disease risk proﬁle and had no effect on the distribution of body fat [76]. From a fundamental viewpoint, extrapolation of CLA animal data to humans seems unrealistic, as CLA apparently has only a limited effect on the immune functions in humans; however, dietary CLA can be incorporated and metabolized as linoleic acid. In this way, it can inﬂuence linoleic acid desaturation and elongation and is beta oxidized in peroxisomes, which, via activation of PPARs, increase free retinol levels, which are linked to gene expression regulation [77]. In a study of 60 abdominally obese men with the metabolic syndrome, the subjects were randomly assigned to supplements containing either 3.4 g/day of a CLA isomer mixture or the puriﬁed t10c12- isomer. After 12 weeks of supplementation, the t10c12-isomer induced statistically signiﬁcant reductions in insulin resistance, in glycemia, and in plasma high-density lipoprotein (HDL) cholesterol concentrations compared with placebo [76]. CLA supplementation with puriﬁed t10c12-CLA isomer decreases fat mass and causes a signiﬁcant reduction in insulin sensitivity in overweight humans [78].

MECHANISM OF CLA EFFECTS: DIFFERENTIATION, ORGANELLES, GENE EXPRESSION, PUTATIVE RECEPTORS, AND IMMUNE RESPONSE ADIPOCYTE

AND

PREADIPOCYTE DIFFERENTIATION

AND

ACTIVATION

Adopogenesis is a multistage process originating in mesenchymal cells capable of forming muscle, bone, or adipose tissue. Adipose tissue plays a key role in the pathogenesis of the obesity-related metabolic syndrome. Adipocyte serves as an important source of proinﬂammatory molecules, including leptin, TNFα, and interleukin 6 (IL-6), as well as antiinﬂammatory molecules, such as adiponectin [79]. Most of these functions are carried out via adipocytokines capable of acting locally or at distant sites [80]. A recent study demonstrated that calcineurin is a critical effector of a calcium-dependent signaling pathway that acts to inhibit adipocyte differentiation [81]. Moreover, a constitutively active nuclear factor of activated T (NFAT) mutant preadipocyte inhibits their differentiation into mature adipocytes. Cells expressing NFAT lose contact-mediated growth inhibition and are protected from apoptosis following growth factor deprivation. The ﬁrst, and best characterized, model of adipogenesis in vitro is the 3T3-L1 mouse ﬁbroblast cell line [82,83]. When conﬂuent/growth-arrested 3T3-L1 cells are subjected to the adipogenic hormones — 3-isobutylmethylxanthine, a phosphodiesterase inhibitor; dexamethasone; and insulin, (collectively known as MDI) — they undergo a deﬁned genetic program of terminal differentiation, giving rise to mature, morphologically distinct adipocytes containing large cytoplasmic triglyceride depots [84]. This process is dependent on the sequential activation of transcription factors, including CCAAT/ enhancer-binding protein (C/EBP), PPAR, and sterol regulatory element-binding protein (SREBP), that results in changes in gene expression [85]. Another cell line, 3T3-F442A, requires only insulin

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at a later stage to differentiate. Also, AP-18, a new non-embryo-derived preadipocyte cell line established from an adult C3H/HeM mouse, provides a useful model for investigating adipocyte differentiation and adipogenesis [86].

ORGANELLE FUNCTIONS: MITOCHONDRIA

AND

ENDOPLASMIC RETICULUM

Increasing evidence suggests that mitochondrial dysfunction in the prediabetic/insulin-resistant state contributes to a variety of human disorders, including cardiac dysfunction, neurodegenerative diseases, obesity, insulin sensitivity, and cancer, and that they play a key role during apoptosis [87–89]. The induction of mitochondrial uncoupling proteins (UCPs) in mouse or human white adipocytes promotes fatty acid oxidation and a resistance to obesity. UCP2 and UCP3 do not mediate adaptive thermogenesis and do not seem to contribute to energy expenditure, but they may be signiﬁcantly thermogenic under speciﬁc pharmacological conditions. Both UCP2 and UCP3 are considered to be potential targets for the treatment of aging, degenerative diseases, and perhaps obesity [90,91]. PPARγ coactivator-1α (PGC-1α) plays a key role in regulating mitochondrial biogenesis and fuel homeostasis, and overexpression favors a shift from incomplete to complete beta-oxidation, thus enabling muscle mitochondria to better cope with a high lipid load [92]. These ﬁndings suggest fundamental metabolic beneﬁts of exercise training, and the upregulation of PGC-1α may be an effective strategy for preventing or reversing insulin resistance and obesity [93]. Obesity-induced endoplasmic reticulum stress has recently been demonstrated to underlie the initiation of inﬂammatory responses and generation of peripheral insulin resistance [94]. It leads to suppression of insulin receptor signaling through hyperactivation of c-Jun N-terminal kinase (JNK) and subsequent serine phosphorylation of insulin receptor substrate-1 [95]. The beneﬁcial effects exerted by low amounts of CLA raises questions about their mitochondrial oxidizability. CLA appeared to be both poorly oxidizable and capable of interfering with the oxidation of fatty acids near the beginning of the beta-oxidation cycle [96]. It was reported that CLA is more effective than vitamin A in protecting mitochondria from the peroxidative damage of 3T3-L1 cells [97]. Our research indicated that CLA induced apoptosis via the mitochondrial pathway through PPARγ signaling, reduced mitochondria transmembrane potential, increased mRNA expression of the apoptosis regulator Bax and Bcl-2, and enhanced cytochrome c release to cytoplasm and activation of caspase-3 (reversed by pan-caspase inhibitor). CLA reduced mRNA expression of cyclin D and increased mRNA expression of p53 and p21waf-1 but increased mRNA expression of GADD45. In addition, research has found that CLA inhibits the elongation and desaturation of 18:2n-6 into 20:4n-6. One might speculate that a diet enriched in CLA would be useful in preventing carcinoma [98].

GENE EXPRESSION, PPARS, SIGNAL TRANSDUCTION,

AND

ADIPOKINES

Adipocytes act not only as fuel storage depots but also as critical endocrine organs that secrete a variety of signaling molecules into the circulation. They play a central role in the maintenance of energy homeostasis by regulating insulin secretion, glucose, and lipid metabolism. These secretory factors include enzymes, growth factors, cytokines, and hormones involved in fatty acid and glucose metabolism. The PPARs are ligand-activated transcription factors; the family of PPARs is comprised of three closely related gene products — PPARα, PPARγ, and PPARδ/β — and is so named because the activation of PPARγ elicits increases in the number and size of peroxisomes. Fatty acids, eicosanoids, and some drugs are PPAR ligands. PPARα regulates fatty acid oxidation, primarily in the liver, PPARγ serves as a key regulator of adipocyte differentiation and lipid storage, and PPARδ is a positive factor for fat burning. PPARs function as important coregulators of energy homeostasis. The PPARγ-1 and PPARγ-2 isoforms are generated by alternative splicing. The PPARγ-1 isoform is expressed in liver and other tissues, and the PPARγ-2 isoform is expressed exclusively in adipose tissue, where it regulates adipogenesis and lipogenesis. Also, oxidized LDL regulates macrophage gene expression through ligand activation of PPARγ [99].

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TABLE 29.1 Inhibitory Effect of c9t11- and t10c12-CLA in Differentiated 3T3-L1 Cells Concentration (ppm)

Sample c9t11-CLA

t10c12-CLA

10 15 20 25 10 15 20 25

Inhibitory Activity (%) SREBP-1

C/EBPα a

4.14 ± 4.56 9.99 ± 2.42a 7.09 ± 3.09a 9.87 ± 1.39a 2.02 ± 2.15a 1.69 ± 6.10a 13.86 ± 2.46a 35.8 ± 3.87b

PPARγ a

6.28 ± 1.53 16.05 ± 2.42b 18.29 ± 1.94b 17.20 ± 1.38b 12.46 ± 1.38a 23.79 ± 2.20b 34.09 ± 1.19c 56.06 ± 3.19d

0.48 ± 4.28a 7.06 ± 2.09a 7.27 ± 5.67a 19.45 ± 2.99b 5.82 ± 2.58a 9.29 ± 4.27a 32.46 ± 3.88c 61.39 ± 5.02d

Note: The values with different superscript letters (a–d) represent signiﬁcant differences (p < 0.05).

When ICR and C57BL/6J mice were fed experimental diets containing CLA, the weights of white adipose tissue and interscapular brown adipose tissue in the two strains were greatly reduced [100]. It is apparent that dietary CLA brings about changes in the gene expression of proteins regulating energy metabolism in white and brown adipose tissues and the skeletal muscle of mice. The inhibition of lipid accumulation induced by t10c12-CLA treatment during adipocyte differentiation is associated with a tight regulatory process between early (PPARγ and C/EBPα) and late (LXRα, aP2, and CD36) adipogenic marker genes [101]. Furthermore, the authors have conﬁrmed the effects of c9t11 and t10c12 isomers of CLA on the expression of adipogenic genes (see Table 29.1). To study the effects of c9t11-CLA on C/EBPα mRNA expression in 3T3-L1 adipocytes, 2-day postconﬂuent 3T3-L1 was differentiated by MDI and treated with CLA. On day 8 after induction of differentiation, total RNA was extracted from 3T3-L1 cells and subjected to reverse transcription–polymerase chain reaction (RT-PCR) with primers speciﬁc for C/EBPα. The t10c12CLA isomer at concentration of 25 µg/L signiﬁcantly decreased the mRNA expression of C/EBPα, PPARγ, and SREBP-1 in a dose-dependent. manner; however, c9t11-CLA has no inhibitory function on the expression of SREBP-1. The t10c12-CLA isomer has also been found to reduce the triglyceride content of newly differentiated human adipocytes by inducing MEK/ERK signaling through the autocrine/paracrine actions of IL-6 and IL-8 [102]. CLA may impart its effects by increasing the expression of genes associated with apoptosis, fatty acid oxidation, lipolysis, and inﬂammation, in addition to decreasing stromal vascular cell differentiation and lipogenesis [72]. Serum leptin is correlated to body fat level and acts in the hypothalamus to regulate satiety [103]. Leptin, a cytokine, is the ob gene product from mature adipocytes; its expression is accelerated in the obesity state to inhibit food intake and accelerate energy expenditure. Dietary CLA produced a signiﬁcant reduction in serum leptin levels in Sprague–Dawley rats [104].

ESTROGEN

AND

RETINOIC ACID RECEPTORS

Estrogen receptor α (ER-α) plays an important role in mediating estrogen signaling and is involved in both osteoporosis and obesity [105,106]. Interestingly, obesity is positively associated with breast cancer for postmenopausal women [107]. Estradiol affects the metabolic action of insulin in a concentration-dependent manner; high concentrations of estradiol inhibit insulin signaling by modulating the phosphorylation of insulin receptor substrate 1 (IRS1) via a JNK-dependent pathway [108]. In addition, estrogens and the phytoestrogen genistein were found to regulate adipogenesis and lipogenesis in males and females [109]. CLA compounds possess potent anti-estrogenic properties that may partly account for their antitumor activity in breast cancer cells [110,111], where they induce the dephosphorylation of ER-α through stimulation of protein phosphatase 2A activity

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Cyclin D beta-actin

120 a 100 % of control

a 80 b 60 c

40

c

20 0 Control

RA

LA

c9t11 CLA

t11c12 CLA

FIGURE 29.3 Effects of 10-µM retinoic acid, 200-µM linoleic acid, c9t11-CLA, and t10c12-CLA on cyclin D mRNA expression. 3T3-L1 preadipocytes treated for 6 hr. Results are expressed as mean ± S.D. for n = 3 each group (p < 0.05).

[112]. At present, no direct evidence has been found in support of the anti-estrogenic pathway of CLA contributing to its anti-obesity functions. Retinoids modulate various biological functions, such as cell differentiation, proliferation, and embryonic development, through speciﬁc nuclear receptors — retinoic acid receptor (RAR) and retinoid X receptor (RXR); their endogenous ligands are all-trans-retinoic acid and 9-cis-retinoic acid, respectively [113–116]. It is possible that CLA induces apoptosis of 3T3-L1 preadipocytes through reduced mRNA expression of cyclin D (see Figure 29.3) and increased mRNA expression of p53, GADD45, and p21waf-1, but it does not activate RAR in a reporter gene assay.

INFLAMMATION

AND

OXIDATIVE STRESS

Metabolic and immune responses are highly integrated and interdependent. Obesity and diabetes are now ﬁrmly linked to inﬂammatory mediators. Peripheral blood mononuclear cells in obesity are in a proinﬂammatory state with an increase in intranuclear nuclear factor kappa-B (NF-κB) binding [117]. NF-κB plays a key role in inﬂammatory and immune responses [118]. TNFα and adiponectin are antagonistic in stimulating NF-κB activation. In the 3T3-L1 adipocyte model, nerve growth factor (NGF), a neurotrophin, is an important inﬂammatory response protein. NGF is secreted in white adipose tissue, and its synthesis is inﬂuenced by TNFα [119]. In response to proinﬂammatory cytokines such as TNFα, the IκB kinase is activated and further stimulates the formation of additional inﬂammatory cytokines, along with adhesion molecules that promote endothelial dysfunction and downstream modulate the metabolic syndrome. TNFα induces oxidative stress, which leads to oxidized LDL and dyslipidemia, insulin resistance, hypertension, endothelial dysfunction, and atherogenesis [120]. Oxidative stress levels are elevated in obesity and correlate with fat accumulation in humans and mice [121]. Reactive oxygen species (ROS) were found to be selectively increased; they augmented expression of NADPH oxidase, decreased expression of antioxidative enzymes, and dysregulated the production of adipocytokines, all of which are important pathogenic mechanisms of the obesity-associated metabolic syndrome [122]. Serum concentrations of C-reactive protein (CRP), TNFα, and IL-6 correlate signiﬁcantly with weight, body mass index (BMI), and visceral adipose tissue [48,49,123,124]. Leptin expression is accelerated in the obesity state; similar to other

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TNFα (ng/106 cells)

3 c9t11-CLA t10c12-CLA 2

1

0 Concentration (µg/L)

FIGURE 29.4 Production of TNFα by human monocytic THP-1 cells treated with CLA. The concentration of TNFα in the cell supernatant was measured by ELISA.

proinﬂammatory cytokines, it promotes Th1 cell differentiation and cytokine production [125]. Leukocyte populations within adipose tissue may be involved in the development of the inﬂammation that is characteristic of obesity [126]. Both the innate and acquired immune responses are affected by dietary CLA supplementation. In vitro studies of the use of immune cells and animal models have demonstrated that CLA modulates immune function and enhances IL-2 production and lymphocyte proliferation but decreases TNFα and IL-6 production [127]. The authors have conﬁrmed the effect of CLA isoforms on TNFα production in a human monocyte assay, and c9t11-CLA seems to work most effectively (Figure 29.4). A slight but signiﬁcant difference was observed between the functionalities of triglycerides and free dietary CLA on immunoglobulin modulation and the production of various cytokines [41]. A double-blind, randomized, parallel, reference-controlled intervention study on human immune function suggests that CLA may beneﬁcially affect the initiation of a speciﬁc response to hepatitis B vaccination [128]. Nitrolinoleic acid (LNO2), formed by nitric-oxide-dependent oxidative inﬂammatory reactions, is a potent endogenous ligand for PPARγ. NO-mediated cell signaling reactions can be transduced by fatty acid nitration products and PPAR-dependent gene expression [129]. The involvement of CLA in endotoxin lipopolysaccharide (LPS)-activated inﬂammatory events in macrophages (e.g., TNFα production) negatively regulates the expression of inﬂammatory mediators [130] and decreases prostaglandin E2 (PGE2) and NO synthesis by suppressing the transcription of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) [131]. CLA was found to signiﬁcantly (p < 0.05) depress rat placental growth factor (PGF) synthesis in the placenta, uterus, and liver [132]. Evidence also suggests that t10c12-CLA supplementation can lead to a marked increase in human plasma C-reactive protein (CRP), a marker of inﬂammation and oxidative stress, as compared to placebo [76]. The adipokine resistin displays potent proinﬂammatory properties by strongly upregulating IL-6 and TNFα, which were diminished by the NF-κB inhibitor [133]. The t10c12-CLA isomer performs as an antioxidant and promotes, at least in part, NF-κB activation and subsequent induction of IL-6, both of which are partly responsible for the suppression of PPARγ target gene expression and insulin sensitivity in mature human adipocytes [134]. In contrast, the c9t11-CLA isomer possesses weak antioxidant activity; in fact, at higher concentrations (200 µM), it acts as a strong pro-oxidant [135]. Take together, it is likely that CLA modulates the accumulation of arachidonic acid in phospholipids, resulting in a reduced arachidonic acid pool and reduced production of downstream PGE2 [34].

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CONCLUSION Aging and hypertrophy are associated with increased body fat and insulin resistance, and with a higher risk for cardiovascular diseases. What happens in obese tissue? Here, we propose that obese tissue may be activated via cell–cell interaction due to sustainable cell proliferation and size enlargement, which trigger progressive inﬂammation. Adipokine (e.g., resistin) secretion from adipocytes demonstrates potent proinﬂammatory properties and induces mitochondrial dysfunction as well as metabolic syndrome. Those complicated mechanisms are involved in the immune response, gene expression, and intracellular signal transduction, and CLA or its speciﬁc isoforms might somehow offer beneﬁcial biological activity in this regard. Having reviewed recent research data from in vitro and in vivo investigations, as well as human clinic studies, that have studied the functions, mechanisms, and safety of dietary CLA, we must conclude that the data are still insufﬁcient and ambiguous. Despite conﬂicting results, likely due to the large variability in protocols used, the use of CLA for weight management in humans should still be considered, under medical control. Meanwhile, the question of the safety of high-dosage dietary CLA supplements must be addressed. A commercially available functional food (CLA in soft gelatin capsules) is perhaps not the best way to accommodate consumer tastes and does not offer the best bioavailability of the active form. A better approach to this problem may be the low glycemic index diet, which considers the effect of food on blood sugar and insulin level after a meal. It may be a practical and safe approach to the prevention and treatment of obesity and its related complications.

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Role of Tea in 30 The Weight Management Chithan Kandaswami CONTENTS Introduction ....................................................................................................................................401 The Composition of Tea ................................................................................................................402 Animal Studies...............................................................................................................................403 Human Studies ...............................................................................................................................405 Conclusion......................................................................................................................................409 References ......................................................................................................................................409

INTRODUCTION Bioactive ingredients of dietary origin show a propensity to stimulate energy expenditure by inﬂuencing subtle cellular and metabolic processes linked with energy dissipation. There is immense interest in these naturally occurring substances in view of their potential application in body weight reduction. Natural ingredients have received particular attention as alternatives to conventional weight management strategies with limited long-term effectiveness. One such natural-productderived ingredient is tea, deemed to possess biological activities relevant to the treatment of obesity. The potential body-fat-suppressive effects of tea have recently drawn attention, and the perceived beneﬁts of tea intake have received increased scientiﬁc scrutiny. Dietary adjuncts, as exempliﬁed by caffeine and tea-associated constituents, exert a facile effect on metabolic rate and substrate oxidation [1,14–16,20,29,34]. Tea components exhibit thermogenic properties [15,16,63] ascribed to their interactions with the sympathoadrenal system [15,16]. The activity of the sympathetic nervous system is pivotal in driving energy metabolism and thermogenesis [5,7,13,36]. Integral to the process of diet-induced thermogenesis is the activation of the sympathetic nervous system by dietary components and the resultant metabolic and cellular processes linked with energy dissipation [7,8,36]. Energy metabolism encompasses a complex network of hormonal and neural mechanisms. The sympathoadrenal system plays a marked role in the intricate regulation of thermogenesis and fat oxidation through circulating epinephrine and sympathetically released norepinephrine [7,8,13,36]. The stimulation of the sympathetic nervous system results in increased plasma norepinephrine levels accompanied by postprandial elevation of lipid oxidation [54]. Tea components appear to have the potential to elevate endogenous levels of catecholamines [15]. This action could have a pronounced effect on energy expenditure (EE) and fat oxidation. Tea is brewed from the dried leaves and buds of the tea plant (Camellia sinensis var. sinensis and Camellia sinensis var. assamica), an evergreen shrub of the family Theaceae. The three principal types of manufactured tea are green (unfermented), oolong (partially fermented), and black (fully fermented) [3,18,38,44]. The manufacture of black tea entails oxidation due to the activation of polyphenol oxidases, which oxidize susceptible tea leaf polyphenol moieties, culminating in the

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formation of brown pigments. It is this process that develops the color and aroma of the liquor [38,39,45,46]. The term fermentation refers to the oxidative transformations undergone by tea phenolics that involve natural browning reactions induced by oxidizing enzymes (polyphenol oxidases) within the plant cell. The production of green tea involves the rolling and steaming of tender tea leaves, a process that minimizes the activation of these enzymes and consequently oxidation. Oolong tea is a partially fermented product having components common to both green and black teas. Tea has been touted as a healthful and medicinal beverage for centuries and is considered a highly desirable drink. Next to water, tea is the most popular beverage in the world; it is consumed by over two thirds of the world’s population [3,18,44] and is an integral part of the diet in many countries. A Chinese legend places the introduction of tea at about 2737 B.C. [38]. Chinese history indicates that emperor Sin-Non declared more than 3000 years ago that the daily consumption of a cup of tea could dissolve many poisons in the body [37]. Traditionally, tea consumption was undertaken to improve blood ﬂow, to eliminate toxins, and to increase resistance to diseases [3]. Tea has been a conventional drink in China used to combat obesity [54], and traditional medicine has frequently attributed the putative anti-obesity effects of herbal medicinal preparations to the inherent properties of tea. Comprehending the salutary effects of tea requires a steadily expanding area of scientiﬁc endeavor. Efforts to elucidate and evaluate the therapeutic potential of tea have been very intense during the past ten years or so, resulting in a spate of information. Key epidemiological studies have highlighted the possible association of tea intake with attenuation of the incidence of chronic disease; laboratory investigations have discerned the ability of tea to impact cellular metabolism and have provided evidence to support the beneﬁcial effects of tea [12,60]. Tea constituents exert profound effects at the cellular and subcellular levels and may subtly inﬂuence metabolic processes linked with energy dissipation. The distinctly different and diverse array of components characteristically constituting tea seems to endow it with a multitude of biological properties. Although the popularity of tea may be mainly due to its alkaloid content, the potential health-promoting effects of tea have been ascribed to the phenolic substances present in tea. Accruing evidence indicates that the pharmacological actions evoked by tea might originate from the intrinsic activities of the phenolic and methylxanthine constituents present in tea. This chapter discusses the role of tea in weight management with regard to thermogenesis and substrate oxidation. It also reviews data garnered from animal studies and clinical investigations.

THE COMPOSITION OF TEA Fresh tea leaves contain on average (related to dry substance mass): 36% polyphenolic compounds, 25% carbohydrates, 15% proteins, 6.5% lignin, 5% ash, 4% amino acids, 2% lipids, 1.5% organic acids, and 0.5% chlorophyll, as well as carotenoids and volatile substances constituting less than 0.1% [3,18,38,39]. Tea leaves contain unusually high concentrations of the polyphenols belonging to the ﬂavanol group denoted as catechins, which may constitute 17 to 30% of the dry leaf weight. The ﬂavanols belong to the broad category of ﬂavans and proanthocyanidins, a distinct class within the immensely diverse group of plant ﬂavonoids [21,26]. A ﬂavanol is a 15-carbon (C6–C3–C6; 6-carbon ring, 3-carbon ring, 6-carbon ring) membered substituted phenylchroman. Fresh tea leaf contains caffeine at an average level of 3% along with smaller amounts of other common methylxanthines: theobromine and theophylline. Tea leaf also contains characteristic catechins such as (–)-epigallocatechin-3-gallate (EGCg), (–)-epigallocatechin (EGC), (–)-epicatechin-3-gallate (ECG), and (–)-epicatechin (EC), as well as (+)-catechin and (–)-gallocatechin (GC) [3,18,38,44–46]. EGCg is the most abundant catechin in tea leaves. Other green tea polyphenols include ﬂavonols (present as glycosides), depsides such as chlorogenic acid, coumarylquinic acid, and a phenolic acid unique to tea, theogallin (3-galloylquinic acid).

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During the manufacture of black tea, a major proportion of monomeric free catechins in the fresh green tea leaf undergoes oxidative changes culminating in the generation of a series of compounds, including bisﬂavanols, theaﬂavins, epitheaﬂavic acids, and thearubigins, which impart the characteristic taste and color properties of black tea [18,28,38,45,46,48]. Unchanged ﬂavanols constitute 3 to 10% of the dry weight in black tea [3,38]. Green tea leaf and commercial oolong tea preparations also contain dimeric proanthocyanidins, free and as gallate esters [23–25,65]. More signiﬁcantly, Nonaka et al. [65] detected two novel and distinct dimeric ﬂavan3-ol gallate esters, theasinensins A and B, in green tea leaf, and Hashimoto et al. [23] detected theasinensins D-G and oolongtheanin in oolong tea. Hashimoto et al. [25] isolated 8- C-ascorbyl(–)-epigallocatechin-3-O-gallate and novel dimeric ﬂavan-3-ols, oolonghomobisﬂavans A and B, from oolong tea. Tea leaf contains a unique amino acid, 5-N-ethyl-L-glutamine (L-theanine), detected by Sakato [47], which is the γ-ethylamide of L-glutamic acid (γ-glutamylethylamide). L-Theanine is a precursor of the nonpeptide antigen ethylamine, an alkylamine [31]. Ethylamine is present in brewed tea as an intact molecule and in its precursor form, L-theanine [9,47]. In addition to catechins, gallic acid, and caffeine, L-theanine (1 to 2%, w/w) also contributes to the quality of green and black teas [2]. L-Theanine is the predominant amino acid component in tea, constituting between 1 and 2% of the dry weight of the tea leaf. It is as prevalent in tea as all other free amino acids combined. The L-theanine content of black tea varietals is similar to or higher than that of green teas [17]. It is present in very high concentrations in certain varietals of black tea [51]. Green and black teas principally differ in terms of their catechin and oxidized catechin (condensation) contents. Because oolong tea is partially oxidized, it contains both native and oxidized catechins; its composition reﬂects an intermediate range between that of green and black teas. In particular, catechins such as EGCg, EGC, ECG, and EC, which are characteristic of green tea, are present in oolong tea, along with catechin oligomers, oligomeric proanthocyanidins, and polymeric polyphenolics, which are typically constituents of black tea.

ANIMAL STUDIES Some studies have investigated the anti-obese effects of green tea powder and tea extracts by examining their effects in the reduction of body weight gain. Studies indicate that green tea and EGCg, the major polyphenol of green tea, reduce body weight in experimental animals [32,50], a ﬁnding that might be attributed to increased EE. Oral administration (3g/100 g of body weight) of a black tea extract for 15 days resulted in a decrease in body and liver weight gain and food intake in rats [52]. The administration (1%, w/v) of a black tea extract as a drink for 25 days attenuated plasma triacylglycerol levels and induced a 29% reduction in weight gain in sucrose-fed rats [61]. A 27% decrease in fat pads was accompanied by a diminution in food intake. A water extract of oolong tea prevented the obesity and fatty liver normally induced by a high-fat diet in mice [19]. Further, this extract of oolong tea, in concert with caffeine, accentuated norepinephrine-induced lipolysis in isolated fat cells. Interestingly, Pu-Erh black tea (product of Yunnan district, China) consumption caused a reduction in plasma triacylglycerol levels in rats ingesting this tea extract (10g/500 mL for 8 to 16 weeks) [49]. A signiﬁcant decrease in the weight of the abdominal tissue was observed. The weight ratio of adipose tissue to whole body was also lower. Lipoprotein lipase activity in the abdominal tissue was low, and the activity of epinephrine-induced lipolysis was signiﬁcantly high in rats fed this tea for 8 or 16 weeks. These observations suggest that the successive administration of this tea could stimulate lipolysis in the adipose tissue and decrease its weight. Sayama et al. [50] studied the anti-obesity effects of tea in female ICR mice by feeding diets containing 1, 2, and 4% green tea powder for 16 weeks. The administration of diets containing 2 and 4% green tea powder resulted in body weight reduction.

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Kao et al. [32] documented a direct effect of EGCg on body weight decrease, independent of caffeine, by employing a very high dose of this catechin in acute studies. Parenteral administration of EGCg (70 to 92 mg/kg) resulted in a signiﬁcant body decrease in both male and female Sprague–Dawley rats. Male rats treated daily with 85 mg EGCg per kg body weight lost 15 to 21% of their body weight relative to their initial weight and 30 to 41% relative to the control weight after 7 days of treatment. The administration of 12.5 mg EGCg (approximately 92 mg/kg body weight) to female Sprague–Dawley rats resulted in a loss of 10% of their body weight relative to their initial weight and 29% relative to the control weight after 7 days of treatment. EGCg treatment signiﬁcantly reduced or prevented an increase in body weight in lean and obese male and female Zucker rats. EGCg administration strikingly reduced food (energy) intake in both Sprague–Dawley and Zucker rats and might have contributed to body weight reduction. The loss in body weight was reversible; the animals regained the lost body weight upon withdrawal of the EGCg treatment. Structurally related catechins other than EGCg were not effective at the same dose in depressing body weight or diminishing food intake. The reduction in food intake and body weight observed in both lean (leptin-receptor-intact) and obese (leptin-receptor-defective) Zucker rats suggested that the effect of EGCg was independent of an intact leptin receptor. The loss of appetite might involve neuropeptides other than leptin. Kao et al. [32] proposed that EGCg might interact speciﬁcally with a component of a leptin-independent appetite control pathway. Zheng et al. [62] examined the anti-obesity effects of three components of green tea — catechins, caffeine, and theanine — in female ICR mice fed on diets containing 2% green tea powder (GTP) and diets containing 0.3% catechins, 0.05% caffeine, and 0.03% theanine, which correspond, respectively, to their concentrations in a 2% GTP diet singly and in combination for 16 weeks. There was a signiﬁcant decrease in the weight of intraperitoneal adipose tissues and in body weight increase for diets containing green tea, caffeine, theanine, caffeine + catechins, caffeine + theanine, and caffeine + catechins + theanine. In particular, the adipose tissue weight decreased by 76.8% in the caffeine + catechins group compared to that of the control group. Green tea, catechins, and theanine resulted in a diminution of serum concentrations of nonesteriﬁed fatty acids (NEFAs). These results indicated that caffeine and theanine were possibly responsible for the effect of GTP in suppressing the weight of adipose tissues and body weight gain. The authors consider that catechins and caffeine interact synergistically in manifesting anti-obesity effects. Very few investigations have evaluated the speciﬁc effects of tea on energy expenditure and the respiratory quotient (RQ) with regard to reduction of body weight and the treatment of obesity in experimental animals. Systematic investigations on body composition and regression of obesity in animals are lacking. Dulloo et al. [16] reported that, in rats, a green tea extract stimulates brown adipose tissue thermogenesis to a much greater extent than can be attributed to its caffeine content per se. They suggested that the thermogenic properties of green tea are due to an interaction between catechin polyphenols and caffeine, constituents of green tea, with sympathetically released catecholamine and norepinephrine that invoked the following mechanisms. By inhibiting catechol-Omethyl transferase (COMT), catechins would protect noradrenaline (NA) against inactivation by O-methylation and thereby would sustain the actions of this catecholamine. Tea phenolics competitively inhibit this enzyme [6]. The inhibitory action of caffeine on the enzyme cyclic adenosine 3′,5′-monophosphate (cAMP)-dependent phosphodiesterase, which degrades cAMP, would result in the intracellular accumulation of cAMP, a critical signaling molecule involved in the direct activation of β-adrenergic receptors [5,8]. The unimpeded cellular availability of cAMP would endow this intracellular messenger with increased capacity to elicit its intracellular actions on catecholamines in prolonging thermogenesis. At this juncture, mention should be made of the fact that tea contains the methylxanthines caffeine and theophylline and that the latter is more potent than caffeine in its inhibition of cAMP phosphodiesterase activity [43]. The autonomic nervous system typically modulates carbohydrate and fat metabolism through direct neural stimulation as well as through hormonal effects. Catecholamine hormones such as norepinephrine and epinephrine can increase thermogenesis and lipolysis, leading to increased EE

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and decreased fat stores. Tappy et al. [53] reported that the stimulation of the sympathetic nervous system increased plasma norepinephrine levels by 27% and lipid oxidation by 72%, whereas it reduced glucose oxidation by 14% in the postprandial state. Beta-adrenergic receptors of the adipocytes mediate the responses to the catecholamines [5]. The potential of tea components to positively impact the pools of endogenous catecholamines [15] could, therefore, have a pronounced effect on EE and substrate oxidation. Alterations of neurotransmission can markedly change the relative contribution of the catecholamine outﬂow to the pancreas, liver, adrenal medulla, and adipose tissues, leading to modulation of carbohydrate and fat metabolism [64]. Klaus et al. [33] examined the acute effects of very high concentrations of orally administered EGCg (500 mg/kg) on body temperature, activity, and EE in male New Zealand black mice by indirect calorimetry. The authors reported no signiﬁcant changes in any of these parameters; however, a decrease in the respiratory quotient was observed at night (activity phase), supportive of increased fat oxidation. The authors suggest that EGCg attenuates diet-induced obesity in mice by decreasing energy absorption and increasing fat oxidation. In a separate study [58], the authors studied the regression of diet-induced obesity by dietary supplementation with EGCg (in a pure form) in Sprague–Dawley rats. Supplemental EGCg reversed established obesity in these rats. In vitro studies support the ability of EGCg to enhance adipocyte lipolysis. The incubation of fully differentiated 3T3-L1 cells with EGCg for 4 hours strongly stimulated lipolysis [41]. Treatment of mature adipocytes (3T3-L1 cells) with GTP in cell culture resulted in enhanced lipolysis [22].

HUMAN STUDIES In an epidemiological study, Wu et al. [59] found an inverse association between the number of cups of tea consumed and body fat content. Tsuchida et al. [56] reported a reduction of body fat in humans following long-term administration of tea catechins. Consecutive intake of tea catechins (588 mg/day) reduced body fat, especially abdominal, fat in humans [55]. Dulloo et al. [15] examined whether an extract of green tea, by virtue of its high content of both caffeine and catechin polyphenols, could effectively promote thermogenesis in human subjects. They assessed the effect of multiple administrations of capsules containing a green tea extract (standardized for catechins and caffeine) and caffeine on 24-hour EE, RQ, and the urinary excretion of nitrogen and catecholamines in 10 healthy men (mean body mass index [BMI], 25.1 kg/m2) in a respiratory chamber. Inclusion criteria included body fatness ranging from lean to mildly obese (8 to 30% body fat). Fat contributed 35 to 40% of dietary energy intake in these subjects, who habitually consumed a typical Western diet, and their estimated intake of methylxanthines (primarily as caffeine-containing beverages) ranged from 100 to 200 mg/day. On three separate occasions, the authors randomly assigned the study subjects among three treatment groups receiving green tea extract (50 mg caffeine and 90 mg EGCg), caffeine (50 mg), or placebo, which they ingested at breakfast, lunch, and dinner. The ingestion of capsules containing the green tea extract provided total daily intake of 150 mg caffeine and 375 mg catechins, of which 270 mg was EGCg. The amounts of catechin polyphenols consumed with each meal were comparable with the amounts commonly ingested by tea drinkers. Compared to placebo, treatment with the green tea extract resulted in a signiﬁcant increase in 24-hour EE (4%) and a signiﬁcant decrease in 24-hour RQ (from 0.88 to 0.85) without any change in urinary nitrogen [15]. None of the subjects experienced any signiﬁcant differences in heart rates across treatments during the ﬁrst 8 hours that the subjects were assessed in the respiratory chamber. The results indicated that the lower RQ during treatment with the green tea extract was due to a shift in substrate utilization in favor of fat oxidation. Also, 24-hour urinary norepinephrine excretion was higher during treatment with the green tea extract than with the placebo (40%). Treatment with caffeine in amounts equivalent to those found in the green tea extract had no effect on EE, RQ, urinary nitrogen, or catecholamines. Dulloo et al. [15] concluded that green tea has thermogenic properties and promotes fat oxidation beyond that explained by its caffeine content alone. The authors believe that caffeine in the dosage (50 mg each treatment, 150 mg total intake per day)

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employed, although ineffective by itself, might have enabled a synergistic interaction with other bioactive ingredients in the green tea extract to promote catecholamine-induced thermogenesis and fat oxidation. They perceived that green tea extract might play a role in the control of body composition via sympathetic activation of thermogenesis, fat oxidation, or both. Dulloo et al. [15] suggested that the interaction between green tea (catechin polyphenols) and caffeine that stimulates and prolongs thermogenesis could be of value in the management of obesity. In an open study, Chantre and Lairon [10] evaluated the effects of a standardized green tea extract in 70 (63 female, 7 male) moderately obese patients (BMI, 25 to 32 kg/m2). Each subject received a daily green tea extract ingestion of 4 capsules (2 capsules in the morning and 2 capsules at midday), which provided a daily total of 375 mg catechins, of which 270 mg was EGCg. After 3 months, body weight and waist circumference decreased by 4.6% and 4.48%, respectively. The authors did not observe any signiﬁcant differences in blood pressure during the 3 months of treatment. Martinet et al. [40] reported that commercial preparations of green tea and 11 other plant preparations had no discernible effect on EE or RQ. In view of the thermogenic activity of deﬁned green tea extracts in humans [15] and animals [16] and oolong tea in human subjects [11,34,64], the constitution and standardization of the composition of the tea extract and the dose ranges selected for administration could be critical in evaluating the efﬁcacy of the extract in elevating metabolic rate and fat oxidation. Chen et al. [11] evaluated the clinical efﬁcacy of oolong tea in Chinese women. They reported that 102 subjects who consumed four cups of oolong tea per day (the brew from four 2-g tea bags) lost over a kilogram of body weight during a 6-week period. The subjects received approximately 125 mg of caffeine per day from the consumption of oolong tea. The data suggested that oolong tea might promote weight loss by increasing EE by 10 to 20%. Rumpler et al. [63] evaluated under controlled conditions whether consumption of oolong tea increases EE or modulates substrate oxidation in comparison to control beverages. Employing a randomized, crossover design, they compared the 24-hour EE of 12 men consuming one of four treatments: (1) water, (2) full-strength tea (daily allotment brewed from 15 g of tea), (3) half-strength tea (brewed from 7.5 g tea), or (4) water containing 270 mg caffeine, equivalent to the concentration in the full-strength tea treatment. Each treatment consisted of consuming a beverage ﬁve times daily that contained one of the four test beverages, over a period of 6 hours (8:30 a.m. to 2:30 p.m.). The total caffeine consumption for subjects consuming ﬁve servings of the caffeinated water, fullstrength tea, or half-strength tea treatments was 270, 270, and 135 mg/day, respectively. The consumption of the full-strength tea and half-strength tea provided a daily total intake of 244 mg of EGCg (662 mg of catechins, 952 mg of polyphenols) and 122 mg of EGCg, (331 mg of catechins, 476 mg of polyphenols), respectively. The subjects refrained from consuming caffeine or ﬂavonoids for 4 days prior to the study. They received each treatment for 3 days; on the third day, EE was determined by indirect calorimetry in a room calorimeter. The increases in EE for the full-strength tea and caffeinated water treatments in comparison to that for the water treatment were 2.9 and 3.4%, respectively, and were signiﬁcant [63]. When subjects consumed the full-strength tea beverage rather than water, the 24-hour fat oxidation was signiﬁcantly higher (12%). Elevations in fat oxidation were 12% and 8% for the full-strength tea and the caffeinated water, respectively. These studies indicate that the consumption of oolong tea may promote weight loss by stimulating EE and fat oxidation. The elevation of metabolic rate and fat oxidation by the consumption of tea conﬁrms the results obtained by Duloo et al. [15]. It is not clear whether one could ascribe the above responses resulting from oolong tea intake exclusively to caffeine. The intake of EGCg from the full-strength (containing 270 mg of caffeine) oolong tea in the Rumpler et al. [63] study was similar to that for the green tea extract employed by Dulloo et al. [15], even though caffeine levels were nearly twice as high; however, the increases in 24-hour EE reported in both investigations were very similar. The administration of oolong tea was as a drink in the Rumpler et al. study, whereas Dullo et al. [15] supplied the green tea extract in capsule form. The elevation in EE associated with the consumption of caffeine (caffeinated water containing 270

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mg caffeine) alone was not signiﬁcantly different from that obtained with the full-strength tea. Rumpler et al. [63] reasoned that the consumption of the full-strength tea would have elicited a much higher thermic effect if there had been some synergistic interaction of caffeine with bioactive components in tea, as suggested by Dulloo et al. [15]. The studies by Rumpler et al. [63] revealed a signiﬁcant effect of tea on 24-hour fat oxidation, which was not evident with caffeinated beverages alone. The observed impact of tea on fat oxidation may reﬂect the synergistic effect of caffeine and tea catechins, as proposed by Dulloo et al. [15]; however, in the absence of data discriminating the independent effect of non-caffeine components of tea in stimulating fat oxidation, it remains to be determined whether caffeine from tea and extracts is essential to produce this effect. Komatsu et al. [34] evaluated the effect of oolong tea on EE in comparison with that of green tea. Randomly divided, 11 healthy Japanese females consumed one of the following three treatments in a crossover design: (1) water, (2) oolong tea, or (3) green tea. The composition of the oolong tea consumed was as follows: caffeine, 77 mg; total catechins, 206 mg (EGCg, 78 mg); and polymerized polyphenols, 68 mg. The green tea beverage provided the following components: caffeine, 161 mg; total catechins, 293 mg (EGCg, 94 mg); and polymerized polyphenols, 17 mg. Resting energy expenditure (REE) and EE after consumption of the test beverage for 120 min were determined using an indirect calorimeter. The cumulative increases of EE for 120 min were 10% and 4% after the consumption of oolong tea and green tea, respectively, and were signiﬁcant. EEs at 60 and 90 min were signiﬁcantly higher after the consumption of oolong tea than that of water. Oolong tea consumed by the subjects contained approximately half the caffeine and EGCg in comparison with the amounts in green tea but the amount of polymerized polyphenols was double. The efﬁcacy of oolong tea was much higher than that of green tea, and the authors suggested that the polymerized polyphenols present in oolong tea promote EE. Bérubé-Parent et al. [4] evaluated the effect of ingestion of four mixtures of green tea (catechins) and guarana (a plant containing caffeine) extracts (containing a ﬁxed dose of caffeine and different amounts of EGCg) on 24-hour EE and fat oxidation in men. Fourteen subjects (mean BMI, 25.7 kg/m2) participated in this randomized, placebo-controlled, double-blind, crossover study. The subjects consumed a capsule of placebo or capsules containing 200 mg caffeine and a variable dose of EGCg (90, 200, 300, or 400 mg) three times daily, 30 min before standardized meals, between 8.00 a.m. and 6:00 p.m. Ingestion of the EGCg–caffeine mixtures signiﬁcantly increased 24-hour EE (by 8%) compared to that for the placebo. Increasing the dose of EGCg in the mixtures induced a mild increase in 24-hour EE, but these differences were not signiﬁcant even between the lowest (270 mg/day; 3 × 90 mg) and the highest (1200 mg/day; 3 × 400 mg) doses. EGCg did not evoke a dose-related effect on 24-hour EE. The intake of EGCg–caffeine mixtures had no effect on RQ, fat oxidation, or catecholamine excretion. It is surprising that the authors did not ﬁnd any effect of EGCg–caffeine mixtures on fat oxidation. Their ﬁndings are at variance with those of Dulloo et al. [15] and Rumpler et al. [63], who demonstrated the elevation of fat oxidation by the ingestion of EGCg-containing green and black teas. Harada et al. [20] investigated the effect of long-term ingestion of tea catechins on postprandial EE and dietary fat oxidation. Twelve healthy male subjects consumed 350 mL of a test beverage daily that contained either a high dose of catechin (592.9 mg) or a low dose of catechin (77.7 mg) for a period of 12 weeks. The authors conducted respiratory analyses before and at 4, 8, and 12 weeks during the test period; they included oxygen consumption and the excretion of (CO2)–13C over 8 hours after a single ingestion of a test meal containing 13C-labeled triglyceride. A signiﬁcant increase was observed in the excretion of (CO2)–13C in the high-dose catechin group (the HC group) at 4 and 12 weeks of the test period compared to the low-dose catechin group (the LC group); this elevation ranged from 8.9% at week 0 to 12.9% at week 12. Diet-induced thermogenesis (DIT), deﬁned as an increase in energy expenditure from the fasting baseline for 8 hours after the single ingestion of a test meal, was signiﬁcantly higher in the HC group at 8 and 12 weeks compared to that in the LC group. The results indicate that enhanced dietary fat oxidation and an increased DIT may play an important role in the anti-obesity effect of tea catechins.

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Kajimoto et al. [30] assessed the effect of consumption of a catechin-containing drink on body fat levels in healthy adults. The beverage (250 mL/bottle) contained 215.3 mg of tea catechins, mostly possessing a galloyl moiety, which included EGCg (74.6 mg), ECG (34.1 mg), (–)-gallocatechin gallate (77.8 mg), and (–)-gallocatechin (24.5 mg). This double-blind study had three parallel groups. The subjects (98 men and 97 women) received 3 bottles of placebo drink (control group), 2 bottles of catechin-containing drink and 1 bottle of placebo drink (low-dose group), or 3 bottles of catechin-containing drink (high-dose group) each day at mealtimes for 12 weeks (the daily consumption of catechins was 41.1, 444.3, and 665.9 mg, respectively). Body weight and BMI were signiﬁcantly lower in both of the catechin groups than in the control group from 4 to 12 weeks. The authors reported a signiﬁcant reduction of total fat and visceral fat areas in both catechin groups compared with the control group at 12 weeks. Nagao et al. [42] performed a 12-week double-blind study to elucidate the effect of catechins on body fat reduction and the relationship between oxidized low-density lipoprotein (LDL) and body fat variables. After a 2-week diet run-in period, healthy Japanese males divided into two groups with similar BMI and waist circumference distributions ingested 1 bottle of oolong tea daily that contained 690 mg catechins (tea extract group; n = 17) or 1 bottle of oolong tea daily that contained 22 mg catechins (control group; n = 18). The authors observed that body weight, BMI, waist circumference, body fat mass, and subcutaneous fat area were signiﬁcantly lower in the tea extract group than in the control group. The results showed a positive association of changes in the concentration of malondialdehyde-modiﬁed LDL with changes in body fat mass and total fat area in the green tea extract group. Kovacs et al. [35] conducted a randomized, parallel, placebo-controlled study to explore whether green tea may improve weight maintenance by preventing or limiting weight regain after a weight loss of 5 to 10% in overweight and moderately obese subjects. The participants included a total of 104 overweight and moderately obese male and female subjects (BMI, 25 to 35 kg/m2). The majority of subjects were women. The treatment study consisted of a very-low-energy diet intervention of 4 week followed by a weight maintenance period of 13 weeks during which the subjects consumed green tea or a placebo. The green tea capsules used in the study contained caffeine (104 mg/day) and catechins (573 mg/day, of which 323 mg was EGCg). The subjects were in a free-living condition and continued their habitual caffeine intake, varying approximately from 0 to 100 mg/day. The results suggested that that green tea was not effective in weight maintenance after a weight loss of 7.5% in originally overweight and moderately obese subjects; however, weight maintenance was stronger with green tea among the low caffeine users compared with the high caffeine consumers. Kovacs et al. [35] indicated that the magnitude of habitual caffeine intake might impair the effectiveness of green tea administration. The plasma leptin concentration at baseline was lower in high caffeine consumers than in low caffeine consumers, indicating that the habitual use of caffeine may reduce leptin levels. The authors indicate the possibility that supplementation with green tea is only effective under conditions of low habitual caffeine intake and that a much higher dose of green tea is required when habitual caffeine intake is high. The investigations of Westerterp-Plantenga et al. [57] further corroborated that the magnitude of habitual intake of caffeine was a critical determinant of the effectiveness of green tea in maintaining body weight. In a randomized, placebo-controlled, double-blind parallel trial study, these authors evaluated the effect of a green tea–caffeine mixture on weight maintenance after body weight loss in 76 overweight and moderately obese subjects (BMI, 27.5 ± 2.7 kg/m2) matched for sex, age, BMI, height, body mass, and habitual caffeine intake. The treatment included a very-lowenergy diet intervention of 4 weeks followed by a weight maintenance period of 13 weeks, during which the subjects consumed a green tea–caffeine mixture (270 mg EGCg + 150 mg caffeine per day) or placebo. During the weight maintenance period, green tea reduced body weight, waist circumference, RQ, and body fat in the low caffeine consumers, but resting EE increased compared with restoration of these variables in the placebo group. The consumption of the green tea–caffeine

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mixture did not have any effect on weight management in the high caffeine consumers, whereas it signiﬁcantly improved weight management in habitual low caffeine consumers, supported by the relatively higher thermogenesis and fat oxidation. The authors furnished evidence to suggest that overweight subjects who lose 5 to 6 kg weight in 4 weeks and who rarely consume coffee or tea or other caffeine-containing products may beneﬁt from a regular intake of green tea–caffeine mixture containing 270 mg of EGCg and 150 mg of caffeine per day. Tea polyphenolics and methylxanthines are known to exhibit strong binding activities. In view of this, the intake of large amounts of tea may be a cause for concern because of the potential consequences of tea drinking on nutrition and other problems. The consumption of tea, however, is remarkably safe, and no solid evidence points to the harmful effects of tea consumption.

CONCLUSION Tea has gained prominence as a functional food and as a repository of pharmacologically active ingredients. Bioactive entities associated with this dietary adjunct could have a propensity to augment EE by inﬂuencing subtle cellular and metabolic processes linked with energy dissipation. Conceivably, some of these ingredients may positively inﬂuence intracellular energy transduction systems in the mitochondrion or promote the mobilization of fat and the catabolic breakdown of triacylglycerol into free fatty acids. Certain animal and human studies have demonstrated the thermogenic properties of tea. The limited information garnered illustrates that the administration of tea as a beverage or as an extract promotes EE and fat oxidation in human subjects. Twenty-four hour EE determinations clearly document that both green and oolong teas containing variable amounts of EGCg (and other catechin components) and caffeine promote thermogenesis and fat oxidation, but no speciﬁc information exists regarding the speciﬁc contributory role of the various tea components in these processes. Green tea provides native catechins (polyphenol monomers), but oolong tea furnishes oxidized catechins and oligomers and polymers derived from catechins, in addition to native catechins. Further studies are necessary to discriminate the exclusive effects of caffeine and non-caffeine components of tea on metabolic rate and fat oxidation in human subjects. Recently gathered evidence indicates that overweight individuals who have experienced a loss in body weight could substantially beneﬁt from a regular intake of a caffeine and green tea mixture to sustain that weight loss. These investigations suggest a promising application of green tea components to the maintenance of body weight. A few encouraging studies have recently emerged illustrating the primary anti-obesity effect of a mixture of EGCg and other tea-derived catechins. These studies document that prolonged (12week) ingestion of a mixture of tea catechins intensiﬁes postprandial EE and fat oxidation in healthy male subjects. Long-term (12-week) administration of a combination of tea-derived catechins signiﬁcantly diminished body weight, body fat mass, and BMI in a large sample of male and female subjects. The intake of tea catechin mixtures resulted in a signiﬁcant reduction of total and visceral fat areas. The outcome of these investigations adds a promising new dimension to evaluating the anti-obesity effect of tea and tea products. Such investigations provide an impetus for the development of “designer” supplements containing tea components and other thermogenic agents to target obesity. The utility of tea as a weight management aid clearly requires further long-term, systematic, and in-depth investigations.

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Kao, Y.H., Hiipakka, R.A., and Liao, S., Modulation of endocrine systems and food intake by green tea epigallocatechin gallate, Endocrinology, 141, 980, 2000. Klaus, S. et al., Epigallocatechin gallate attenuates diet-induced obesity in mice by decreasing energy absorption and increasing fat oxidation, Int. J. Obes. Relat. Metab. Disor., 29, 615, 2005. Komatsu, T. et al., Oolong tea increases energy metabolism in Japanese females, J. Med. Invest., 50, 170, 2003. Kovacs, E.M.R. et al., Effects of green tea on weight maintenance after body-weight loss, Br. J. Nutr., 91, 431, 2004. Landsberg, L., Saville, M.E., and Young, J.B., Sympathoadrenal system and regulation of thermogenesis, Am. J. Physiol., 247, E181, 1984. Liao, S., The medicinal actions of androgens and green tea epigallocatechin gallate, Hong Kong Med. J., 7, 369, 2001. Lunder, T.V., Tea, Technical Assistance, Nestec, Ltd., Lausanne, Switzerland, 1988, p. 42. Lunder, T., Tannins of green and black tea: nutritional value, physiological properties and determination, Farm. Tijdschr. Belg., 66, 34, 1989. Martinet, A., Hostettman, K., and Schutz, Y., Thermogenic effects of commercially available plant preparations aimed at treating human obesity, Phytomedicine, 6, 231, 1999. Mochizuki, M. and Hasegawa, N., Effects of green tea catechin-induced lipolysis on cytosol glycerol content in differentiated 3T3-L1 cells, Phytother. Res., 18, 945, 2004. Nagao, T. et al., Ingestion of a tea rich in catechins leads to a reduction in body fat and malondialdehyde-modiﬁed LDL in men, Am. J. Clin. Nutr., 81, 122, 2005. Rall, T.W., Drugs used in the treatment of asthma, in The Pharmacological Basis of Therapeutics, 8th ed., Goodman-Gilman, A., Rall, T.W., Nies, A.S., and Taylor, P., Eds., Pergamon Press, New York, 1990, pp. 618–637. Roberts, E.A.H., Economic importance of ﬂavonoid substances: tea fermentation, in The Chemistry of Flavonoid Compounds, Geissman, T.A., Ed., Pergamon Press, Oxford, 1962, pp. 468–512. Roberts, E.A.H. and Myers, M., The phenolic substances of manufactured tea. IV. Enzymic oxidations of individual substrates, J. Sci. Food Agric., 10, 167, 1959. Roberts, E.A.H., Cartwright, R.A., and Oldschool, M., The phenolic substances of manufactured tea. I. Fractionation and paper chromatography of water-soluble substances, J. Sci. Food Agric., 8, 72, 1959. Sakato, Y., Studies on the chemical constituents of tea. Part III. On a new amide theanine [in Japanese], Nippon Nogeikagaku Kaishi, 23, 262, 1949. Sanderson, G.W., The chemistry of tea and tea manufacturing, Rec. Adv. Phytochem., 5, 247, 1972. Sano, M. et al., Effects of Pu-Erh tea on lipid metabolism in rats, Chem. Pharm. Bull., 34, 221, 1986. Sayama, K., Lin, S., and Oguni, I., Effects of green tea on growth, food utilization and lipid metabolism in mice, In Vivo, 14, 481, 2000. Scharbert, S. and Hofmann, T., Molecular deﬁnition of black tea taste by means of quantitative studies, taste reconstitution, and omission experiments, J. Agric. Food Chem., 53, 5377, 2005. Sugiyama, K., et al., Teas and other beverages suppress d-galactosamine-induced liver injury in rats, J. Nutr., 129, 1361, 1999. Tappy, L. et al., Metabolic effects of an increase in sympathetic activity in healthy humans, Int. J. Obes. Relat. Metab. Disord., 19, 419, 1995. Tian, W-X. et al., Weight reduction by Chinese medicinal herbs may be related to inhibition of fatty acid synthase, Life Sci., 74, 2389, 2004. Tokimitsu, I., Effects of tea catechins on lipid metabolism and body fat accumulation, Biofactors, 22, 141, 2004. Tsuchida, T., Itakura, H., and Nakamura, H., Reduction of body fat in humans by long-term ingestion of catechins, Prog. Med., 22, 2189, 2003. Westerterp-Plantenga, M.S., Lejeune, M.P.G.M., and Kovacs, E.M.R., Body weight loss and weight maintenance in relation to habitual caffeine intake and green tea supplementation, Obes. Res., 13, 1195, 2005. Wolfram, S. et al., TEAVIGO (epigallocatechin gallate) supplementation prevents obesity in rodents by reducing adipose tissue mass, Ann. Nutr. Metabol., 49, 54, 2005. Wu, C.H. et al., Relationship among habitual tea consumption, percent body fat, and body fat distribution, Obes. Res., 11, 1088, 2003.

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and Clinical 31 Laboratory Studies of Chitosan Harry G. Preuss, Debasis Bagchi, and Gilbert R. Kaats CONTENTS Introduction ....................................................................................................................................413 Proposed Mechanisms of Action Behind Use of Chitosan for Body Weight Loss......................414 Toxicology of Chitosan..................................................................................................................414 Effect of Fiber in General on Fecal Fat Excretion and Body Weight Loss .................................414 Inﬂuence of Chitosan on Gastrointestinal Absorption of Fats......................................................415 In Vitro Studies Examining Fat Trapping...............................................................................415 Animal Studies Examining Lipid Binding.............................................................................415 Clinical Studies Examining Lipid Absorption ..............................................................................415 Clinical Studies on the Role of Chitosan in Body Fat Loss.........................................................417 Conclusion: Chitosan As a Weight Management Option..............................................................419 References ......................................................................................................................................419

INTRODUCTION Because public attention has largely been focused on avoiding dietary saturated fats with the hope of preventing or ameliorating atherosclerosis, less emphasis has been placed on limiting overall caloric intake. This fact may account, at least in part, for the so-called “obesity epidemic” [1]. It is difﬁcult to understand how this diversion became so prolonged, because it has long been held that overweight and obesity are responsible for thousands of deaths each year via heart disease, stroke, and diabetes. To add to the problem, it is common knowledge that most individuals who work so hard to lose fat weight subsequently regain it. Americans are not alone. The World Health Organization (WHO) has acknowledged the global spread of overweight and obesity [2]. Accordingly, strategies to prevent the further widening of America and the world are necessary. Oral intake of chitosan, a soluble ﬁber with reputed special properties that prevent gastrointestinal fat absorption, offers a possible partial solution to the problem [3,4]. What do we know about chitosan? Pulverized powders from the exoskeleton of crustaceans were originally noted for their ability to soak up oils after environmental spills [3,4]. Based on this ability, it was hypothesized that chitosan powder might also soak up fats in the human gastrointestinal tract, thus limiting the consumption of calories from them. Indeed, animal studies demonstrate that chitosan does bind neutral fats under a variety of conditions.

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PROPOSED MECHANISMS OF ACTION BEHIND USE OF CHITOSAN FOR BODY WEIGHT LOSS Chitin is a cellulose-like polymer found principally in exoskeletons of marine invertebrates and arthropods such as shrimp, crabs, and lobsters [3,4]. Chitin is composed of long chains of acetylated glucosamine, and chitosan results from the deacetylation of chitin. Theoretically, weight loss associated with chitosan consumption could occur through a number of physiological mechanisms that are not mutually exclusive; for example, the most popular concept is that positively charged chitosan might bind to negatively charged fat molecules and prevent absorption of calorie-containing fat [3]. In a similar vein, the positive charges of chitosan appear to bind bile acids and thus could indirectly increase fecal fat excretion [5,6]. Also, the ability of other viscous ﬁbers such as guar and psyllium to augment fecal fat loss suggests that chitosan may work like many uncharged soluble ﬁbers in general. What is the mechanism behind the latter? In an acid stomach, chitosan is a soluble ﬁber, readily dispersed among the digestive secretions and food particles [7–9]. Binding several times its weight in water, the chitosan ﬁber begins to swell, entrapping and encapsulating dietary fats and oils [7–9]. As chitosan ﬁber passes along into the small intestines, it encounters an environment that is no longer acidic. In a non-acid environment, chitosan ﬁber becomes insoluble and forms a gel-like complex that binds fats and bile acids. This insoluble complex passes undigested through the large intestine and is naturally eliminated. Another possibility to explain weight loss is that the bulk of chitosan could act to suppress appetite.

TOXICOLOGY OF CHITOSAN Although chitosan appears quite safe based on data from animal and human studies [10–12], theoretically it can be detrimental, like all substances taken improperly or in gross excess. Although minerals and electrolytes could be depleted, evidence for such is rare [11]. Dietary chitosan reportedly affects calcium metabolism in animals [13]. In a large clinical trial [14], allergic reactions were seen in 2 to 3% of subjects, mainly in those with an allergy to seafood, and constipation was reported in 20% of the subjects. For the most part, constipation passed over time, especially when the intake of ﬂuids was increased [14]. Problems encountered with extremely high doses of chitosan are caused by gastric dehydration and impaction due to expansion of the ﬁber [12,14].

EFFECT OF FIBER IN GENERAL ON FECAL FAT EXCRETION AND BODY WEIGHT LOSS Based on previous experiences with other ﬁbers, a precedent exists for chitosan to augment fecal fat loss and hasten body fat loss. Bran, resins, pectin, etc. have been used successfully in the past for weight loss and cholesterol reduction [9]. Krotkiewski [15] examined the viscous ﬁber guar and noted reduced hunger and positive effects on lipid and carbohydrate metabolism in obese individuals. Pectin increased fecal fat excretion by 44% (p < .001), neutral steroids by 17% (p < .001), and fecal bile acids by 33% ( p < .02) [16]. In African Green Monkeys, psyllium husk was associated with increased volatile fatty acid output [17]. Ganji and Kies [18], investigating the effects of psyllium ﬁber supplementation on fat digestibility and fecal fatty acid excretion in healthy humans, reported increased fecal fat loss, decreased fat digestibility, and increased fecal palmitic acid excretion with psyllium supplementation. They hypothesized that these associations played a prominent role in the cholesterol-lowering action of psyllium ﬁber.

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INFLUENCE OF CHITOSAN ON GASTROINTESTINAL ABSORPTION OF FATS The original rationale for using chitosan in weight loss regimens is based on the belief that this natural substance could trap calorie-loaded fat in the gastrointestinal tract — preventing absorption of this densely rich macronutrient.

IN VITRO STUDIES EXAMINING FAT TRAPPING Many in vitro studies have corroborated previous environmental studies showing that chitosan can trap neutral fats [3,14].

ANIMAL STUDIES EXAMINING LIPID BINDING Animal studies, usually performed on rats, have consistently demonstrated the ability of chitosan to trap fat in the gastrointestinal tract [19]. In one study, a low-molecular-weight chitosan hydrolysate inhibited cholesterol absorption in the intestine and increased fecal neutral steroid excretion similar to highly viscous chitosan [20]. The mechanism for the inhibition of fat digestion by chitosan and also a synergistic effect in the presence of ascorbate were examined extensively in animal models [21]. Chitosan dissolves in the stomach and then changes to a gel in the intestines that entraps fat. The mechanisms behind the synergistic effect of ascorbate are considered to be (1) viscosity reduction in the stomach, (2) an increase in the oil-holding capacity of the chitosan gel, and (3) the chitosan–fat gel being more ﬂexible and less likely to leak entrapped fat in the intestinal tract. One study examined 23 different ﬁbers added at 5% w/w to a puriﬁed diet containing 20% w/w corn oil [22]. After 2 weeks of this regimen, feces were collected from each animal during a 3-day period. Ten of the tested ﬁbers signiﬁcantly increased fecal lipid excretion compared with the cellulose control. Chitosan reduced the fat digestion to one half of control and did not inﬂuence protein digestibility. Because it was noted that the fatty acid composition of the fecal lipids closely resembled that of dietary fat, these results strongly suggest that chitosan has the potential for interfering with fat digestion and absorption in the intestinal tract. In an excellent experimental design, rats had their lymphatics cannulated and were subsequently gavaged with a test emulsion containing: (1) 25 mg of [14C] cholesterol; (2) 50 mg of guar gum, cellulose, or chitosan; and (3) 200 mg of safflower, high-oleic safflower, or palm oil [23]. Both the type of dietary fiber (p < 0.001) and the type of fat (p < 0.05) examined significantly influenced cholesterol absorption; for example, chitosan effectively lowered cholesterol absorption more than guar gum or cellulose. In addition, the effect of chitosan was more significant when given with safflower or high-oleic safflower oil than with palm oil. Dietary fiber also significantly lowered triglyceride absorption (p < 0.05). Absorption tended to be low with chitosan, high with cellulose, and intermediate with guar gum. The results show that the type of dietary fat significantly influences the effect that dietary fiber can exert on lipid absorption.

CLINICAL STUDIES EXAMINING LIPID ABSORPTION The ﬁrst reported clinical study on chitosan was performed in Norway [24], where the resultant weight loss found in the test subjects was attributed to the fat-binding abilities of chitosan. In ﬁve ensuing studies, all performed in Italy, many included the observation that stools in weight-losing treatment subjects were larger and softer than placebo-receiving subjects [25–31]. Among 30 subjects in a study, Macchi reported that “fecal excretion of fats … was observed only in those taking chitosan” [27]. Girola et al. [25] conducted a clinical study on 150 subjects of both sexes and noted that the administration of the dietary integrator containing 240 mg chitosan per capsule caused signiﬁcant weight loss. The subjects were also evaluated for changes in circulating triglycerides on the 28th day of study. The placebo group showed a 13.2% reduction, whereas the treatment

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groups showed a greater decrease of 26.6%. The most likely explanation for the exaggerated decrease in triglyceride concentrations in the presence of chitosan is decreased fat absorption. In support of this assumption, Hoffman La Roche investigators found that the triglyceride levels in their animals were lower after chitosan per os and believed the reduced blood triglycerides were directly correlated with reduced fat availability via digestive processes [32]. While some observers believe that the appearance of stools is a good indicator of the presence of fat, direct measurements are still necessary for corroboration. Many studies have measured fat in the feces directly to gauge absorption. These measurements, mostly performed using a gravimetric procedure, have shown varying results. A group from the University of California, Davis, performed direct measurements of fecal fat on healthy subjects in three similar studies [33–35]. In these studies, subjects consumed extraordinary amounts of fat, and no placebo controls were followed. Fecal fat excretion was increased under some circumstances but not others; nevertheless, the investigators questioned the clinical signiﬁcance of the small differences [35]. In a different study, 12 healthy adult volunteers within 20% of ideal body weight entered a 7-day run-in diet period before half of them were randomized to the drug orlistat (120 mg) and the other half to chitosan (890 mg) 3 times daily for 7 days [36]. Subjects were then crossed over for the other treatment regimen. Fecal fat excretion increased markedly with orlistat, but the 20% average increase with chitosan did not achieve statistical signiﬁcance. It was concluded that chitosan had no signiﬁcant effect on fecal fat excretion. Not all studies have been negative, however. Nesbitt et al. [37] examined a formula containing chitosan. Nineteen female subjects received 2.0 g of formula containing chitosan (40% w/w), psyllium (51% w/w), apple pectin (4% w/w), and glucomannan (4% w/w) twice a day preceding lunch and dinner; 18 female subjects were simultaneously given a placebo under similar conditions. After 30 days, the treatment group showed a statistically signiﬁcantly greater increase in fecal fat content; the supplement group experienced an average 2.48% increase in fecal fat content over baseline, whereas the placebo group had an average decrease of 3.73% in fecal fat content (p = 0.0002). In another weight loss study examining chitosan, total fecal fat was analyzed at baseline and week 8 in a small set of subjects, three in the placebo group and four in the treatment group [38]. In this small population, a statistical trend for chitosan to increase fecal fat excretion was observed. Total fecal fat excretion increased on an average +6.0 g ± 2.7 SEM over baseline in the treatment group and decreased –2.3 g ± 2.4 SEM under baseline in the placebo group (p < .07). Borosso-Arranda et al. [39] measured fecal fat directly after chitosan administration. Although the increase in fecal fat was statistically signiﬁcant, it could account for only 30 to 40 kcal/day savings in calories. A paper from Japan discussed the use of chitosan to treat Crohn’s disease [40]. The investigators found that a mixture of chitosan (1.05 g/d) and ascorbic acid signiﬁcantly increased fat concentrations in the feces during treatment (average 60 mg/day dry weight before vs. 79 mg/day after 8 weeks; p < 0.035). None of the above studies that made direct measurements of fecal fat reported the accuracy of the methodology. This is particularly important, because the presence of chitosan could affect such measurements; therefore, it is necessary to examine ﬁndings utilizing other methods to estimate fecal fat excretion. In a study by Maezake et al., levels of total fecal volatile fatty acid increased signiﬁcantly from 14.3 ± 3.2 mg/g to 20.3 ± 2.4 mg/g on day 14 of chitosan intake (p < 0.01), with a signiﬁcant increase of acetic (p < 0.05) and propionic (p < 0.01) acids [41]. Utilizing a breath test involving radioactive materials, Swedish investigators reported that subjects receiving chitosan showed reduced fat uptake compared to placebo [14]. In the entire group, the reduction in animal fat uptake with the chitosan compound was approximately 13% after 6 hours. The results were statistically signiﬁcant (p < 0.05) at the 5-hr mark. Four volunteers did not react at all, but the rest showed an average reduced fat uptake of approximately 25%. Blum [42] believed (as mentioned previously [32]) that the amount of fat absorbed from a fatcontaining meal is proportional to an incremental increase in plasma triglycerides; therefore, the

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effects of chitosan after fat challenge were estimated by examining multiple triglyceride levels over the time necessary for the triglyceride levels to return to baseline. One gram of chitosan was taken 5 to 10 minutes before a fatty meal purchased at a local restaurant. Out of 13 subjects, 9 (roughly 2/3) responded favorably. The investigators estimated that chitosan inhibited the absorption of dietary fat in the range of 20 to 28 g of fat for every gram of chitosan in 5 of the subjects. The overall weight of evidence favors the long-held assumption that chitosan ﬁber taken properly under proper conditions increases fecal fat loss, but whether the trapped fecal fat could account for signiﬁcant weight loss remains open to question at this time.

CLINICAL STUDIES ON THE ROLE OF CHITOSAN IN BODY FAT LOSS Results may differ among studies, because conditions are rarely the same. To give examples: (1) The quality of chitosan material often ﬂuctuates [43,44]; (2) the quantity of material used (dosage) frequently varies [44]; (3) the timing of the dosing may also be an important variable; (4) the diet offered with chitosan (e.g., low or high fat, low or high caloric content) can inﬂuence outcome; (5) the different methodologies used for assessing endpoints (e.g., weight loss rather than fat loss) may affect interpretations; (6) the individual biological responses may be dissimilar; and, ﬁnally, (7) the compliance of subjects may differ markedly. Accordingly, a broad and complete picture emanating from many studies must be used to assess the effectiveness of chitosan as a weight loss agent. The initial weight loss investigation using chitosan, performed over 10 years ago, was a doubleblind, placebo-controlled study on 18 subjects ingesting a low-caloric diet and consuming 1.92 g of chitosan per day [24]. Weight loss in test subjects compared to controls was signiﬁcant after 14 and 28 days. The next studies, performed in Italy, were very similar in format — randomized, double-blind, and placebo-controlled [25–27,31]. In these particular studies, subjects consumed a 1000-kcal diet and received four tablets of chitosan or placebo per day for 28 days. Unfortunately, the amount of chitosan in each tablet was never revealed. In addition, other ingredients, such as guar and psyllium, were added to a formula, although the authors tended to attribute beneﬁts principally to chitosan. Giustini and Ventura [28,29] reported that weight loss of the chitosan group signiﬁcantly exceeded the placebo group in 100 subjects. Sciutto and Columbo [30] wrote that the chitosan weight loss signiﬁcantly exceeded placebo in 90 subjects. Girola et al. [25], in 150 subjects, noted that weight loss on an integrator containing chitosan signiﬁcantly exceeded placebo. Veneroni et al. [26] similarly showed that weight loss in the chitosan group signiﬁcantly exceeded placebo in 80 subjects. When Colombo and Sciutto [31] studied 86 subjects, the weight loss in the chitosan group signiﬁcantly exceeded placebo. Macchi [27] found that weight loss in the chitosan group also signiﬁcantly exceeded placebo in 30 subjects. The earliest studies were performed on subjects consuming very caloric restricted diets; therefore, the question was raised concerning the inﬂuences of chitosan on individuals consuming more normal levels of calories. Wuolijoki et al. [45] showed an effect of chitosan on lipid lowering but discovered no signiﬁcant change in body weight; however, they raised the possibility of poor compliance in their report. The authors hypothesized that reduced lipid absorption from the gastrointestinal tract decreased energy intake, stimulating hunger. Pittler et al. [46] in a double-blinded, placebo-controlled study on 34 subjects, reported that weight loss in the chitosan group did not exceed placebo. The subjects ate regular diets and were supposed to consume 1.2 g of chitosan per day for 28 days. Unfortunately, the amount of chitosan given was lower than expected (i.e., 60% of the designated amount); thus, the treatment group, eating regular amounts of fat, received a relatively small dose. In an open-label study composed of 332 subjects [12], 221 of the subjects responded to chitosan per os by losing a signiﬁcant amount of weight (–4.1 kg). Nesbitt et al. [37] provided 1.6 g of chitosan per day for 30 days in a formulation comprised mainly of chitosan to

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37 mildly to moderately obese subjects and saw a signiﬁcant decrease in body weight (placebo gained +2.3 lb and treatment lost –3.6 lb). It must be noted that the average body weight of the treatment group at the initiation of the study was 192 lb compared to 172 lb for the placebo group. Obviously, this discrepancy makes interpretation more difﬁcult, even though this weight loss was accompanied by a corresponding signiﬁcant increase in fecal fat content in the treatment group vs. the placebo group. Likewise, total cholesterol and low-density lipoprotein (LDL) decreased, and high-density lipoprotein (HDL) increased in the treatment group compared to the placebo group. All differences were statistically signiﬁcant. Schiller et al. [38] performed a randomized, double-blind, placebo-controlled study in overweight and mildly obese individuals. Subjects took either three capsules of a rapidly soluble chitosan (1.5 g, b.i.d.) or matched placebo twice daily for 8 weeks. Interestingly, the study overlapped a holiday period when increased caloric intake might be expected, but the subjects continued to consume their regular diet. To back this assumption, the placebo group showed a mean weight gain of +1.5 kg over the holiday period, but the mean weight loss was –1.0 kg within the treatment group over the 8-week period. Chi-square analysis for weight loss between the groups indicated signiﬁcantly more subjects lost weight within the treatment group than within the placebo group (63% and 17%, respectively; p < 0.001). Krotkiewski et al. [47] reported that their treatment subjects received a low-caloric diet (1000 kcal/day for 6 months) along with chitosan in a randomized, placebo-controlled, double-blind study. The chitosan group received 1.5 g three times daily. Signiﬁcantly greater body weight losses and decreased systolic blood pressure were noted compared to the placebo group. Ho et al. [48] examined 68 subjects who were overweight and hypercholesterolemic and found no signiﬁcant changes in the measured parameters and no severe side effects in chitosan-treated subjects; however, the investigators stated: “We believe that subjects could have inadvertently increased their caloric intake under the false belief that chitosan would bind all fat that was consumed.” Further, it was noted that the patients took approximately 80% of the correct dose of chitosan. The authors postulated that this might represent underdosing. A 24-week randomized, double-blind, placebo-controlled trial, conducted at the University of Auckland, examined 250 participants (82% women) with a mean body mass index (BMI) of 35.5 kg/m2 [49]. Participants in the treatment group, who were given advice on diet and lifestyle, received 3 g of chitosan per day. In an intention-to-treat analysis with the last observation carried forward, the chitosan group lost more body weight than the placebo group (–0.4 ± 0.2 kg vs. +0.2 ± 0.2 kg; p = 0.03). The investigators did not deem these differences to be clinically signiﬁcant. Unfortunately, the report did not give information on a singled-out group of compliant individuals. Similar small changes occurred in the circulating total and LDL cholesterol and glucose (p < 0.01). Kaats et al. [50] examined the effects of chitosan on fat loss using DEXA, the state-of-theart means to estimate body fat. Over an 8-week study period, 150 subjects were examined to evaluate the effects of a novel chitosan formulation on body weight, body composition (lean-tofat ratios), bone density, and blood chemistries under real-life conditions. Subjects were randomly assigned to one of three 50-subject groups: (1) a treatment group that was provided with a behaviormodiﬁcation program and consumed a dietary supplement containing principally chitosan, (2) a placebo group that was provided with the same behavior-modiﬁcation program but consumed a placebo supplement, and (3) a control group that was asked to follow any program of their choosing but who also completed the same beginning and ending tests as the treatment and placebo groups. A total of 131 (87%) of the subjects completed the study. For those completing the study, highly statistically signiﬁcant differences were found between the treatment group compared to placebo and control in body weight loss. The loss of body weight in the treatment group was –3.4 lb ± 5.9 SEM compared to placebo (–0.9 lb ± 4.2 SEM; p = 0.028) and control (+0.6 lb ± 4.4 SEM; p = 0.001). In addition, there were highly signiﬁcant differences between treatment and placebo in reduced percent fat (–1.1% ± 2.0 SEM vs. 0.4% ± 1.7 SEM; p = 0.001) and fat mass (–3.2 lb ± 4.7 SEM vs. +0.5 lb ± 4.1 SEM; p = 0.001). Comparing treatment to control, the loss of fat

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mass was signiﬁcantly reduced (control = –0.1 lb ± 4.4 SEM; p = 0.002), but only trends in lowering percent fat were observed. These data provide compelling evidence for the efﬁcacy of the novel chitosan product to facilitate the depletion of excess body weight, presumably fat weight, under free-living conditions very similar to those in which these products are most likely to be used.

CONCLUSION: CHITOSAN AS A WEIGHT MANAGEMENT OPTION After examining all data presented on chitosan as a weight-loss supplement, some could question its importance for a number of reasons. First, only a limited number of human clinical trials have been conducted on chitosan for the purposes of weight management, and, with few exception, these dealt only with scale weight, not including fat mass. As a second point, the results among studies are not as consistent as one would like, probably due to the multiple differences in protocols — different types of chitosan, different doses, different timing of the doses, different diets, different endpoints, and different populations. As a third point, so-called “weight-loss studies” in general, even randomized, double-blinded, placebo-controlled ones, present problems. First, the odds are stacked against showing signiﬁcant weight loss in most clinical studies using the randomized, double-blind, placebo-controlled protocol. We base this on the following realities. Regimens that simultaneously increase muscle mass may mask any fat loss when only scale weight is assessed [51]; in reality, fat loss rather than overall scale weight loss is important. As a ﬁnal point, most subjects invariably weigh themselves and subsequently believe they are on placebo whether that is true or not. This leads to poor compliance. Noncompliance will adversely cloud the positive results in the treatment group, especially when an intention-to-treat analysis is used. It is our opinion that merely counting pills is not sufﬁcient to judge compliance. It is our contention that, even in randomized, placebo-controlled, double-blind studies on weight loss, the odds are stacked against positive results. Accordingly, when such studies are positive, those consumers willing to comply with directions may have even better success.

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Obesity: Epidemiology, Pathophysiology, and Prevention Ylitalo, R., Lehtinen, S., Wuolijoki, E., Ylitalo, P., and Lehtimaki, T., Cholesterol-lowering properties and safety of chitosan, Arzneimittelforschung, 52, 1, 2002. Wada, M., Nishimura, Y., Watanabe, Y., Takita, T., and Innami, S., Accelerating effect of chitosan intake on urinary calcium excretion by rats, Biosci. Biotech. Biochem., 61, 1206, 1997. Wadstein, J., Thom, E., Heldman, E., Gudmunsson, S., and Lilja, B., Biopolymer L112, a chitosan with fat binding properties and potential as a weight reducing agent, in Chitosan Per OS: From Dietary Supplement to Drug Carrier, Muzzarelli, R.A., Ed., Atec, Grottammare, Italy, 2000, pp. 65–76. Krotkiewski, M., Effect of guar gum on body weight, hunger ratings and metabolism in obese subjects, Br. J. Nutr., 52, 97, 1984. Kay, R.M. and Truswell, A.S., Effect of citrus on blood lipids and fecal steroid excretion in man, Am. J. Clin. Nutr., 30, 171, 1977. Costa, M.A., Mehta, T., and Males, J.R., Effects of dietary cellulose, psyllium husk and cholesterol level on fecal and colonic microbial metabolism in monkeys, J. Nutr., 119, 986, 1989. Ganji, V. and Kies, C.V., Psyllium husk ﬁber supplementation to soybean and coconut oil diets of humans: effect of fat digestibility and faecal fatty acid excretion, Eur. J. Clin. Nutr., 48, 595, 1994. Nagyvary, J.J., Falk, J.D., Schmidt, M.L., Wilkins, A.K., and Bradbury, E.L., The hypolipidemic activity of chitosan and other polysaccharides in rats, Nutr. Rep. Intern., 30, 677, 1979. Ikeda, I., Sugano, M., Yoshida, K., Sasaki, E., Iwamoto, Y., and Hatano, K., Hydrolysates with cholesterol and fatty acid absorption and metabolic consequences in rat, J. Agric. Food Chem., 41, 431, 1993. Kanauchi, O., Deuchi, K., Imasato, Y., Shizukuishi, M., and Kobayashi, E., Mechanism for the inhibition of fat digestion by chitosan and for the synergistic effect of ascorbate, Biosci. Biotech. Biochem., 59, 786, 1995. Deuchi, K., Kanauchi, O., Imasato, Y., and Kobayashi, E., Decreasing effect of chitosan on the apparent fat digestibility by rats fed on a high-fat diet, Biosci. Biotech. Biochem., 58, 1613, 1994. Ikeda, I., Tomari, Y., and Sugano, M., Interrelated effects of dietary ﬁber and fat on lymphatic cholesterol and triglyceride absorption in rats, J. Nutr., 119, 1383, 1989. Abelin, J. and Lassus, A., Biopolymer Fat Binder, The Helsinki Report, L-112, ARS Medicina, Helsinki, 1994. Girola, M., De Bernardi, M., Contos, S., Tripodi, S., Ventura, P. et al., Dose effect in lipid-lowering activity of a new dietary integrator (chitosan), Garcinia cambogia extract and chrome, Acta Toxicol. Ther., 17, 25, 1996. Veneroni, G., Veneroni, F., Contos, S., Tripodi, S., De Bernardi, M. et al., Effect of a new chitosan dietary integrator and hypocaloric diet on hyperlipidemia and overweight in obese patients, Acta Toxicol. Ther., 17, 53, 1996. Macchi, G., A new approach to the treatment of obesity: chitosan’s effects on body weight reduction and plasma cholesterol levels, Acta Toxicol. Ther., 17, 303, 1996. Giustini, A. and Ventura, P., Weight-reducing regimens in obese subjects: effects of a new dietary ﬁber integrator, Acta Toxicol. Ther., 16, 199, 1995. Ventura P., Lipid lowering activity of chitosan, a new dietary integrator, Chitin Enz., 2, 55, 1996. Sciutto, A.M. and Colombo, P., Lipid-lowering effect of chitosan dietary integrator and hypocaloric diet in obese subjects, Acta Toxicol. Ther., 16, 215, 1995. Colombo, P. and Sciutto, A.M., Nutritional aspects of chitosan employment in hypocaloric diet, Acta Toxicol. Ther., 17, 287, 1996. Angerer, J.D., Cyron, D.M., Iyer, S., and Jerrell, T.A., Dry Acid–Chitosan Complexes, U.S. Patent No. 6,326,475, 2001. Gades, M.D. and Stern, J.S., Chitosan supplementation does not affect fat absorption in healthy males fed a high-fat diet, a pilot study, Int. J. Obes. Relat. Metab. Disord., 26, 119, 2002. Gades, M.D. and Stern, J.S., Chitosan supplementation and fecal fat excretion in men, Obes. Res., 11, 683, 2003. Gades, M.D. and Stern, J.S., Chitosan supplementation and fat absorption in men and women, J. Am. Diet. Assoc., 105, 72, 2005. Guercolini, R., Radu-Radulescu, L., Boldrin, M., Dallas, J., and Moore, R., Comparative evaluation of fecal fat excretion induced by orlistat and chitosan, Obes. Res., 9, 364, 2001.

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Nesbitt, L., Ricart, C.M., Miranda-Massari, J., and Gonzales, M.J., Long-term effect of a high ﬁber dietary supplement on total body weight, fecal fat, lipid proﬁle and blood pressure in female human subjects, Biomedicina, 2, S9–S12, 1999. Schiller, R.N., Barrager, E., Schauss, A.G., and Nichols, E.J., A randomized, double-blind, placebocontrolled study examining the effects of a rapidly soluble chitosan dietary supplement on weight loss and body composition in overweight and mildly obese individuals, J. Am. Nutraceut. Assoc., 4, 34, 2001. Borosso-Arranda, J., Contreras, F., Bagchi, D., and Preuss, H.G., Efﬁcacy of a novel chitosan formulation on fecal fat excretion: a double-blind, crossover, placebo-controlled study, J. Med., 33, 209, 2002. Tsujikawa, T., Kanauchi, O., Andoh, A., Saotome, T., Sasaki, M. et al., Supplement of a chitosan and ascorbic acid mixture for Crohn’s disease: a pilot study, Nutrition, 19, 137, 2003. Terada, A., Hara, H., Sato, D. et al., Effect of dietary chitosan on faecal microbiota and fecal metabolites of humans, Microb. Ecol. Health Dis., 8, 15, 1995. Blum, J.M., Executive Summary (Internal Report): Chitosol Triglyceride Testing, February 2000. Muzzarelli, R.A., Tanfani, F., Emanuelli, M., Muzzarelli, M.G., and Celia, G., The production of chitosans of superior quality, J. Appl. Biochem., 3, 316, 1981. Bough, W.A., Salter, W.L., Wu, A.C.M., and Perkins, B.E., Inﬂuence of manufacturing variables on the characteristics and effectiveness of chitosan products. 1. Chemical composition, viscosity, and molecular-weight distribution of chitosan products, Biotechnol. Bioeng., 20, 1931, 1978. Wuolijoki, E., Hirveld, T., and Yulizalo, P., Decrease in serum LDL cholesterol with microcrystalline chitosan, Methods Find. Exp. Clin. Pharmacol., 21, 357, 1999. Pittler, M.H., Abbott, N.C., Harkness, E.F., and Ernst, E., Randomized, double-blind trial of chitosan for body weight reduction, Eur. J. Clin. Nutr., 53, 379, 1999. Zahorska-Markiewicz, B., Krotkiewski, M., Olszanecka-Glinanowicz, M., and Zurakowski, A., Effect of chitosan in complex management of obesity, Pol. Merkuriusz Lek., 13, 129, 2002. Ho, S.C., Tai, E.S., Eng, P.H.K, Tan, E.C., and Fok, A.C.K., In the absence of dietary surveillance, chitosan does not reduce plasma lipids or obesity in hypercholesterolemic obese Asian subjects, Singapore Med. J., 42, 6, 2001. Mhurchu, C.N., Poppitt, S.D., McGill, A.T., Leahy, F.E., Bennett, D.A. et al., The effect of the dietary supplement, chitosan, on body weight: a randomized controlled trial in 250 overweight and obese adults, Int. J. Obes. Relat. Metab. Disord., 28, 1149, 2004. Kaats, G.R., Michelak, J.E., and Preuss, H.G., Efﬁcacy and safety of a novel chitosan ﬁber product, J. Am. Coll. Nutr., 25, 389–394, 2006. Crawford, V., Scheckenbach, R., and Preuss, H.G., Effects of niacin-bound chromium supplementation on body composition of overweight African-American women, Diab. Obes. Metab., 1, 331, 1999.

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vulgaris and 32 Phaseolus α-Amylase Inhibition Dennis E. Meiss CONTENTS Introduction ....................................................................................................................................423 Natural Amylase Inhibitors: Occurrence and Chemical Characterization....................................425 Clinical Studies: Crude White Bean Extract .................................................................................425 Clinical Studies: Partially Puriﬁed White Bean Extract ...............................................................425 Clinical Studies: Phase 2® Standardized White Bean Extract ......................................................426 Safety Studies.................................................................................................................................429 Conclusions ....................................................................................................................................429 Disclosures .....................................................................................................................................429 References ......................................................................................................................................430

INTRODUCTION Obesity and being overweight are serious health crises confronting the United States, with the prevalence of obesity increasing nearly 65% over the past decade. Currently, it is estimated that 60% of adult Americans are either overweight, deﬁned as having a body mass index (BMI) greater than 25 kg/m2, or clinically obese (BMI greater than 30 kg/m2). This represents about 110 million overweight adults and 39 million obese adults [1,2]. In addition, obesity is reaching epidemic proportions in adolescents and teens; approximately 25% of American children are overweight and about 10 to 15% are obese [3,4]. Overweight individuals have an increased risk of adult-onset diabetes, coronary heart disease, hypertension, stroke, degenerative arthritis, obstructive apnea, cancer, and perhaps asthma [5,6]. Mortality related to obesity is approximately 300,000 lives per year in the United States. Annual medical costs for diabetes alone are at least $100 billion [2]. In addition to the health risks, overweight individuals often experience a decreased quality of life, including depression, impaired mobility, and poor self-esteem [7]. Fortunately, obesity and overweight are treatable and in many individuals respond favorably to dietary modiﬁcation and moderate exercise. Even a modest weight loss (5%) is associated with a signiﬁcant reduction in the risk of developing chronic diseases, particularly diabetes and heart disease [8]. Numerous pharmacological treatments are available today for weight management. These include serotonergic agents (ﬂuoxetine), noradrenergic agents (sibutramine), and lipase inhibitors (orlistat). While these have been shown to be effective as adjunctive agents to a sensible diet and exercise program, their utility is limited by adverse side effects that include hypertension, seizures, irregular or rapid heartbeat, decreased sexual drive, and fecal incontinence [8].

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Natural-based products (vitamins, minerals, herbs, and other nutritional supplements) and mealreplacement preparations are also promoted for weight loss. These include products that are reported to restrict fat absorption (chitosan) and lipogenesis (Garcinia cambogia); products that are thermogenic and increase metabolic rate (e.g., ephedrine, caffeine, cayenne, medium-chain triglycerides, conjugated linoleic acid, Citrus aurantium); products that enhance insulin sensitivity (e.g., chromium and banaba leaf extract); products that act as diuretics (e.g., vitamin B6, dandelion root, Uva ursi); and products that serve as bulking agents (soluble ﬁbers, such as guar gum, glucomannan, and pectin, and insoluble ﬁbers, such as bran and psyllium). Unfortunately, few of these products are backed by rigorous scientiﬁc research establishing their effectiveness and, in many cases, safety in humans. Furthermore, many of them are not without adverse side effects that may include increased blood pressure and heart rate, insomnia, anxiety, ﬂatulence and gastrointestinal discomfort, and nutrient losses [9]. The general public is using several popular diets that promote weight loss through severe dietary restriction (e.g., high protein, avoidance of carbohydrates, extreme low fat). Individuals often fail to stick with these diets due, in large part, to the difﬁculty of changing eating preferences that have developed from an early age. Many people who go on and off diets not only gain their original weight back but also put on additional pounds as well. The result is a new and higher base-level weight, one that is more difﬁcult to lose the next time a diet is attempted. Further, avoidance diets may not ensure that the individual’s diet contains an appropriate balance of macronutrients (protein, carbohydrate, and fat) and micronutrients (vitamins, minerals, trace elements, amino acids, and essential fatty acids) [10]. Obviously, in conjunction with regular physical exercise, an effective approach to weight management is the restriction of calorie intake under conditions in which all of the essential nutrients are maintained at optimal levels. Although simple in theory, calorie restriction is often impractical because of the instinct to overeat and the difﬁculty in making long-term changes to dietary habits. One promising mechanism is the limitation of calorie contribution from starches, as these contribute nearly one half of the total calorie intake in the average American diet [11]. Starches (also referred to as complex carbohydrates) are large polysaccharides present in plant foods and are provided in the diet primarily from potatoes, bread, pasta, and rice. When starches are eaten, the ﬁrst step in their digestion takes place in the mouth, where salivary α-amylase is secreted by the parotid glands. Starches are hydrolyzed primarily into the disaccharide maltose. Because of the brief time that food is chewed, however, salivary digestion accounts for only a small percentage (approximately 5%) of total starch digestion. The majority of starch digestion takes place in the upper small intestine (duodenum and jejunum), where pancreatic cells secrete a large quantity of another form of α-amylase that is nearly identical to the salivary enzyme but is many times more powerful. In general, starches are almost completely converted to maltose and other small glucose polymers at about the time the contents are passed farther into the intestine, where other enzymes break the disaccharides into monosaccharides, primarily glucose. These sugar molecules are absorbed by the brush border of the small intestine. Once absorbed, these sugars are delivered to the liver via the portal vein and enter into intermediary metabolism, where they are stored as glycogen and eventually burned by cells for energy. However, if caloric intake exceeds energy output, the sugars are converted to and stored as fat. Inactivity leads to the progressive accumulation of fat and increase in body weight. Starches that escape digestion and absorption in the intestine pass into the colon, where they are fermented into short-chain fatty acids, organic acids, carbon dioxide, and hydrogen by anaerobic bacteria [12]. The extent of carbohydrate digestion can be measured by hydrogen exhalation [13] or a combination of carbon dioxide and hydrogen exhalation [14]. It is estimated that approximately 10% of all starch consumed by humans passes through the GI tract undigested [15]. An increase in the amount of undigested starch may have multiple health beneﬁts, including weight loss, blood lipid improvement, glycemic control, and antioxidant protection.

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NATURAL AMYLASE INHIBITORS: OCCURRENCE AND CHEMICAL CHARACTERIZATION Common beans (Phaseolus vulgaris) and grains (wheat, barley, rye) are natural sources of α-amylase inhibitors. Although the physiologic role of these inhibitors is not completely elucidated, they are proposed to be a defense mechanism against insects or metabolic regulators [16]. Three different glycoprotein isoforms (αAI-1, αAI-2, and αAI-3) have been isolated from P. vulgaris that differ with respect to electrophoretic mobility, heat stability, and subunit composition [17–19]. αAI-1, a 43-kDA dimeric glycoprotein, inhibits porcine [19] and human [20] pancreatic amylase and is thermostable. Kinetic data suggest that αAI-1 binds tightly to speciﬁc locations on the amylase molecule and induces an irreversible conformational change, resulting in impairment of enzyme activity [19,20].

CLINICAL STUDIES: CRUDE WHITE BEAN EXTRACT In the 1970s, researchers reported the presence of a proteinaceous component of the white kidney bean (Phaseolus vulgaris L.) that speciﬁcally inhibited α-amylase activity [21]. Several crude bean extracts were subsequently marketed promising to reduce body weight by limiting starch digestion in humans. Subsequent clinical studies, however, failed to show signiﬁcant effectiveness in humans [22–25], and the U.S. Food and Drug Administration halted further sales in 1983 [26]; however, later studies conducted at the Mayo Clinic conﬁrmed that the commercial preparations exerted antiamylase activity in test tube experiments but did not have sufﬁcient activity to decrease starch digestion when ingested by humans.

CLINICAL STUDIES: PARTIALLY PURIFIED WHITE BEAN EXTRACT Subsequently, a partially puriﬁed extract was synthesized from the white kidney bean that had much higher anti-α-amylase activity and was stable in gastric and intestinal solutions [27]. The extract (puriﬁed six- to eightfold by total protein content), perfused into the duodenum of seven human subjects, inactivated amylase in the intestinal lumen in a dose-dependent fashion as measured by continuous aspiration of gastric and duodenal contents. At 2.0-, 3.5-, and 5.0-mg/mL perfusions, amylase inhibition of 94%, 99%, and 99.9%, respectively, was observed. It was concluded that a partially puriﬁed amylase inhibitor that is stable in gastric ﬂuid may decrease intestinal digestion of starch in humans. Four fasting subjects were intubated with an oroileal tube for measurement of duodenal, jejunal, and ileal intraluminal amylase activity following ingestion of 50 g of rice starch given with placebo, 5 g of the white bean extract, or 10 g of extract [28]. The extract signiﬁcantly (p < 0.05) reduced amylase activity by more than 95% in as soon as 15 minutes and persisted for up to 2 hours. It also increased postprandial delivery of carbohydrates to the bowel, increased breath hydrogen, and shortened duodenoileal transit time. Additionally, decreases in insulin, C-peptide, gastric inhibitory peptide, and postprandial glucose levels were observed. The extract did not affect trypsin secretion, suggesting a speciﬁc action of the extract on amylase. Coingestion of the partially puriﬁed white bean extract with 50 g of starch substantially reduced postprandial release of insulin and plasma glucose concentrations both in normal and diabetic individuals [29]. The extract was thus proposed to be possibly beneﬁcial for the clinical management of individuals with diabetes mellitus. A placebo, 2.0 g, or 2.9 g of the white bean extract was administered to 8 healthy subjects along with a 650-calorie mixed meal containing protein, fat, and carbohydrate [30]. Compared to placebo and 2.0 g of extract, individuals consuming 2.9 g of extract showed signiﬁcant increase in breath hydrogen excretion between 45 and 180 minutes after the meal. Postprandial glucose, C-peptide, and gastric inhibitory peptide were also lowered. No diarrheic side effect was observed, indicating that the extract may be a safe and effective adjunctive aid for use in obesity or diabetes mellitus.

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Carbohydrate malabsorption was observed in 13 volunteers who ingested lactulose as a starch substrate, spaghetti alone, and spaghetti with inhibitor [31]. Breath hydrogen excretion was increased more than twofold with amylase inhibitor over an 8-hour test period compared to the other two test conditions (p < 0.05). Calculation of the percentage of malabsorbed starch showed signiﬁcant reduction with spaghetti plus inhibitor (7.0 ± 1.4%) compared to spaghetti alone (4.7 ± 1.9%; p < 0.05). Six non-insulin-dependent diabetics were given 4 to 6 g of the partially puriﬁed white bean extract with each meal over a 3-week test period [32]. Signiﬁcant reductions (p < 0.05) were seen at days 7, 14, and 22 in postprandial plasma glucose, C-peptide, gastric inhibitory peptide concentrations, and total carbohydrate absorption (measured by breath hydrogen). Diarrhea occurred on the ﬁrst day of administration of the extract but decreased thereafter, presumably due to changes in probiotic metabolism of undigested carbohydrate. Eighteen healthy volunteers were intubated with an oroileal tube and administered a standardized mixed meal over 10 minutes [33]. Simultaneously, test solutions of normal saline or carbohydrate were perfused over a 7-hour period. The perfusate administered to one half of the test subjects contained white bean amylase inhibitor. Gastric emptying (measured by dual-headed camera) was signiﬁcantly slowed by amylase inhibitor compared to placebo or carbohydrate alone. Plasma concentrations of hormones and the amount of carbohydrates passing the ileum were measured every 10 minutes. Slowing of gastric emptying time was positively associated with decreased concentrations of gastric inhibitory peptide and neurotensin and increased concentrations of peptide YY. No association was seen between slowing of gastric emptying and plasma concentrations of C-peptide, glucagons, motilin, gastrin, and human pancreatic peptide. Thus, the white bean amylase inhibitor extract increases gastric emptying through mediation of gastrointestinal hormones. Sixty-two overweight (BMI = 26 to 30 kg/m2) and obese (BMI > 30 kg/m2) subjects were randomized to receive either 150 mg of Phaseolus vulgaris extract mixed with 25 mg of locust bean extract or placebo [34]. Subjects were instructed to take two capsules three times daily at the main meals and to avoid any changes in daily diet and exercise. After 3 months, serum cholesterol levels were modestly reduced in the extract group but not in the placebo. No change was seen in high-density cholesterol, low-density cholesterol, or triglyceride levels in either group; however, after 9 months, low-density cholesterol and the ratio of low- to high-density cholesterol were reduced in the active group without accompanying further change in total cholesterol. Placebo group values remained unchanged. Neither the extract nor the placebo was associated with changes in other nutritional parameters, including serum vitamin B12, folic acid, ferritin, and albumin. Overall, long-term supplementation with white bean extract increased fecal fat excretion and improved serum lipoprotein proﬁles. These studies demonstrate that a partially concentrated extract of the white kidney bean containing a natural amylase inhibitor demonstrates an ability to reduce carbohydrate absorption in humans and the subsequent rise in blood sugar levels in healthy and diabetic individuals. This suggests potential beneﬁt for weight loss and management of glucose metabolism.

CLINICAL STUDIES: PHASE 2® STANDARDIZED WHITE BEAN EXTRACT Recently, a standardized extract from the white kidney bean (Phaseolus vulgaris) was developed that appears to effectively reduce starch absorption in humans. The extract survives undiluted gastric and intestinal solutions, retaining about 70 to 80% of its activity. It is also speciﬁc to α-amylase, and no effect is seen on other digestive enzymes [35]. The following studies were all performed using the Phase 2® proprietary white bean extract. A double-blind, placebo-controlled pilot study on ten human subjects (male and female) comparing Phase 2® to placebo in normoglycemic individuals measured pre- and postprandial glucose levels as an index of starch digestion and absorption [36]. After an overnight fast, baseline

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plasma glucose levels were obtained and participants were then randomized to receive a standardized meal containing 60 g of starch (4 slices of white bread) and either a placebo or 1500 mg of Phase 2®. Participants (laboratory personnel) went about their regular work activity. Plasma glucose was measured every 30 minutes postprandial for 4 hours. After one week, the participants crossed over and repeated the procedure with the other product. The plasma glucose levels of the Phase 2® group showed consistently lower values and returned to baseline 20 minutes earlier than the placebo group. In addition, the area under the curve (a measure of glucose absorption), averaged 57% less in subjects taking Phase 2® compared to those taking a placebo. Statistical signiﬁcance was not reported. No adverse effects were reported by any of the test subjects following consumption of the extract. A second pilot study was identical in design to the ﬁrst, with the exception that test subjects were inactive during the course of the study, and plasma glucose measurements were taken every 15 minutes for the ﬁrst hour and every 20 minutes for the second hour [37]. The same test meal that was used in the previous study was given to the subjects, and the Phase 2® dosage remained at 1500 mg. This study was undertaken to determine whether physical activity may have signiﬁcantly inﬂuenced the observed differences in the earlier pilot study. Although only 4 subjects completed the study (2 withdrew unrelated to side effects and 4 because they were classiﬁed as nonresponders due to negative areas under the curve), participants receiving Phase 2® averaged an 85% reduction in plasma glucose response as determined by the area under the curve. Results did not reach statistical signiﬁcance due to the small sample size. Again, no adverse side effects were reported. Seven subjects were fed two standardized mixed meals (630 calories; 64 g carbohydrate, 29 g protein, 29 g fat) in random fashion with and without coadministration of one half (750 mg) the dosage of Phase 2® used in the previous two pilot studies [38]. Plasma glucose levels were monitored at 10-minute intervals for the ﬁrst hour and at 20-minute intervals for the second hour. The area under the curve was 28% lower when Phase 2® was consumed with the meal, and plasma levels returned to baseline faster than control. If the contribution of simple sugars consumed in the dessert portion of the meal is excluded, then the area under the curve was 42% lower for the Phase 2® group. Compared to earlier studies described above, Phase 2® white bean extract appears to exert a dose–response effect at 750 mg and 1500 mg per meal dosage. The results of these pilot studies indicate that a proportion of the starch calories from the test meal were undigested when coingested with Phase 2® white bean extract as indicated by reduced postprandial glucose absorption and metabolism. Participants reported no adverse side effects in any of these studies. A 12-week randomized, double-blind, placebo-controlled study was conducted on 40 overweight and obese subjects of both sexes ages 18 years or older [39]. Subjects in the active group consumed 400 mg of Phase 2® three times daily immediately before each meal. Subjects consuming Phase 2® showed statistically signiﬁcant body weight loss, BMI reduction, and body fat loss compared to those consuming the placebo. Subjects in the active group lost an average of 3.5 kg (7.7 lb) by the end of the study. Body fat analyses by two different methods (bioimpedance and near-infrared) showed that the majority (>85%) of the weight loss was accounted for by body fat. No signiﬁcant differences in hip and waist circumferences in the active group were found. The placebo group showed no signiﬁcant changes in any of the test parameters. None of the subjects in either group reported any adverse side effects. The results are somewhat complicated by the inclusion of inulin (derived from chicory root) and Garcinia cambogia in the formula. Inulin is particularly interesting, as it is approved by the German Commission E for use as an appetite stimulant. Garcinia cambogia (and its active ingredient, (–)-hydroxycitrate) is purported to assist weight loss by preventing the uptake of fat from the small intestine [40], although few studies have been published to conﬁrm this. Twenty-seven (BMI > 30 kg/m2) individuals completing a randomized, double-blind, placebo-controlled study were instructed to take either 1500 mg of Phase 2® white bean extract or placebo twice daily with lunch and dinner for a period of 8 weeks [41]. Participants taking the

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active material lost an average of 3.8 lb at the end of the 8-week study period, whereas those on placebo lost an average of 1.65 lb. Active participants thus lost 129% more than those on placebo. Patients on the active material also lost an average of 1.47 in. around their waists which was 36% more than those on placebo (average loss, 1.07 in.). While not statistically signiﬁcant due to the limited sample size, the results are consistent with other human weightloss studies using Phase 2®. Another favorable result of this study was the effect of the active extract on serum triglycerides, which are directly associated with body fat storage. Test subjects taking the white bean extract exhibited an average 26.3 mg/dL decrease in triglyceride levels, whereas those on placebo averaged an 8 mg/dL decrease. Again, while not statistically signiﬁcant due to sample size, the difference in average values between the two groups was more than 300%. Additionally, subjects on the extract reported a 13% increase in energy as measured by the Likert Scale compared to those on placebo who reported no improvement. Although this is a subjective measure and not statistically signiﬁcant, this is worth noting because amylase inhibitors do not exert any stimulant action. A more extensive study involved 60 healthy males and females ages 25 to 45 years [42]. Volunteers were selected for the double-blind, placebo-controlled study based on a stable body weight ranging from 5 to 15 kg (12 to 33 lb) over optimal body weight for 30 days prior to participation in the study. They were instructed to follow a recommended diet with daily consumption of starchy foods during one of the principal meals. Study participants consuming 445 mg of white bean extract once daily before one of the principal meals lost an average of 6.45 lb (3.96% of body weight) by the end of the 30-day study, whereas those consuming a placebo lost an average of 0.76 lb (0.47% body weight). In addition, those on Phase 2 ® lost 10.45% of fat body mass, 3.44% waist circumference, 1.44% thigh circumference, and 1.39% hip circumference. These losses occurred without any change in lean muscle mass. Placebo participants had losses of 1.30%, 0.53%, 0.39%, and 0.10%, respectively. The observed differences were statistically signiﬁcant for all test parameters (p < 0.001, Student’s t-test). No signiﬁcant adverse effects were reported by any of the patients taking the extract, indicating that it is safe and well tolerated. A randomized, double-blind, placebo-controlled study (with crossover) was performed using 60 overweight and obese subjects [43]. Subjects received either 1000 mg of Phase 2® white bean extract (combined with 500 mg of fennel seed powder) or placebo with lunch and dinner. Subjects were randomly allocated into two groups. Group 1 received placebo for 12 weeks, then crossed over to active for the next 12 weeks. Group 2 received the active treatment for the entire 24-week study period. Subjects were instructed to include at least 100 to 200 g of carbohydrates in each lunch and dinner meal. Preliminary data analysis failed to demonstrate a signiﬁcant difference in body weight, waist and hip circumference, or body fat composition between active and placebo. This appears to reﬂect wide variation in patient values and differences in adherence to study protocol. However, serum cholesterol levels decreased 10.7 mg/dL in the active group and increased 1.6 mg/dL in the placebo group (p = 0.07) and triglycerides showed a decrease of 10.22 mg/dL in the active group compared to an increase of 1.5 mg/dL in the placebo group (p = 0.07). No differences were seen in diastolic or systolic blood pressure. No adverse events were reported by any of the subjects in either test group. Ten subjects (ﬁve male, ﬁve female) with body fat > 25% and BMI of 25 to 30 kg/m 2 were administered 750 mg of Phase 2® 30 minutes prior to lunch and dinner for 8 weeks [44]. The test supplement also contained 100 mg clove powder and 10 mg each of L-lysine, L-arginine, and L-alanine. The following results comparing baseline and end-of-study average values were determined to be statistically signiﬁcant at the 0.5 level. Body weight decreased 1.8 kg, body fat ratio decreased 1.2%, body fat decreased 1.4 kg, BMI decreased 0.7, waist circumference decreased 4.8 cm, and hip circumference decreased 3.1 cm. Favorable effects were observed on cardiovascular parameters. Systolic pressures decreased an average of 9 mmHg, and diastolic pressures decreased 11 mmHg. Triglycerides were lowered an average of 37 mg/dL. Lean muscle

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mass was similar for all test subjects at the beginning and at the end of the 8-week study period. No unfavorable effects were reported, and standard serum chemistry panel results showed no changes that might indicate an adverse clinical effect.

SAFETY STUDIES Acute toxicity studies of Phase 2® Phaseolus vulgaris extract showed that ingestion of amounts up to 2.5 g/kg body weight produced no changes in hematological, biochemical, or histopathological parameters after 7 days administration to rats [45]. Similarly, no adverse changes were seen after 90 days when Phase 2® was chronically administered at dosages as high as 3.0 g/kg body weight [46]. The results of these studies indicate that Phase 2® Phaseolus vulgaris extract is safe and support its use as a weight management adjunct. High amounts of white bean amylase inhibitor may cause diarrhea and ﬂatulence due to the increased amount of fermentable ﬁber passing into the colon [30,32]. The effect was transient and resolved quickly, leading to the suggestion that there was an inducible change in probiotic ﬂora that compensated for the increased ﬁber content; however, the majority of the human clinical studies using Phaseolus vulgaris reported no adverse events. This is in contrast to prescription α-glucosidase inhibitors (e.g., acarbose), which frequently induce ﬂatulence, diarrhea, or abdominal discomfort [47]. No reported drug interactions with amylase inhibitors have been reported. Given that the effective dosage seen in human clinical studies is between 500 and 1500 mg and is without adverse effect or drug interactions, Phaseolus vulgaris amylase inhibitor extract promises to be a safe and effective weight management adjunct.

CONCLUSIONS Control of carbohydrate absorption through the inhibition of α-amylase activity offers promise as an effective adjunct to a sensible weight management program. Amylase inhibitors can be extracted from a number of plant sources, especially those in the legume family (Phaseolus vulgaris) and wheat. The studies reported here suggest that ingestion of moderate (500 to 1500 mg) amounts of an extract of the white bean Phaseolus vulgaris containing a natural amylase inhibitor with starch-rich meals shows promise as a safe and effective therapeutic adjunct for reducing absorption of dietary starches, thus lessening the caloric load. In addition to the potential beneﬁts for weight management, a reduction in carbohydrate absorption through amylase inhibition appears to help normalize blood cholesterol and triglyceride levels. The long-term beneﬁt may be a reduction in comorbidities associated with excess body weight and obesity including diabetes and heart disease. Additional research is necessary to fully understand the potential beneﬁts of this mechanism for human use. More randomized, double-blind, placebo-controlled studies are needed to conﬁrm statistical differences in weight loss induced by limiting carbohydrate calories through α-amylase inhibition. Such studies should be extended over several months to determine if the effect of calorie neutralization is lasting. More information is required to establish the optimal effective dose and time of administration. Through sound, rigorous scientiﬁc research on natural weight-control products, we will ensure a healthier population, improved quality of life, and reduced risk of chronic disease.

DISCLOSURES The author discloses that he has provided consulting services to Pharmachem Laboratories, Kearney, NJ, to assist in the development of Phase 2® extract derived from Phaseolus vulgaris. The author has no ﬁnancial interest in Pharmachem Laboratories. He is the President/CEO and founder of ProThera®, Inc., which distributes a line of dietary supplements, including one containing Phase 2®, to the professional medical market.

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in 33 Glucomannan Weight Loss: A Review of the Evidence Barbara Swanson and Joyce K. Keithley CONTENTS Introduction ....................................................................................................................................433 Prevalence of Dietary Supplement Use for Weight Reduction..............................................434 Dietary Fiber and Weight Reduction......................................................................................434 Glucomannan .................................................................................................................................435 Structure ..................................................................................................................................435 Proposed Mechanisms of Action............................................................................................435 Dilution of Energy Density .............................................................................................435 Promotion of Satiety........................................................................................................435 Fecal Energy Loss ...........................................................................................................436 Pharmacokinetics ....................................................................................................................436 Safety ......................................................................................................................................436 Drug Interactions ....................................................................................................................437 Dosage.....................................................................................................................................437 Glucomannan and Weight Loss: Review of Controlled Trials .....................................................437 Clinical Implications ......................................................................................................................438 Case Study......................................................................................................................................438 Past Medical History ..............................................................................................................439 Conclusions and Future Directions ...............................................................................................440 References ......................................................................................................................................440

INTRODUCTION Treatment of overweight and obesity is exceedingly difﬁcult. Conventional management consists of low-calorie diets, physical activity, behavioral interventions, and pharmacological agents; however, long-term adherence to these approaches is problematic, and most individuals regain the majority of lost weight within one or two years [1]. It has been suggested that the addition of novel approaches to conventional treatments may produce sustainable weight loss. One approach is ﬁber supplements. Glucomannan, a water-soluble dietary ﬁber supplement, has been associated with reductions in body weight in a few small studies [2–9] and may be an effective adjunct for overweight and obese individuals.

433

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PREVALENCE OF DIETARY SUPPLEMENT USE FOR WEIGHT REDUCTION In 2001, retail sales of weight-loss supplements in the United States totaled $1.3 billion [10], likely reﬂecting the aggressive marketing of these products by their manufacturers. A multistate survey (N = 14,679) found that, within the previous two years, 14.3% of persons who were currently trying to lose weight and 11.3% of obese persons had used nonprescription weightloss supplements. Among obese women, usage rates rose to 28.4%. Interestingly, 5.1% of normal-weight persons reported use of nonprescription supplements, potentially exposing themselves to supplement-speciﬁc risks that are not offset by the beneﬁts of weight reduction [11]. Among the many categories of dietary supplements used for weight loss are those containing dietary ﬁber.

DIETARY FIBER

AND

WEIGHT REDUCTION

Dietary ﬁber refers to indigestible plant and nonplant dietary substances. Dietary ﬁber and ﬁber supplements are postulated to promote weight loss by modulating energy intake and loss. Because of their low energy density, coupled with their bulking and viscosity-producing properties, ﬁber and ﬁber supplements can supplant energy-dense nutrients, decrease hunger and appetite, and reduce protein, carbohydrate, and fat absorption [12,13]. Studies examining the association between dietary ﬁber and weight loss date back to the late 1950s. Epidemiologic studies have generally found that ﬁber intake is inversely associated with body weight and body mass index (BMI) in individuals consuming self-selected diets [14–17]. With few exceptions, the majority of clinical studies have found that high-ﬁber diets are associated with reduced energy intake, reduced hunger and increased satiety, and increased weight loss. In a recent systematic review [13], beneﬁcial effects were seen with both highﬁber diets and ﬁber supplements. Almost all studies reported decreases in energy intake, increases in satiety or decreases in hunger, and increases in weight loss. Greater reductions in energy intake (82% vs. 94% of baseline intake) and weight (2.4 kg vs. 0.8 kg) were noted in overweight and obese individuals compared to normal-weight individuals. In the majority of studies, ﬁber supplements yielded better results than high-ﬁber diets, suggesting greater beneﬁts from ﬁber supplements, as well as easier use and adherence, compared to ﬁber-rich foods. Fiber supplement dosages ranged from 5 to 40 g/day (mean, 7 to 10 g/day), and the effects of solubleﬁber vs. insoluble-ﬁber vs. mixed-ﬁber supplements were comparable. Other comprehensive reviews provide additional evidence that increased ﬁber consumption is associated with increases in satiety and reductions in hunger, energy intake, and body weight [18,19]. The most widely used ﬁber supplements for achieving weight loss include guar gum, plantago psyllium, and glucomannan. The safety and efﬁcacy of guar gum, a water-soluble ﬁber, for reducing body weight were evaluated in a meta-analysis [20]. Statistically pooled data from 11 double-blind prospective randomized clinical trials indicated that guar gum was ineffective for promoting weight loss and was associated with numerous adverse events, including diarrhea, ﬂatulence, and other gastrointestinal complaints. Plantago psyllium, another water-soluble ﬁber, has been evaluated in one prospective randomized clinical trial [21]. No signiﬁcant changes in weight were reported, although glucose and lipid parameters were signiﬁcantly improved. Although ﬁber is hypothesized to promote weight maintenance following weight loss, few long-term trials have been conducted. Two small studies have shown that mildly obese participants who were given ﬁber supplements were better able to sustain weight loss over 6 months to 1 year than those given a placebo [22,23]. Limited evidence indicates that glucomannan may be a promising ﬁber supplement for weight loss.

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Glucomannan in Weight Loss: A Review of the Evidence 6

CH2OH H

5

O

H

H OH

H

H

OH

CH2OCOCH3

O

4

H

O

3

H

Glucose

CH2OH H

H OH

H

435

1

H

O

CH2OH

O

H

H OH HO

O H

O H OH HO

O H

2

OH

Glucose with acetate group on carbon 6

H

OH

Mannose

H

H

Mannose

FIGURE 33.1 Structure of a segment of glucomannan with repeating glucose and mannose units.

GLUCOMANNAN STRUCTURE Glucomannan is a water-soluble, fermentable dietary ﬁber extracted from the tuber or root of the elephant yam, also known as konjac (Amorphophallus konjac or Amorphophallus rivieri). Glucomannan consists of a polysaccharide chain of β-D-glucose and β-D-mannose with attached acetyl groups in a molar ratio of 1:1.6 with β-1,4 linkages (Figure 33.1) [24–26]. Human amylase cannot split β-1,4 linkages, thus glucomannan passes relatively unchanged into the colon, where it is highly fermented by colonic bacteria. It has a high molecular weight (average, 1,000,000 Daltons) and can absorb up to 50 times its weight in water, making it one of the most viscous dietary ﬁbers known [25]; therefore, much smaller doses of glucomannan are needed compared to other types of ﬁber supplements.

PROPOSED MECHANISMS

OF

ACTION

See Table 33.1. Dilution of Energy Density Fiber has a low calorie content and can lower the energy-to-weight ratio of consumed food [13]. Because studies suggest that eating patterns are driven by the weight of food consumed, rather than caloric intake [27,28], ﬁber can displace the energy of other nutrients for a given weight of food and still induce satiety [29]. Promotion of Satiety Glucomannan may promote satiety via several mechanisms. Eating ﬁber requires increased mastication effort that may induce cephalic- and gastric-phase signals that promote satiety [13]. Glucomannan increases the viscosity of the gastrointestinal contents, thus slowing gastric emptying and

TABLE 33.1 Mechanisms by Which Glucomannan May Induce Weight Loss Stomach Absorption of water → ↑ intraluminal viscosity, ↓ energy intake, ↑ satiety, ↓ gastric emptying, ↓ insulin secretion

Small Bowel

Colon

Feces

Mechanical barrier to enzymatic digestion

Fermentation → short-chain fatty acids → ↓glucose production, ↑insulin sensitivity, ↓insulin secretion

Excretion of most shortchain fatty acids and some undigested glucomannan

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TABLE 33.2 Physiochemical Characteristics of Glucomannan Characteristic Molecular weight Molar ratio Solubility Digestibility Absorption

Property Average, 1 million Daltons 1 glucose:1.6 mannose Highly water soluble; expands up to 50 times its weight in digestive tract Small intestine, resistant to hydrolysis by digestive enzymes Large intestine, fermented by colonic bacteria Minimal from large intestine

inducing satiety. Moreover, evidence suggests that the short-chain fatty acid byproducts of glucomannan fermentation in the gut regulate satiety [18]. Additionally, glucomannan can attenuate postprandial insulin surges by reducing absorption, accelerating the delivery of food to the terminal ileum where satiety signals are transmitted, and elevating plasma cholecystokinin levels, a hormone postulated to mediate fat-induced satiety [12,13,30–32]. Fecal Energy Loss Soluble ﬁbers have been shown to reduce fat and protein absorption [33], possibly by reducing their physical contact with intestinal villi; however, it remains unclear whether this mechanism leads to weight loss. Evidence suggests that this energy loss is offset by the energy produced through the fermentation of soluble ﬁbers and trapped nutrients in the colon [13]. Considerable evidence indicates that soluble ﬁber inhibits carbohydrate absorption [34] and improves glycemic parameters [35,36].

PHARMACOKINETICS The bioavailability of glucomannan is very low; only small amounts are absorbed and reach the plasma (Table 33.2). To date, no validated methods exist to measure plasma concentrations of glucomannan or its metabolites in humans following therapeutic doses, thus limiting investigation of its pharmacokinetic properties. Glucomannan is resistant to hydrolysis by digestive enzymes, so it is only minimally digested in the small intestine. Substantial fermentation by colonic bacteria occurs in the large intestine, producing short-chain fatty acids and several byproducts (e.g., formic acid, acetic acid, butyric acid, propionic acid, glucose, mannose). Although small amounts of some of these products may be absorbed from the large intestine, most are excreted in the feces, along with some undigested glucomannan [37].

SAFETY The konjac tuber is widely used in Asia as an ingredient in the manufacture of jelly candies, tofu, and noodles. Konjac ﬂour has been used as a food stabilizer and gelling agent and has been approved by the U.S. Department of Agriculture as a binder for meat products. Because of its water-absorptive properties, konjac jelly candies have been implicated in several choking deaths around the world, leading to its ban in the United States, Europe, and Australia [38]. Glucomannan is available in capsule form or as a drink mix. It is no longer available in tablet form, as contact with water can cause the tablets to swell before they reach the stomach. Nine cases of esophageal obstruction caused by ingestion of glucomannan tablets have been reported [39]. No reports of esophageal obstruction associated with ingestion of glucomannan capsules have been reported, presumably because the outer casing shields the ﬁber from water prior to reaching the stomach [40]. There

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TABLE 33.3 Clinical Studies of Glucomannan and Weight Loss Study

Sample

Design

Intervention

Duration

Weight Results

Walsh et al. [9] Reffo et al. [5]

20 F, OB 31 NW hypertensives

Parallel Parallel

1 g 3×/day 1 g 3×/day

8 weeks 4 weeks

Reffo et al. [6] Livieri et al. [4] Vita et al. [8] Vido et al. [7] Cairella et al. [3] Birketvedt [2]

28 NW post-MI 53 OB children 50 OB 60 OB children 30 OW/OB children 176 OW

Parallel Parallel Parallel Parallel Parallel Parallel

1.5 g 2×/day 2–3 g/day 4 g/day 2 g/day Not speciﬁeda 1.24 g/day

8 weeks 4 months 3 months 8 weeks 8 weeks 5 weeks

–5.5 lb, p ≤ 0.005 –1.4 kg, p < 0.001; –2.4 kg, p < 0.01 with calorie restriction –2.2 kg., p < 0.001 Signiﬁcant reductionsa Signiﬁcant reductionsa Signiﬁcant reductionsa Substantial reductionsa –3.8 kg, p < 0.01

a

From English abstract of Italian manuscript.

Abbreviations: F, females; OB, obese; OW, overweight; NW, normal weight; MI, myocardial infarction

have been few adverse events associated with the use of glucomannan capsules. Most events have involved minor gastrointestinal complaints, such as bloating, gas, and mild diarrhea; in clinical studies of glucomannan, the overall rate of adverse effects is less than 0.05% [41,42]. One case report in Spain indicated a possible association between acute hepatitis of cholestatic type and the use of glucomannan in a patient with a previous history of drug use and recent use of several other herbal supplements [43].

DRUG INTERACTIONS Glucomannan has been shown to lower blood glucose levels and should not be taken in association with medications or other dietary supplements that have hypoglycemic effects [35,36,44]. Glucomannan reduces the absorption of sulfonylurea medications [45] and may reduce the bioavailability of other oral medications taken concomitantly. Glucomannan also may reduce the absorption of fat-soluble vitamins in supplements or in foods. For these reasons, oral medications should be taken 1 hour before or 4 hours after ingesting glucomannan capsules [42].

DOSAGE The recommended dosage for weight loss is 1 g three times a day, 1 hour before meals. For managing type 2 diabetes or insulin resistance, 3.6 to 13 g/day have been administered [41].

GLUCOMANNAN AND WEIGHT LOSS: REVIEW OF CONTROLLED TRIALS A few small studies suggest that glucomannan may be well tolerated, promote moderate weight loss in overweight and obese individuals, and have beneﬁcial effects on lipid and glucose parameters. Seven studies with weight loss as the primary outcome measure found that daily supplementation with glucomannan (dosage range, 2 to 4 g; treatment duration, 4 to 16 weeks; mean sample size, 39) produced signiﬁcant or nonsigniﬁcant decreases (–3.08 to –5.5 lb) in body weight in healthy overweight and obese individuals (Table 33.3) [3–9]. Similar effects were seen whether the participants consumed self-selected, normocaloric, or hypocaloric diets. Other beneﬁcial effects were increased satiety, improved lipid proﬁle, improved diet adherence, and improved glycemic status. Adverse events were minimal and included a few reports of mild bloating/ﬂatulence, which

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caused two participants to drop out of one study [6]. These ﬁndings are consistent with those of a recent short-term study in which glucomannan supplements in conjunction with a 1200-kcal diet resulted in a weight loss of approximately 8.8 lb over a 5-week period in healthy overweight individuals [2]; the addition of guar gum and alginate to glucomannan did not confer additional weight loss effects. Limitations of these studies include the use of sample sizes not supported by power analysis, the use of heterogeneous samples of overweight and obese individuals with lack of appropriate controls for comorbidities and confounders, and the use of mostly Caucasian participants. It is also noteworthy that most of the studies were conducted 10 or more years ago, and four of the studies were published in Italian, limiting the depth and amount of information abstracted. A series of studies have examined the safety and efﬁcacy of glucomannan for modulating lipoprotein and glucose parameters in patients with type 2 diabetes and/or hypercholesterolemia with body weight loss as a secondary outcome measure [35,36,44,46,47]. The lipid proﬁles (total cholesterol, LDL-C, and TC/HDL-C) were signiﬁcantly improved in three of the studies [36,44,47]. Other ﬁndings included signiﬁcant reductions in systolic blood pressure [35], serum fructosamine [35,36], and apolipoprotein B [36,44], as well as greater excretion of fecal neutral sterol and bile acids [44,47]. Similar to the weight-loss studies, either no adverse events or only a few transient gastrointestinal symptoms (ﬂatulence, soft stools) were reported. These ﬁndings suggest that glucomannan favorably modulates metabolic parameters independent of weight loss. Interestingly, all of the studies that measured weight loss as a secondary endpoint showed no reductions in body weight, when presumably many of the participants were overweight. One explanation might be that the duration of these studies (3 to 4 weeks) was inadequate to observe a statistically signiﬁcant weight loss. Additionally, these studies generally had small sample sizes and may have been underpowered to detect statistically signiﬁcant weight changes.

CLINICAL IMPLICATIONS Clinicians should encourage patients to use glucomannan supplements from manufacturers that are state certiﬁed as compliant with good manufacturing practices. Additionally, when possible, they should select products whose composition and purity have been tested by an independent laboratory. Such products may contain quality labels, such as USP ®, ConsumerLab®, or TruLabel®. Unless purity data are available, supplements imported from foreign countries should be avoided, as manufacturing practices may fall short of U.S. standards. Some glucomannan products contain multiple pharmacologically active ingredients. For example, Glucomannan+® (Swanson Health Products; Fargo, ND) contains glucomannan, as well as chromium, chitosan, guar gum, gymnema, psyllium, and L-carnitine. Chromium and gymnema both have hypoglycemic properties, thus the risk of hypoglycemia, as well as pharmacodynamic interactions with oral hypoglycemics or insulin, may be increased. This underscores the need for clinicians to consider the safety proﬁle and potential drug interactions of each ingredient when reviewing multi-ingredient supplements with their patients. The following case study illustrates other clinical implications of glucomannan.

CASE STUDY BF, a 42-year-old female, presents to the clinic for consultation on weight loss. She mentions that she began taking glucomannan a week ago and has lost 2 pounds. You have seen BF routinely for several months, and she wonders what you think of glucomannan. She has tried a number of fad diets — Slim·Fast®, the grapefruit diet, Sugar Busters!® — all without success. You are concerned about her weight (192 lb prior to starting glucomannan), particularly because at her last visit she had an elevated fasting blood glucose (180 mg/dL) and was hypertensive (180/95).

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PAST MEDICAL HISTORY BF is overweight with history of multiple fad diets and cycles of weight gain and loss. • • • • • •

Lifestyle history — BF denies use of wine, hard liquor, and beer and denies current use of tobacco products. She has no structured activity or exercise patterns. Social history — BF is married with four children (ages 3 to 14); a homemaker; collegeeducated with a degree in English. Family history — Her family has a tendency to be overweight. Her mother has a history of diabetes, and her father is hypertensive with coronary artery disease. Medications — Hydrochlorothiazide (HCTZ), 12.5 mg/day; Mavik® (ACE inhibitor), 4 mg/day. Over-the-counter — Glucomannan, but does not remember type or amount; she reports no other use of dietary supplements or herbal therapies. Physical assessment — Height, 61 inches; weight, 190 lb; pulse, 90; BP, 145/90; waist circumference, 35.5 inches (90 cm); BMI, 35.9.

Comment: This case highlights the growing use of dietary supplements, such as glucomannan, for weight loss. It also highlights the importance of assessing for complementary and alternative medicine (CAM) use and advising patients about dietary supplements for weight loss. Long-term weight loss and maintenance through lifestyle changes are difﬁcult to attain, and adjunctive therapies have become increasingly popular weight loss options. Question: How would you ascertain more about the type and amount of glucomannan that BF is taking? Comment: It is laudable that BF mentions that she is taking glucomannan and wants your opinion. An estimated 70% of individuals who use CAM therapies do not report it to their healthcare providers, because: (1) healthcare providers either neglect to ask or are uncomfortable asking about CAM therapies, and (2) patients are fearful or embarrassed or do not see the importance of reporting CAM use. To elicit more speciﬁc information about the glucomannan product that BF is using, questions might include: (1) Where did you learn about glucomannan? (2) What encouraged you to try glucomannan? (3) How often and when do you take it? (4) What form is it in? and (5) Where did you obtain the glucomannan? Additionally, arrange to have BF call or e-mail the product brand and ingredients to you. Question: How would you advise BF with regard to the safety and efﬁcacy of glucomannan? Comment: Results from a few, limited studies suggest that glucomannan in doses of 2 to 4 g/day may be safe and effective in promoting weight loss. Potential advantages of glucomannan are its tolerability and low rate of side effects; however, additional studies of standardized glucomannan products are needed before they are recommended as a weight-loss adjunct. One concern is that many over-the-counter preparations of glucomannan contain a combination of products that may have dangerous side effects. Some examples to review with BF are bitter orange, country mallow, and caffeine from natural or disguised sources, such as extracts of guarana or tea. A second concern is that glucomannan may reduce the absorption of fat-soluble vitamins and oral medications; therefore, BF should be advised to take other oral medications 1 hour before or 4 hours after taking glucomannan capsules [42]. Another concern is the high solubility of glucomannan capsules; thus, discuss the importance of taking capsules with 8 oz. of water and notifying the healthcare provider if any side effects occur (e.g., difﬁculty swallowing, abdominal distention). Some reliable sources of information about dietary supplements are the National Center for Complementary and Alternative Medicine (http://nccam.nih.gov), the Natural Medicines Comprehensive Database (available through many library databases), and the Ofﬁce of Dietary Supplements (http://dietary-supplements.info.nih.gov/). Additionally, clinicians can keep abreast of new safety information about dietary supplements through the FDA MedWatch program (http://www.fda.gov/medwatch/).

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CONCLUSIONS AND FUTURE DIRECTIONS Studies have shown that dietary ﬁber is a safe and effective adjunct to weight-reducing diets. Fiber has been shown to promote and prolong satiety [48–50], to increase long-term adherence to lowcalorie diets [51,52], and to be inversely associated with weight gain [53]. However, commonly used dietary ﬁber supplements, such as guar gum and psyllium, have not been consistently shown to promote weight loss [54,55]. In contrast to other ﬁber supplements, glucomannan appears to possess properties that promote weight loss when used in conjunction with either a normocaloric or a hypocaloric diet. The ﬁndings of controlled trials suggest that doses of 2 to 4 g/day will signiﬁcantly reduce body weight in overweight and obese persons. Moreover, glucomannan is well tolerated and inexpensive and has relatively few side effects. Limited data show it improves risk factors for cardiovascular disease and diabetes, so it may be an acceptable alternative for overweight individuals who are unable or unwilling to increase their ﬁber intake through food sources. Yet, before glucomannan can be safely recommended, additional trials of standardized preparations are necessary to further describe its safety, efﬁcacy, and weight-reducing mechanisms of action.

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Tsai, A.G. and Wadden, T.A., Systematic review: an evaluation of major commercial weight loss programs in the United States, Ann. Intern. Med., 142, 56, 2005. Birketvedt, G.S. et al., Experiences with three different ﬁber supplements in weight loss, Med. Sci. Monitor, 11, P15, 2005. Cairella, M. and Marchini, G., Evaluation of the action of glucomannan on metabolic parameters and on the sensation of satiation in overweight and obese patients, Clin. Terapeut., 146, 269, 1995. Livieri, C., Novazi, F., and Lorini, R., The use of highly puriﬁed glucomannan-based ﬁbers in childhood obesity, Ped. Med. Chir., 14, 195, 1992. Reffo, G.C., Ghirardi, P.E., and Forattini, C., Glucomannan in hypertensive outpatients: pilot clinical trial, Curr. Ther. Res., 44, 22, 1988. Reffo, G.C., Ghirardi, P.E., and Forattini, C., Double-blind evaluation of glucomannan versus placebo in postinfarcted patients after cardiac rehabilitation, Curr. Ther. Res., 47, 753, 1990. Vido, L. et al., Childhood obesity treatment: double blinded trial on dietary ﬁbres (glucomannan) versus placebo, Padiatr. Padol., 28, 133, 1993. Vita, P.M. et al., Chronic use of glucommanan in the dietary treatment of severe obesity, Minerva Med., 83, 135, 1992. Walsh, D.E., Yaghoubian, V., and Behforooz, A. Effect of glucomannan on obese patients: a clinical study, Int. J. Obes., 8, 289, 1984. Saper R.B., Eisenberg, D.M., and Phillips, R.S., Common dietary supplements for weight loss, Am. Fam. Physician, 70, 1731, 2004. Blanck, H.M., Khan, L.K., and Serdula, M.K., Use of nonprescription weight loss products: results from a multistate survey, JAMA, 286, 930, 2001. Burton-Freeman, B., Dietary ﬁber and energy regulation, J. Nutr., 130, 272S, 2000. Horwath, N.C., Saltzman, E., and Roberts, S.B., Dietary ﬁber and weight regulation, Nutr. Rev., 59, 129, 2001. He, K. et al., Changes in intake of fruits and vegetables in relation to risk of obesity and weight gain among middle-aged women, Int. J. Obes., 28, 1569, 2004. Liu, S. et al., Relation between changes in intakes of dietary ﬁber and grain products and changes in weight and development of obesity among middle-aged women, Am. J. Clin. Nutr., 78, 920, 2003. Ludwig, D.S. et al., Dietary ﬁber, weight gain, and cardiovascular risk factors in young adults, JAMA, 282, 1539, 1999. Newby, P. et al., Dietary patterns and changes in body mass index and waist circumference in adults, Am. J. Clin. Nutr., 77, 1417, 2003. Pereira, M.A. and Ludwig, D.S., Dietary ﬁber and body-weight regulation, Ped. Clin. North Am., 48, 969, 2001.

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Rolls, B.J., Ello-Martin, J.A., and Tohill, B.C., What can intervention studies tell us about the relationship between fruit and vegetable consumption and weight management?, Nutr. Rev., 62, 1, 2004. Pittler, M.H. and Ernst, E., Guar gum for body weight reduction, Am. J. Med., 110, 724, 2001. Rodriquez-Moran, M., Guerrero-Romero, F., and Laczano-Burciago, M., Lipid and glucose-lowering efﬁcacy of plantago psyllium in type II diabetes, J. Diabet. Complications, 12, 273, 1998. Cairella, G., Cairella, M., and Marchini, G., Effect of dietary ﬁbre on weight correction after modiﬁed fasting, Eur. J. Clin. Nutr., 49, S325, 1995. Ryttig, K.R. et al. A dietary ﬁbre supplement and weight maintenance after weight loss: a randomized, double-blind, placebo-controlled long-term trial, Int. J. Obes., 13, 165, 1989. Shimahara, H. et al., Isolation and characterization of oligosaccharides from enzymic hydrolysate of konjac glucomannan, Agric. Biol. Chem., 39, 293, 1975. Doi, K., Effect of konjac ﬁbre (glucomannan) on glucose and lipids, Eur. J. Clin. Nutr., 49(Suppl.), 190S, 1995. Tye, R., Konjac ﬂour: properties and applications, Food Technol., 45, 11, 1991. Bell, E.A. et al., Energy density of foods affects energy intake in normal weight women, Am. J. Clin. Nutr., 68, 412, 1998. Rolls, B.J. et al., Energy density but not fat content of foods affected energy intake in lean and obese women, Am. J. Clin. Nutr., 69, 863, 1999. Burton-Freeman, B., Dietary ﬁber and energy regulation, J. Nutr., 130, 272S, 2000. Vuksan, V. et al., Konjac-Mannan and American ginseng: emerging alternative therapies for type 2 diabetes mellitus, J. Am. Coll. Nutr., 20, 370S, 2001. McCarty, M.F., Glucomannan minimizes the postprandial insulin surge: a potential adjuvant for hepatothermic therapy, Med. Hypotheses, 58, 487, 2002. Bourden, I. et al., Postprandial lipid, glucose, insulin, and cholecystokinin response in men fed barley pasta enriched with beta-glucan, Am. J. Clin. Nutr., 69, 55, 1999. Baer, D.J. et al., Dietary ﬁber decreases the metabolizable energy content and nutrient digestibility of mixed diets fed to humans, J. Nutr., 127, 579, 1997. Jenkins, D.L. et al., Low glycemic index: lente carbohydrates and physiological effects of altered food frequency, Am. J. Clin. Nutr., 59, 706S, 1994. Vuksan, V. et al., Konjac-mannan (glucomannan) improves glycemia and other associated risk factors for coronary heart disease in type 2 diabetes: a randomized controlled metabolic trial, Diabetes Care, 22, 913, 1999. Vuksan, V. et al., Beneﬁcial effects of viscous dietary ﬁber from konjac-mannan in subjects with the insulin resistance syndrome: results of a controlled metabolic trial, Diabetes Care, 23, 9, 2000. Matsuura, Y., Degradation of konjac glucomannan by enzymes in human feces and formation of shortchain fatty acids by intestinal anaerobic bacteria, J. Nutr. Sci. Vitaminol., 44, 423, 1998. FDA. FDA Issues a Second Warning and an Import Alert About Konjac Mini-Cup Gel Candies That Pose Choking Risk, U.S. Food and Drug Administration, Washington, D.C., 2001, http://www.fda.gov/ bbs/topics/NEWS/2001/NEW00770.html. Gaudry, P., Glucomannan diet tablets, Med. J. Australia, 142, 204, 1995. Consumerlab.com, Glucomannan, http://www.consumerlab.com/tnp.asp?siteid=consumerlab&docid= /tnppg000631. Keithley, J.K. and Swanson, B., Glucomannan and obesity: a critical review, Alt. Ther. Health Med., 11, 30, 2005. Natural Medicines Comprehensive Database, Therapeutic Research Center, Stockton, CA, 2005. Villaverde, A.F. et al., Acute hepatitis of cholestatic type possibly associated with the use of glucomannan (amorphophalus konjac) [letter to the editor], J. Hepatol., 41, 1061, 2004. Chen, H.L. et al., Konjac supplement alleviated hypercholesterolemia and hyperglycemia in type 2 diabetic subjects: a randomized double-blind trial, J. Am. Coll. Nutr., 22, 36, 2003. Shima, K. et al., Effect of dietary ﬁber, glucomannan, on absorption of sulfonylurea in man, Hormone Metab. Res., 15, 1, 1983. Arvill, A. and Bodin, L., Effect of short-term ingestion of konjac glucomannan on serum cholesterol in healthy men, Am. J. Clin. Nutr., 61, 585, 1995.

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Obesity: Epidemiology, Pathophysiology, and Prevention Gallaher, D.D. et al., A glucomannan and chitosan ﬁber supplement decreases plasma cholesterol and increases cholesterol excretion in overweight normocholesterolemic humans, J. Am. Coll. Nutr., 21, 428, 2002. Burley, V.J., Paul, A.W., and Blundell, J.E., Inﬂuence of a high-ﬁbre food (myco-protein) on appetite: effects on satiation (within meals) and satiety (following meals), Eur. J. Clin. Nutr., 47, 409, 1993. Hill, A.J. and Blundell, J.E., Macronutrients and satiety: the effects of a high protein or high carbohydrate meal on subjective motivation to eat and food preferences, Nutr. Behav., 3, 133, 1986. Rigaud, D. et al., Effect of psyllium on gastric emptying, hunger feeling and food intake in normal volunteers: a double blind study, Eur. J. Clin. Nutr., 52, 239, 1997. Astrup, A., Vrist, E., and Quaade, F., Dietary ﬁbre added to a very low calorie diet reduced hunger and alleviates constipation, Int. J. Obes., 14, 105, 1990. Pasman, W.J. et al., Effect of one week of ﬁbre supplementation on hunger and satiety ratings and energy intake, Appetite, 29, 77, 1997. Liu, S. et al., Relation between changes in intakes of dietary ﬁber and grain products and changes in weight and development of obesity among middle-aged women, Am. J. Clin. Nutr., 78, 920, 2003. Allison, D.B. et al., Alternative treatments for weight loss: a critical review, CRC Crit. Rev. Food Sci. Nutr., 41, 1, 2001. Pittler, M.H. and Ernst, E., Dietary supplements for body-weight reduction: a systematic review, Am. J. Clin. Nutr., 79, 529, 2004.

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of Caralluma fimbriata 34 inRoleWeight Management Ramasamy V. Venkatesh and Ramaswamy Rajendran CONTENTS Introduction ....................................................................................................................................443 History of Use................................................................................................................................443 Active Ingredient, Preparation of Extracts, and Mode of Action of Caralluma ﬁmbriata ..........444 Safety Evaluation of Caralluma ﬁmbriata ....................................................................................445 Conclusion......................................................................................................................................448 References ......................................................................................................................................449

INTRODUCTION Caralluma ﬁmbriata, a succulent belonging to the family Asclepiadaceae, is a large group of tender succulents found growing wild in India, Pakistan, the Canary Islands, Arabia, southern Europe, Ceylon, and Afghanistan. The plants of this group (Figure 34.1 and Figure 34.2) vary from thin, recumbent stems 1/2 to 1-1/2 inches thick to erect-growing clumps up to 8 inches tall. The spines that cover the angled stems are actually leaves. The star-shaped, ﬂeshy ﬂowers of these plants are some of the worst smelling of the succulent plants. Ordinarily borne in late summer, the foulsmelling blossoms are usually colored purple, black, yellow, tan, maroon, red, or dark brown. They are from 1/2 to 2 inches or more across and are borne at the base of the plant. In the wild, these blossoms are pollinated by ﬂies, which are greatly attracted to the plant. The succulent is also referred to as Caralluma adscendens and Caralluma attenuata [3]. It has several local names in India, including Ranshabar, Makad shenguli, Shindala makadi [1], Kullee Mooliyan, Karallamu, and Yungmaphallottama [2,3].

HISTORY OF USE Caralluma ﬁmbriata has been in use for centuries in India. It is commonly used as a vegetable in semi-arid regions of India. It is eaten raw or cooked with spices. It is also used in pickles and chutneys. Caralluma is also classiﬁed as famine food; in arid and semi-arid regions, when no food is available, it is consumed as a substitute for food. Indian tribals are known to chew chunks of C. ﬁmbriata to suppress hunger while on a day’s hunt. The cactus is used among the tribals in South India to suppress appetite and enhance endurance. They make their living as hunters, wood collectors, plant collectors, and foragers, and they do not eat or carry cooked food with them when they go into the forests to hunt. To relieve their hunger and to ensure that they have the endurance necessary for long forays into the forest, they chop off the stems of this succulent and chew a handful of them during the hunt. The tribesmen state that their energy levels are maintained without food and water and that they do not feel any fatigue or tiredness. Daily consumption of C. ﬁmbriata by the tribesmen in this manner is estimated to be about 100 g [3].

443

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FIGURE 34.1 Flower of Caralluma ﬁmbriata.

FIGURE 34.2 Stem of Caralluma ﬁmbriata.

ACTIVE INGREDIENT, PREPARATION OF EXTRACTS, AND MODE OF ACTION OF CARALLUMA FIMBRIATA The key constituents (Figure 34.3) of Caralluma ﬁmbriata are pregnane glycosides, saponin glycosides, and bitter principles. A standardized extract of C. ﬁmbriata (Slimaluma™) developed by Gencor Paciﬁc, Ltd., in partnership with Green Chem, India, was designed and developed based on the traditional usage of the herb. A full-spectrum aqueous alcoholic extract of the herb was developed to ensure that all of the vital constituents of the herb were present in the product. Highpressure liquid chromatography and other techniques were used to validate the proﬁle of the raw herb, dried herb, and ﬁnal extract to ensure and verify that consumption of 100 g of the herb by the tribals was equivalent to consumption of 1 g of the standardized extract. The extract was standardized for pregnane glycosides, saponin glycosides, and bitter principles. When we eat, the nerves from the stomach send a signal to the hypothalamus in the brain. This is the part of the brain that controls appetite. When the stomach is full, the hypothalamus signals the brain to stop eating. When a person is hungry, the hypothalamus sends a signal to the brain that food is needed. It appears as though Caralluma ﬁmbriata extract inhibits this hunger mechanism of the hypothalamus. The pregnane glycosides contained in C. ﬁmbriata interfere with the signaling mechanism and create a signal on their own which fools the brain into thinking that the stomach is full, even when the person has not eaten.

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O

445 HO

CH3

CH3

OH

OH XO

XO Caratuberside A

Caratuberside B

X = Gal[3-OMe, 6-deoxy](4 → 1)Glu Pregnane Glycoside

Molecular Formula

Molecular Weight

Caratuberside A

C34H57O12

657.819

Caratuberside B

C34H59O12

659.835

Pure Caratuberside A is a white crystalline substance. Melting point is 170–171°C Rotation is [α] at 20°C D+60° (C=0.66 in methanol) Pure Caratuberside B is a white crystalline substance. Melting point is 182–158°C (dec)

FIGURE 34.3 Pregnane glycosides of Caralluma ﬁmbriata extract. (Courtesy of Green Chem, Bangalore, India.)

One reason why most weight-loss programs fail is because of the fatigue caused by the loss of weight, which forces dieters back to their old eating habits and results in a rebounding weight gain. Caralluma ﬁmbriata extract, however, has demonstrated in controlled clinical trials that it helps participants to feel more energetic while inducing a gain in lean muscle mass and loss of fat. It appears that this happens because the extract inhibits fat synthesis by blocking the formation of acetyl co-enzyme A and malonyl co-enzyme A, which are the building blocks of fat synthesis. The extract also seems to increase the burning of fat by the body. This makes more energy available to the body which makes the person tend to be more active. It is a well-known fact that muscle cells burn more calories than fat cells. When more energy is available to the body, muscle cells burn energy faster. Muscle cells are heavier than fat cells but they are also more dense than fat cells, so they occupy less space; consequently, a person with more lean muscle cells appears trimmer and more compact.

SAFETY EVALUATION OF CARALLUMA FIMBRIATA The Caralluma ﬁmbriata extract was put through two human clinical trials to validate its safety and efﬁcacy. The ﬁrst clinical trial was done in Bangalore, India, at St. John’s National Academy of Health Sciences. The full-spectrum aqueous alcoholic extract of the herb described above was used in the study. The extract dosage was 1 g a day, administered as two doses of 500 mg each 30 to 45 minutes before the two main meals of the day. The participants consisted of 50 overweight and obese subjects (body mass index [BMI] > 26); of these, 25 received the active compound and 25 received a placebo (Table 34.1). The study was randomized, double blind, and placebo controlled. Over 8 weeks, the subjects were tested for weight loss, anthropometry, body fat composition, BMI, net weight, and systemic functions (Table 34.2). During the study, no changes were made in diet, but all subjects were advised to walk 30 minutes in the morning and evening. The adverse events

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TABLE 34.1 Results of the Indian Clinical Study Parameter Age (years) Body weight (kg) Height (cm) Body Mass Index (kg/m2) Waist circumference (cm) Hip circumference (cm) Percent body fat (%)

Experimental Group (Mean ± SD; n = 25) 38.6 ± 7.8 79.5 ± 16.9 160.9 ± 9.1 30.6 ± 5.5 96.9 ± 11.6 106.3 ± 11.4 34.6 ± 5.6

a Calculated from the sum of four skin-fold measurements and applying the formulae of Durnin and Womersley [11].

Note: No signiﬁcant differences were observed between the physical characteristics of the subjects of the two groups (independent t-test). Source: Kurpad, A.V. et al., Use of Caralluma ﬁmbriata Extract on Appetite and Weight Control, St. John’s National Academy of Health Sciences, Bangalore, India.

were minor and limited to mild upset of the gastrointestinal tract. Importantly, these adverse events were present equally in the active and placebo groups. Constipation and ﬂatulence subsided within a week and were attributed to the gelatin capsules more than the cactus ingredients in the capsules. Examination of fasting and postprandial glucose, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, serum creatinine, blood urea nitrogen (BUN), total protein, serum albumin, total bilirubin, conjugated bilirubin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), alkaline phosphatase, gamma-glutamyl transpeptidase (γ-GT), and hemoglobin failed to reveal any overall toxicity from the extract. Blood pressure and electrocardiography also showed no toxic reactions secondary to ingesting C. ﬁmbriata. Statistically significant differences for body weight, BMI, waist circumference, hip circumference, body fat, blood pressure, and hunger levels were found between time points in the experimental group, but differences in the blood sugars and lipid proﬁle (Table 34.3) did not show any signiﬁcance [5]. A second clinical study was performed under the auspices of the Western Geriatric Research Institute (Los Angeles, CA). The subjects were taken from two active practices in the Los Angeles area. The subjects were randomly assigned to either the active group or a placebo group. The trial was carried out on 26 patients, 9 of whom were males. They ranged in age from 31 through 73. One patient from each category did not show up for the ﬁnal visit (dropouts). All patients signed an informed consent. The substance was administered as one capsule to be taken 30 minutes before each meal. Each subject was weighed before and after completion of the study, height was ascertained at each visit, and the waist was measured in inches as well as the hips. The hips were measured at the widest girth, and the waist was measured at the umbilicus. In addition, blood pressure was measured in a standard fashion at the brachial artery in the left upper extremity. From the weight and height measurements, the BMI of each subject was ascertained. Patients were instructed not to change their daily activity pattern (exercise) or their food intake. Almost every patient taking the active ingredient lost signiﬁcant weight, but almost no weight loss was observed in patients on placebo (Table 34.4). Out of the patients on the actives, 83% lost weight. Patients with a higher BMI lost more weight. Out of the patients on the actives, 72% reduced their waist by 0.5 to 3 in., and 28% felt an increase in energy while on the active substance [6]. These two

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447

TABLE 34.2 Anthropometric Parameters of the Subjects at Baseline, Month 1, and End of Study Parameter

Baseline (Mean ± SD)

Month 1 (Mean ± SD)

End of Study (Mean ± SD)

Body weight (kg) Body mass index (kg/m2) Waist circumference (cm) Hip circumference (cm) Percent fat (%)a

79.5 ± 16.9 30.6 ± 5.5 96.9 ± 11.6 106.3 ± 11.4 34.6 ± 5.6

78.3 ± 16.5b 30.2 ± 5.6b 95.1 ± 12.0b 105.8 ± 11.5 34.2 ± 5.3

77.5 ± 16.0b,c 29.9 ± 5.6b.c 93.9 ± 11.3b,c 105.0 ± 11.6b,c 33.4 ± 5.6b

a

Calculated from the sum of two, three, or four skinfold measurements and applying the formulae of Durnin and Womersley [11]. b Mean value was signiﬁcantly different from that of baseline (ANOVA for repeated measures with post hoc tests; p < 0.05). c Mean value was signiﬁcantly different from that of month 1 (ANOVA for repeated measures with post hoc tests; p < 0.05). Source: Kurpad, A.V. et al., Use of Caralluma ﬁmbriata Extract on Appetite and Weight Control, St. John’s National Academy of Health Sciences, Bangalore, India.

TABLE 34.3 Biochemical Parameters of the Subjects at Baseline, Month 1, and End of Study Parameter

Baseline (Mean ± SD)

Month 1 (Mean ± SD)

End of Study (Mean ± SD)

Fasting blood sugar (mg/dL) Post prandial sugar (mg/dL) Total cholesterol (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Serum triglycerides (mg/dL)

89.8 ± 16.8 110.9 ± 35.3 192.5 ± 27.1 65.9 ± 11.0 120.0 ± 39.8 111.9 ± 52.0

89.3 ± 10.3 108.3 ± 25.2 191.0 ± 25.9 63.6 ± 10.0 118.0 ± 27.9 112.1 ± 55.0

88.9 ± 10.4 108.6 ± 27.2 191.8 ± 27.0 64.1± 9.95 115.7 ± 30.3 110.3 ± 51.5

Note: No signiﬁcant differences were found in the biochemical parameters at various time points. Source: Kurpad, A.V. et al., Use of Caralluma ﬁmbriata Extract on Appetite and Weight Control, St. John’s National Academy of Health Sciences, Bangalore, India.

clinical trials showed that the use of C. ﬁmbriata extract along with dietary and physical activity changes may provide an effective method of weight reduction. In addition to the human studies, which demonstrated safety and efﬁcacy, safety studies on animal models were performed to evaluate the long-term chronic effects and mutagenicity. An acute oral toxicity study conducted at St. John’s National Academy of Health Sciences on Wistar rats did not demonstrate any mortality or toxicity nor did a preliminary study with a lower dose of 2 g per kg body weight or a very high dose of 5 g per kg body weight. Body weight, feed, and water intake in all of the treated rats were comparable with those of the control group [7]. Similarly, a subchronic toxicity study conducted at the Bombay College of Pharmacy, India, on Wistar rats showed no mortality or chronic effects at 90 mg/kg bodyweight (equivalent to the recommended

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TABLE 34.4 Appetite and Food Intake Assessment Parameter

Baseline (Mean ± SD)

Month 1 (Mean ± SD)

End of Study (Mean ± SD)

Experimental group (n = 25) Thoughts of food (%) Feeling of fullness (%) Urge to eat (%) Hunger (%) Energy intake (kcal/day) Fat intake (g/day) Carbohydrate intake (g/day) Protein intake (g/day)

34.5 ± 24.3 33.3 ± 19.3 44.0 ± 25.3 47.6 ± 22.6 2276.5 ± 202.3 59.0 ± 6.4 360.9 ± 26.1 62.9 ± 6.3

36.2 41.7 39.3 39.2

± 21.6 ± 20.5 ± 21.5 ± 21.4 — — — —

33.2 ± 23.6 40.5 ± 21.9 34.5 ± 21.2 27.9 ± 18.8a 2088.8 ± 183.4a 54.3 ± 3.9a 340.5 ± 23.7a 59.3 ± 7.2a

Placebo group (n = 25) Thoughts of food (%) Feeling of fullness (%) Urge to eat (%) Hunger (%) Energy intake (kcals/day) Fat intake (g/day) Carbohydrate intake (g/day) Protein intake (g/day)

33.1 ± 20.3 37.8 ± 26.9 35.3 ± 25.3 41.9 ± 24.1 2303.6 ± 107.9 61.7 ± 2.8 377.9 ± 21.1 59.1 ± 4.5

33.6 36.6 35.2 41.6

± 15.3 ± 17.9 ± 17.5 ± 17.3 — — — —

32.0.2 ± 17.5 38.6.3 ± 21.2 33.5 ± 19.71 40.7 ± 18.9 2299.0 ± 10.9.0 60.9 ± 3.9 376.8 ± 21.3 59.3 ± 4.8

a

Mean value was signiﬁcantly different from that of baseline.

Note: The appetite assessment was carried using visual analog scales, and the results are expressed as a percentage of the scale. Signiﬁcant differences between time points were assessed using ANOVA for repeated measures with post hoc corrections. The food intake assessment was carried out using food frequency questionnaires at baseline and at the end of the study, and signiﬁcant differences between time points were assessed using the paired t-test with post hoc corrections. Source: Kurpad, A.V. et al., Use of Caralluma ﬁmbriata Extract on Appetite and Weight Control, St. John’s National Academy of Health Sciences, Bangalore, India.

human dosage of 1 g a day) [8]. Mutagenicity studies (Ames test) utilizing the Salmonella typhimurium reverse mutation test were conducted at Intox Pvt., Ltd., India, and researchers concluded that the product was nonmutagenic in all ﬁve strains of S. typhimurium [9].

CONCLUSION Obesity is indeed becoming a menace, having assumed epidemic proportions. The physiological and psychological problems caused by obesity are enormous. A proper diet and exercise plan combined with efﬁcacious and safe supplementation seems to be the way to proceed as a ﬁrst step toward combating obesity. Controlling weight by reducing calorie intake seems to be a vital factor in this jigsaw puzzle. The extract of Caralluma ﬁmbriata could ﬁll the role of an ideal, clinically tested, safe, and efﬁcacious appetite suppressant for the control of calorie intake, leading to reduction in body weight.

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REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]

Laddha, K.S., Report, Medicinal Natural Products Research Laboratory, University of Mumbai, Matunga, Mumbai, India. Jayashree, K.S., Report, Dravyaguna Dept., Ayurvedic Holistic Center, Bangalore, India. Wealth of India: A Dictionary of Indian Raw Materials and Industrial Products, Vol. 3, Vedams, New Delhi, India, 1992, pp. 266–267. Jeyachandran, V., Report, Tagore Arts College, Pondicherry, India. Aroumougame, S., Report, Society for Health, Environment and Research for Biodiversity, Pondicherry, India. Kurpad, A.V. et al., Use of Caralluma ﬁmbriata Extract on Appetite and Weight Control, St. John’s National Academy of Health Sciences, Bangalore, India. Lawrence, R.M. and Choudhary, S., Caralluma ﬁmbriata in the Treatment of Obesity, Western Geriatric Research Institute, Los Angeles, CA. Venkataraman, B.V., Suresh, S., and Kurpad, A.V., Acute Oral Toxicity of Caralluma ﬁmbriata in Rats, Department of Pharmacology, St. John’s Medical College, Bangalore, India, 2004. Jagtap, A. et al., Subchronic Oral Toxicity Study of Caralluma ﬁmbriata Extract, Bombay College of Pharmacy, Mumbai, India, 2005. Deshmukh, N.S. and Naik, P.Y., Mutagenicity Study of Caralluma ﬁmbriata Extract by Salmonella typhimurium Reverse Mutation Test, Intox Pvt., Ltd., Maharashtra, India, 2004. Durnin, J. and Womersley, J., Body fat assessment from total body density and its estimation from skinfold thickness: measurements on 481 men and women aged from 16 to 72 years, Br. J. Nutr., 32, 77–97, 1974.

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of Medium-Chain 35 Role Triglycerides in Weight Management Mary G. Enig CONTENTS Introduction ....................................................................................................................................451 History of Food Fats and Oils in the U.S. Diet ............................................................................452 Changes in the Food Fats Used in the United States During the Past Century...........................453 Fat Functions and Structure...........................................................................................................453 Major Classes of Lipids.................................................................................................................453 Deﬁnition of the Term “Omega” ...................................................................................................454 Essential and Non-Essential Fatty Acids.......................................................................................454 Fatty Acid Categories Found in Food ...........................................................................................455 Medium-Chain Fatty Acids: Lauric Acid ......................................................................................455 Importance of Lauric Oil Composition (Coconut Oil, Palm Kernel Oil).....................................455 Coconut as a Commercial Source of Lauric Acid ........................................................................456 Medium-Chain Fats as Functional Foods......................................................................................457 Medium-Chain Fatty Acids and Thermogenesis ...........................................................................458 Biochemical Functions and Weight Loss from Medium-Chain Fats............................................459 Immune-Enhancing Properties of Medium-Chain Fatty Acids.....................................................459 Beneﬁcial Effects of Coconut Oil on Atherosclerosis Risk Factors.............................................460 Conclusion......................................................................................................................................460 References ......................................................................................................................................460

INTRODUCTION Low-fat diets, which have been promoted by U.S. government agencies and various health organizations, have not prevented obesity and other health problems [1–3]. In the United States, the food fats that are abundant are high in trans-fatty acids or omega-6 fats and relatively low in omega-3 fatty acids as well as missing medium-chain saturated fatty acids such as lauric acid [1,2]. Anti-saturated fat rhetoric has been instrumental in most of the above changes, and protective fats have been lost [1,2]. Lipids make up a diverse group of biological moieties known for their solubility primarily in nonpolar solvents such as chloroform, benzene, and hexane. This solubility mimics the behavior of lipids in mammalian tissues [1].

451

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TABLE 35.1 Recommended List of Fats and Oils Most Appropriate for Domestic or Commercial Use Domestic/Household Use For frying: animal tallows, coconut oil, or stable mixtures (blends) of oils such as coconut oil, sesame oil, and olive oil (1/3 each) (can substitute sunﬂower seed oil or peanut oil for the olive oil; coconut oil is necessary in the mix for lauric acid; sesame oil is necessary in the mix for sesamin) For baking: any natural fat or oil that the recipe calls for with the caveat that the recipe should be from a good natural foods cookbook For salad dressings: any natural, non-genetically modiﬁed organism (GMO), cold-pressed, unreﬁned liquid oil (e.g., olive oil, mixtures of ﬂaxseed and olive oils, canola oil, or soybean oil) For spreads: butter and coconut butter Commercial Use For frying: coconut oil (if the food is low moisture), palm oil, sunﬂower oil with added sesame oil, tallow For bakery goods: butter, coconut oil, lard, palm oil, tallow For salad dressings: any natural, non-GMO, cold-pressed, unreﬁned liquid oil For spreads: butter and coconut butter

HISTORY OF FOOD FATS AND OILS IN THE U.S. DIET There was a time when a cookbook or a treatise on cookery discussed the use of different fats based on the qualities those fats bestowed to the foods they were part of. The special ﬂavor imparted to a sauce by olive oil, the superior ﬂavor and texture imparted to a crust or pudding by beef tallow (suet) or lard, the subtle ﬂavor of Chinese foods fried in peanut oil, and the distinctive ﬂavoring of coconut oil in Polynesian cooking were all important to the cook. That emphasis is almost completely gone today. No longer is the cook encouraged to salvage the fat that cooks out of the meat by turning it into gravy to top the potatoes or the rice or the homemade biscuit (and chances are the biscuit is no longer homemade) [1]. Table 35.1 provides a list of recommended fats and oils that are most appropriate for domestic and commercial use. Any discussion about fats today, in cookbooks or in magazines devoted to food and cookery, is likely to be negative and reﬂect the anti-saturated-fat propaganda that started about 40 years ago in the United States and spread to most of the world where the United States has inﬂuenced the food, nutrition, and biomedical communities. As a result, nearly every article about fats and oils in the diet begins with a faulty premise. That faulty premise is that cholesterol and the saturated fats are the culprits for the myriad of chronic ailments that afﬂict modern populations. This premise was basically invented in the late 1950s for the purpose of protecting the margarine and shortening industry from the challenges that were newly emerging from some of the scientiﬁc critics of hydrogenation who saw this as the cause of the epidemic of heart attacks. This chain of events has been reviewed by Hastert [4] in a 1983 article on hydrogenation. The resulting misinformation that was generated has virtually removed the safe and important natural fats from the diets of many people and has replaced these desirable fats with various partially hydrogenated fats and oils, or with a myriad of nonfood stabilizers, extenders, and emulsiﬁers in the low-fat and nofat versions of traditional foods.

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TABLE 35.2 Fats and Oils in the U.S. Food Supply: 1890 vs. 2000a 1890

2000

Lard tallow (suet) Chicken fat

Rapeseed oil (e.g., canola oil; usually partially hydrogenated)

Butter fat

Cottonseed oil

Olive oil

Peanut oil

Palm oil

Corn oil

Coconut oil

Palm oil

Peanut oil Cottonseed oil a

Soybean oil (usually partially hydrogenated)

Coconut oil

Listed in descending order of market share.

CHANGES IN THE FOOD FATS USED IN THE UNITED STATES DURING THE PAST CENTURY Fats and oils in the U.S. food supply come from several sources. Either they are added fats, such as table spreads, shortenings, and salad and cooking oils, or they come from the fat component of meat and dairy products, from nuts and seeds, or from vegetable and fruit tissues. Added fats in the form of oils, shortenings, spreads (butter and margarine), salad dressing, etc. are listed in government documents such as those published by U.S. Department of Agriculture (USDA) and the Commerce Department as “table and cooking fats” [1]. In the late 1800s, commercial shortenings advertised to the housewife were fats such as cotolene (a blend of cottonseed oil and beef tallow), reﬁned leaf lard, or coconut butter (oil). These commercially available fats, as well as fat rendered from beef, poultry, chicken, and pork in the home, were used for frying and as shortening in baking. Butter and cream were valued for table use as well as for cooking and baking. In addition to cottonseed oil and coconut oil, olive oil and poppy seed oil were listed as principal vegetable oils. Table 35.2 shows the major changes in the use of fats and oils in the U.S. food-supply chain during the last 100-plus years [1,2].

FAT FUNCTIONS AND STRUCTURE Fat provides energy for immediate use by cells and is stored as fat for later use. Saturated fat is a major fuel for heart, kidney, and skeletal muscle; it has a protein-sparing action during growth; it cushions vital organs; it maintains body temperature through thermal regulation (insulation, brown fat); it promotes healthy skin; it has protective barrier function; and it carries fat-soluble vitamins and aids in their absorption [1,2,12]. Fat is a major part of brain (white matter), where it forms the covering for nerve tissue. Fat forms special structures (cellular and subcellular lipid membranes), and it performs special functions (such as the regulation of enzyme activity) [1,2,12].

MAJOR CLASSES OF LIPIDS The three major classes of lipids are neutral lipids, phospholipids, and steroids. The lipids soluble in nonpolar medium are typically the triglycerides, which are neutral lipids. Triglycerides are formed from three molecules of fatty acids and one molecule of glycerol. The human body uses fatty acids from food to build tissue and to make phospholipids and steroids for lipid function [1–4]. A major

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group of fatty acids is the essential fatty acids, and these fatty acids are represented by omega-6 and omega-3 fatty acids. The term “essential” refers to the fact that these groups of fatty acids are essential to the function and structure of the human body and must be obtained in the diet [1–4].

DEFINITION OF THE TERM “OMEGA” Fatty acids are identiﬁed by the families to which they belong. Families differ from classes, and the word “omega” is used to describe a particular family of fatty acids. Omega-6 fatty acids are a family of polyunsaturated fatty acids where the ﬁrst fatty acid in the metabolic lineup is linoleic acid, an 18-carbon fatty acid with two double bonds where the ﬁrst double bond occurs at the sixth carbon–carbon bond. One omega-6 fatty acid is an essential fatty acid (linoleic acid), but the other omega-6 fatty acids are not necessarily essential, although they are conditionally essential. Examples of omega-6 fatty acids include γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic acid [1–3]. Omega-3 fatty acids belong to the family of polyunsaturated fatty acids, where the ﬁrst fatty acid in the metabolic lineup is α-linolenic acid. This fatty acid is an 18-carbon fatty acid found in a number of foods such as leafy greens and many seeds. Other omega-3 fatty acids are more essential because the body needs them in amounts that are not always readily made from the 18-carbon α-linolenic acid. These are the 20- and 22-carbon fatty acids called eicosapentaenoic acid and docosahexaenoic acid, respectively [1,2]. Monounsaturated fatty acids are referred to as omega-9, the most common of which is oleic acid. Monounsaturated fatty acids are not essential in the same way that polyunsaturated fatty acids are essential because they are readily made by the tissues when they are needed. They are, however, necessary fatty acids, and, under conditions of severe essential fatty acid deprivation, oleic acid is elongated and desaturated to make mead acid [1,2]. Saturated fatty acids are not given a designation of “omega” because they are not unsaturated. Saturated fatty acids come in basic lengths referred to as long, medium, and short. The most common of the saturated fatty acids found in foods and made in tissues is palmitic acid. Palmitic acid is a long-chain saturate that is 16 carbons long and it is the de novo fatty acid. Stearic acid is a long-chain saturate that is common but is not found in large amounts in food [1,2]. The most important medium-chain fatty acid is the 12-carbon saturate lauric acid. Lauric acid is found in very small amounts in foods except as a major fatty acid in certain fats and oils called lauric oils, which include coconut oil and palm kernel oil, as well as human and animal milks [1,2].

ESSENTIAL AND NON-ESSENTIAL FATTY ACIDS Linoleic acid is an omega-6 essential fatty acid; it is essential because the body cannot build or function without it or its metabolites and cannot always manufacture the various other fatty acids. Omega-3 fatty acids are essential for building other structures and for other functions [1,2]. In the metabolic lineup, linoleic acid becomes arachidonic acid, which is important for many functions including certain proinﬂammatory and antiinﬂammatory ones. Sometimes linoleic acid is needed by the body to manufacture special prostaglandins to ﬁght certain inﬂammatory processes. When the metabolic lineup fails to form γ-linolenic acid or dihomo-γ-linolenic acid, the body needs to obtain the fatty acid as a conditionally essential fatty acid [1,2]. Another essential omega-3 fatty acid is α-linolenic acid. These neutral lipids are the usual storage fats, but they also are part of the body’s normal metabolism [1,2]. Some fatty acids that belong in the neutral lipid category are not natural or useful except to the food industry. These are the trans-fatty acids (TFAs), formed by the partial hydrogenation process. They are formed from polyunsaturated fatty acids such as omega-6 oils and from any omega-3 fatty acids present in the original oils. In the United States, most of the trans-fatty acids are formed from omega-6 oils, because the most common oils in the United States are omega-6 oils such as soybean oil [1,2,10,11].

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Fatty acids range from 3 carbons to nearly 30 carbons in length. Generally, the fatty acids are even numbered, except for small numbers of fatty acids of bacterial origin found in ruminant fats. Three-carbon fatty acids are found in dairy foods, and four-carbon fatty acids are also primarily found in animal milk [1,2]. The saturated fatty acids are almost all even numbers of carbons in length, but the saturated fatty acids in dairy foods are commonly seen as small amounts of oddnumber-chain saturated fatty acids [1,2]. The major saturated fatty acids found in many foods vary and include palmitic acid.

FATTY ACID CATEGORIES FOUND IN FOOD For labeling purposes, food fats are classiﬁed as saturated, monounsaturated, trans, or polyunsaturated [1,2]. Fatty acid categories are widely distributed in natural foods and in animal and human tissues. Table 35.3 provides a list of saturated fatty acids ranging in length from 3 carbons to 30 carbons, monounsaturated fatty acids, and polyunsaturated fatty acids.

MEDIUM-CHAIN FATTY ACIDS: LAURIC ACID The unfortunate attitude toward the consumption of fats has had a particularly devastating effect on the coconut oil industry, as coconut oil is the major source of medium-chain fatty acids in the diet. Coconut oil is one of the most saturated of the natural fats, one of the oldest in use, and one of the most desirable of the natural fats to include at least small amounts of in a person’s diet. It is considered a lauric fat [5]. Today, we have ended up with a situation where the fats that have been used for centuries are out, and the fabricated fats that should be out are in. The emphasis is on low fat, but most of the foods that are being marketed today are ﬁlled with fat. Usually, this fat is a partially hydrogenated fat that has such a high melting point that it is not always noticed by the consumer when the food containing it is eaten.

IMPORTANCE OF LAURIC OIL COMPOSITION (COCONUT OIL, PALM KERNEL OIL) Most of the people in the United States have been given some unfortunate propaganda regarding the properties of lauric oils and their health effects [11]. Coconut oil contains 27.5% long-chain saturated fatty acids, 65% medium-chain saturated fatty acids, and the balance unsaturated fatty acids. Of the medium-chain saturated fatty acids, approximately 55% are lauric acid and capric acid, which are antimicrobial fatty acids. Lauric acid, the major medium-chain saturated fatty acid in coconut oil, is found in mother’s milk, and it protects babies from viral and bacterial infections. (Cottonseed oil contains approximately 28.5% long-chain saturated fatty acids but no lauric acid.) Heart disease is currently recognized to be multifactorial and to be caused by, among other things, such substances as oxidized fats, cytomegalovirus, Helicobacter pylori, homocysteine, and various toxic chemicals, as well as other inﬂammatory components. The increased cholesterol levels are related to the body’s attempt to heal the lesions. As a pathologist who is an expert on atherosclerosis has pointed out, the cholesterol does not cause an atheroma any more than the white blood cells cause an abscess; they are both trying to heal. Cholesterol is one of the body’s major repair substances [1,2,11]. Lauric oils (of which coconut is the most widely grown) do not become oxidized (only polyunsaturated fatty acids can become oxidized) [1–3,11]. The monoglyceride of lauric acid (which the body makes when lauric oils are eaten) kills cytomegalovirus and Helicobacter pylori and thus would be an appropriate treatment or preventative substance in heart disease. Also, a number of studies showed that heart disease patients who were fed coconut oil got better, so it is clear that there is no reason to repeat misinformation. Even Harvard medical school researchers have taken out a patent to use lauric oils to treat disease [1,2,11].

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TABLE 35.3 Fatty Acid Categories Found in Food and as Part of Animal/Human Tissues Fatty Acids

Length of Carbon Chain

Saturated Fatty Acids Short-chain saturated fatty acids Propionic acid 3C Butyric acid 4C Caproic acid 6C Medium-chain saturated fatty acids Caprylic acid 8C Capric acid 10 C Lauric acid 12 C Long-chain saturated fatty acids Myristic acid 14 C Palmitic acid 16 C Stearic acid 18 C Very-long-chain saturated fatty acids Arachidic acid 20 C Behenic acid 22 C Lignoceric acid 24 C Cerotic acid 26 C Montanic acid 28 C Melissic acid 30 C Unsaturated Fatty Acids Short-chain unsaturated fatty acid Crotonic acid 4 C=C Long-chain monounsaturated fatty acids Palmitoleic acid 16 C=C omega-9; omega-7 Oleic acid 18 C=C omega-9 Long-chain polyunsaturated fatty acids Linoleic acid 18 C=C omega-6 α-Linolenic 18 C=C=C omega-3 γ-Linolenic 18 C=C=C omega-6 Stearidonic 18 C=C=C=C omega-6 Very-long-chain unsaturated fatty acids Arachidonic acid 20 C=C=C=C omega-6 Adrenic acid 22 C=C=C=C omega-6 Eicosapentaenoic acid (EPA) 20 C=C=C=C=C omega-3 Docosapentanoic acid 22 C=C=C=C=C omega-3 Docosahexanoic acid (DHA) 22 C=C=C=C=C=C omega-3 Nisinic acid 24 C=C=C=C=C=C=C omega-3

COCONUT AS A COMMERCIAL SOURCE OF LAURIC ACID Coconut (Cocos nucifera L.) is one of the most important palms providing food. It differs from palms such as oil palms (with which it should not be confused) and date palms. Coconut products are shipped to parts of the world where the coconut does not grow and are considered

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TABLE 35.4 Largest Producers of Coconut Asia Philippines Indonesia India Sri Lanka Malaysia Thailand Vietnam The Americas Mexico Brazil Jamaica Caribbean Islands Dominican Republic El Salvador

Africa Benin Cape Verde Comoros Islands Cote d’Ivoire Ghana Mozambique Tanzania Kenya Somalia Oman The Paciﬁc Islands Papua New Guinea Solomon Islands Vanuatu Federated States of Micronesia

an important food import [6–9]. Coconut palms grow throughout the world in the wet or humid tropics and have been given the name the “tree of life” [6,7]. They spread on the waters from island to island and from coast to coast in the tropical areas of the continents. The trees are grown individually along the coast and in groves, where they are tended by the owners of the land. Coconut is grown on approximately 12 million hectares spread over at least 86 countries around the world [10]; Table 35.4 provides a list of the largest producers of coconut. Most of the larger countries produce a commercial grade of coconut oil and other coconut products from copra; however, many of the coconut growers are actually raising organic coconut. These growers are small holders, and with some encouragement they have converted their production to organic oils. This is especially true for the small island countries. The coconut oil, coconut milk and cream, and dried coconut products from many of the small countries continue to be available in American and Canadian markets and are of good quality [6–9]. Oil palms (Elaeis guineensis) originated in the rain forests of Africa and now grow largely in plantations around the world. The fruits of the oil palm provide a stable oil that differs from the lauric oil of the coconut. The seed in the oil palm is a kernel, which provides an oil called palm kernel oil, which is a lauric oil similar to coconut oil [8–10]. Other palms include babassu, which grows in the wild in Brazil and has a fruit that provides an oil that has a composition similar to coconut. While we are not likely to ﬁnd babassu oil on the market in North America, it is traded with Brazil and it is always possible that bakery goods such as crackers could enter the market. It is useful to know that products made with babassu oil would be a source of mediumchain saturates [6–8]. Date palms should not be mixed up with the oil palms or coconut; they grow in dry areas and are a useful carbohydrate food but they do not provide any fat or oil in their fruit and thus are not a source of medium-chain fats [7,8].

MEDIUM-CHAIN FATS AS FUNCTIONAL FOODS Functional foods provide a health beneﬁt over and beyond the basic nutrients [12]. This is exactly what desiccated coconut and coconut oil do. As a functional food, coconut has fatty acids that provide both energy (nutrients) and raw material for antimicrobial monoglycerides (functional

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component) when it is eaten. Desiccated coconut is about 69% coconut fat. Palm kernels are not large enough to provide a desiccated component [4–9,12]. Approximately 50% of the fatty acids in coconut fat are lauric acid. Lauric acid is a medium-chain fatty acid that provides additional beneﬁts when it is converted to monolaurin in the human or animal body [11–15]. Monolaurin is the antiviral, antibacterial, and antiprotozoal monoglyceride used by the human or animal to destroy lipid-coated viruses such as human immunodeﬁciency virus (HIV), herpes, cytomegalovirus, inﬂuenza, various pathogenic bacteria (e.g., Listeria monocytogenes and Helicobacter pylori), and protozoa such as Giardia lamblia [16]. Some studies have also shown some antimicrobial effects of the free lauric acid [16]. Approximately 6 to 7% of the fatty acids in coconut fat are capric acid. Capric acid is another medium-chain fatty that has a similar beneﬁcial function when it is converted to monocaprin in the human or animal body [1,2,11]. Monocaprin from the fat in coconut has been shown to have an antiviral effect against HIV and is being tested for antiviral effects against herpes simplex and antibacterial effects against Chlamydia. Dr. Halldor Thormar is an Icelandic scientist who showed that monolaurin, which comes from the fat in coconut, kills lipid-coated DNA and RNA viruses, including HIV and herpes viruses, as well as other microorganisms such as Gram-positive bacteria. He has just announced the potential effectiveness of monocaprin dissolved in a gel in killing HIV and plans to continue testing monocaprin against Chlamydia and herpes simplex virus [12,16]. A variety of research published from 2003 to today supports the importance of coconut oil [8–10]. A few researchers have known for some time that derivatives of coconut oil (lauric acid and monolaurin) are safe antimicrobial agents that can either kill completely or stop the growth of some of the most dangerous viruses and bacteria [11,16]. Many bacteria have become resistant to antibiotics but not to herbal oils, such as oregano oil and lauric acid, the major fatty acid from coconut oil which the body turns into the monoglyceride monolaurin. Monolaurin has been shown to be useful in the prevention and treatment of severe bacterial infections, especially those that are difﬁcult to treat or are antibiotic resistant. Herbal treatment of difﬁcult bacteria such as Staphylococcus aureus has been studied in the United States by such research groups as Preuss’ group at Georgetown University Medical Center [16]. It has been asked whether the consumption of trans-fat alters the coating of lipid viruses in an adverse manner, leading to mutation. No research has been conducted on this topic, but the consumption of trans-fat has been shown to alter other lipid bilayer membranes to the disadvantage of the organ system [11].

MEDIUM-CHAIN FATTY ACIDS AND THERMOGENESIS Animal studies have shown that a diet containing medium-chain triacylglycerols (MCTs) results in diet-induced thermogenesis, which leads to less body fat accumulation compared to diets containing long-chain triacylglycerols (LCTs) [15]. A study in humans used a comparative protocol to measure diet-induced thermogenesis by feeding 5 to 10 g of MCTs to healthy humans. The results suggested that the intake of MCTs caused greater diet-induced thermogenesis than the intake of LCTs, regardless of the meal containing the MCTs [14]. In a double-blind, crossover protocol designed to test the different effects of MCT vs. LCT in overfed males ages 22 to 44, the MCTs stimulated thermogenesis to a greater extent than LCT and resulted in excess dietary energy. This increased energy expenditure was considered most likely due to lipogenesis in the liver and provided evidence that excess energy derived from MCTs is stored with lesser efﬁciency than equivalent excess energy derived from dietary LCTs [13]. When the thermic effects of MCTs were studied in both lean and obese subjects to evaluate postprandial thermogenesis after the ingestion of mixed meals, the results showed that postprandial thermogenesis was enhanced in both lean and obese subjects when LCTs in a mixed meal were replaced by MCTs [17].

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BIOCHEMICAL FUNCTIONS AND WEIGHT LOSS FROM MEDIUM-CHAIN FATS Because medium-chain fatty acids (MCFAs) are oxidized to produce energy and are not stored in adipose tissue as are long-chain fatty acids (LCFAs), MCFAs raise the body temperature and effectively use more energy. Researchers have shown that fatty acids that are more likely to be oxidized are less likely to be stored in adipose tissue. Research by Bray et al. [3] indicates that the most highly oxidized fatty acid is the MCFA lauric acid (as noted previously, coconut oil is almost 50% lauric acid). This research was conducted in male humans using labeled fatty acids. The cumulative oxidation of lauric acid was 41% over the 9-hour test period, whereas oxidation of the LCFA stearic acid was 13%. In critical reviews of research on MCFA metabolism [18–23], it was found that the intermediary metabolism (i.e., oxidation) of fatty acids differs depending on the chain length and degree of unsaturation. MCFAs differ in metabolism from LCFAs, as indicated by data for both animals and humans that demonstrate increases in postprandial energy expenditure even after short-term feeding of MCFAs. It was concluded that MCFAs hold potential as weightloss agents. Studies in both lean and obese humans have reported a postprandial thermic effect from a mixed meal with 30 g of MCTs plus 8 g of LCTs that was signiﬁcantly greater than the thermic effect of 38 g of LCTs alone [17]. In a review from France [5], researchers demonstrated that, when comparing LCT-fed animals with MCT-fed animals, the ﬁnal body weight was signiﬁcantly reduced by all the regimens that provided at least 50% of the fat energy as MCTs. According to this research group, the threshold of 50% energy had to be reached to obtain a reproducible body-weight-reducing effect, a threshold that they do not feel is practical in human feeding.

IMMUNE-ENHANCING PROPERTIES OF MEDIUM-CHAIN FATTY ACIDS Fats in our diet affect our immune systems in several ways. A major factor is the presence in our food supply of trans-fatty acids [24]. Another is the extent of processed and incomplete foods in our diets. A third is the amount of virus load in our environment and systems. Different aspects of a diet affect different parts of the immune system (e.g., helper T cells, proinﬂammatory cytokines, immunoglobulins) [24]. Many of the good effects from coconut oil and its derivatives, such as monoglycerides of medium-chain saturated fatty acids, are indirect and some of the scientiﬁc pathways can only be postulated; also, their actions are different in different people [11,24]. Coconut, in the form of desiccated coconut in foods such as macaroons and coconut oil as it is added to baked goods or snack foods such as popcorn or used in the home for cooking, is a major source of the lauric acid used by the body to make the antimicrobial monoglyceride monolaurin. Lauric acid has its own antimicrobial properties. Humans need an antiviral, antibacterial, and antiprotozoal component such as monolaurin, which the human body can make if it receives adequate amounts of lauric acid [11,24]. Viruses that are pathogenic to humans and are known to be inactivated or destroyed in the body by monolaurin include the HIV virus, measles virus, herpes viruses (including cytomegalovirus), vesicular stomatitis virus, visna virus, inﬂuenza virus, pneumonovirus, synsitial virus, and rubeola virus. Bacteria that are pathogenic to humans and are known to be inactivated or destroyed in the body by monolaurin include Listeria monocytogenes, Helicobacter pylori, Staphylococcus aureus, numerous streptococci (including groups A, B, F, and G), Gram-positive organisms, and some Gram-negative organisms if pretreated with chelator. Protozoa that are pathogenic to humans and are known to be inactivated or destroyed in the body by monolaurin include Giardia lamblia [11,16]. Veriﬁcation of these immune-enhancing properties is somewhat complex, as it has not been examined or measured in homogeneous groups. As an example, consider a person who has a lowgrade infection from a virus that is not active. That person should be evaluated individually for the

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immune response, but in a study that person will most likely be included in a group of other individuals who are harboring different viruses, and the effect of monolaurin on the interleukins (the immune factors) might be the same or different among them. Most of the research conducted thus far has not been designed to answer speciﬁc questions regarding immunity. One important paper discusses the potential effect of monolaurin and consequently coconut oil in a rather general manner (i.e., monolaurin modulates immune cell proliferation) and describes the mechanism that monolaurin is thought to exert on the cell membrane that leads to the inhibition of a variety of toxins being produced by various group A streptococci and staphylococci [11,24]. Monolaurin has been shown to block toxic shock syndrome; thus, it is especially important for women to have an adequate intake of coconut oil in their diets, even if they do not need to lose weight [11,24].

BENEFICIAL EFFECTS OF COCONUT OIL ON ATHEROSCLEROSIS RISK FACTORS Published studies in laboratory animals (Sprague–Dawley rats) have demonstrated the beneﬁcial effects of consuming virgin coconut oil [6–9]. In one study [9], virgin coconut oil obtained by the wet process lowered total cholesterol, triglycerides, phospholipids, and low-density lipoproteins (LDLs). In serum and tissues, very-low-density lipoprotein (VLDL) cholesterol levels were lowered and high-density lipoprotein (HDL) cholesterol was increased. The polyphenol fraction of virgin coconut oil was also found to prevent in vitro LDL oxidation. The results in this study were interpreted as being due to the biologically active polyphenol components present in the oil. Another study done in women showed that coconut-oil-based diets lowered levels of postprandial tissue plasminogen activator and lipoprotein(a) [8]. The researchers found that levels of serum lipoprotein(a), an important heart disease marker previously thought to be unaffected by various forms of dietary fat intake, were lowered when the subjects consumed a high-saturated-fat diet based on coconut oil and somewhat lowered when they consumed a diet slightly lower in saturated fat based on monounsaturated oil.

CONCLUSION Overall, these studies suggest that medium-chain triglycerides offer a signiﬁcant number of health beneﬁts and may serve as novel, natural therapeutics in weight management.

REFERENCES [1] Enig, M.G., Fat, calories and tropical oils in perspective, Food Product Design, May, 16–17, 1991. [2] Enig, M.G., Know Your Fats: The Complete Primer for Understanding the Nutrition of Fats, Oils, and Cholesterol, Bethesda Press, Silver Spring, MD, 2000. [3] DeLany, J.P., Windhaauser, M.M., Champagne, C.M., and Bray, G.A., Differential oxidation of individual dietary fatty acids in humans, Am. J. Clin. Nutr., 72, 905, 2000. [4] Hastert, R.C., in Dietary Fats and Health, Perkins, E. and Visek, W., Eds., AOCS Press, Champaign, IL, 1983, chap. 4. [5] Bach, A.C., Ingenbleek, Y., and Frey, A., The usefulness of dietary medium-chain triglycerides in body weight control: fact or fancy?, J. Lipid Res., 37, 708, 1996. [6] Kaunitz, H. and Dayrit, C.S., Coconut oil consumption and coronary heart disease, Philippine J. Intern. Med., 30, 165, 1992. [7] Lim-Sylianco, C.Y., Anticarcinogenic effect of coconut oil, Philippine J. Coconut Stud., 12, 89, 1987. [8] Muller, H., Lindman, A.S., Blomfeldt, A., Seljeﬂot, I., and Pedersen, J.I., A diet rich in coconut oil reduces diurnal postprandial variations in circulating plasminogen activator antigen and fasting lipoprotein (a) compared with a diet rich in unsaturated fat in women, J. Nutr., 133, 3422, 2003.

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[12]

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[18]

[19]

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Nevin, K.G. and Rajamohan, T., Beneﬁcial effects of virgin coconut oil on lipid parameters and in vitro LDL oxidation, Clin. Biochem., 37, 830, 2004. Persley, G.J., Replanting the Tree of Life: Toward an International Agenda for Coconut Palm Research, CAB International, Oxfordshire, U.K., 1992. Enig, M.G., Lauric oils as antimicrobial agents: theory of effect, scientiﬁc rationale, and dietary application as adjunct nutritional support for HIV-infected individuals, in Nutrients and Foods in AIDS, Watson, R.R., Ed., CRC Press, Boca Raton, FL, 1998, p. 81. Proc. of Functional Foods for Health Promotion: Physiologic Considerations; Experimental Biology ’99, Washington, D.C., April 17, 1999, sponsored by International Life Sciences Institute, Technical Committee on Food Components for Health Promotion. Hill, J.O., Peters, J.C., Yang, D., Sharp, T., Kaler, M. et al., Thermogenesis in humans during overfeeding with medium-chain triglycerides, Metabolism, 38, 641, 1989. Kasai, M., Nosaka, N., Maki, H., Suzuki, Y., Takeuchi, H. et al., Comparison of diet-induced thermogenesis of foods containing medium- versus long-chain triacylglycerols, J. Nutr. Sci. Vitaminol. (Tokyo), 48, 5364, 2002. Noguchi, O., Takeuchi, H., Kubota, F.D., Tsuji, H., and Aoyama, T., Larger diet-induced thermogenesis and less body fat accumulation in rats fed medium-chain triacylglycerols than in those fed long-chain triacylglycerols, J. Nutr. Sci. Vitaminol. (Tokyo), 48, 524, 2002. Preuss, H.G., Echard, B., Enig, M.G., Brook, I., and Elliott, T.B., Minimum inhibitory concentrations of herbal essential oils and monolaurin for Gram-positive and Gram-negative bacteria, Mol. Cell. Biochem., 272, 29, 2005. Scalﬁ, L., Coltorti, A., and Contaldo, F., Postprandial thermogenesis in lean and obese subjects after meals supplemented with medium-chain and long-chain triglycerides, Am. J. Clin. Nutr., 53, 1130, 1991. Bourque, C., St.-Onge, M.P., Papamandjaris, A.A., Cohn, J.S., and Jones, P.J., Consumption of an oil composed of medium-chain triacylglycerols, phytosterols, and N-3 fatty acids improved cardiovascular risk proﬁle in overweight women, Metabolism, 52, 771, 2003. Papamandjaris, A.A., White, M.D., Raeini-Sarjaz, M., and Jones, P.J., Endogenous fat oxidation during medium chain versus long chain triglyceride feeding in healthy women, Int. J. Obes. Relat. Metab. Disord., 24, 1158, 2000. Papamandjaris, A.A., MacDougall, D.F., and Jones, P.J., Medium-chain fatty acid metabolism and energy expenditure: obesity treatment implications, Life Sci., 62, 1203, 1998. St.-Onge, M.P. and Jones, P.J., Greater rise in fat oxidation with medium-chain triglyceride consumption relative to long-chain triglyceride is associated with lower initial body weight and greater loss of subcutaneous adipose tissue, Int. J. Obes. Relat. Metab. Disord., 27, 1565, 2003. St.-Onge, M.P., Ross, R., Parsons, W.D., and Jones, P.J., Medium-chain triglycerides increase energy expenditure and decrease adiposity in overweight men, Obes. Res., 11, 395, 2003. St.-Onge, M.P. and Jones, P.J., Physiological effects of medium-chain triglycerides: potential agents in the prevention of obesity, J. Nutr., 132, 329, 2002. Witcher, K.J., Novick, R.P., and Schlievert, P.M., Modulation of immune cell proliferation by glycerol monolaurate, Clin. Diagn. Lab. Immunol., 3, 10, 1996.

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by 36 Anti-Obesity Marine Lipids Kazuo Miyashita CONTENTS Introduction ....................................................................................................................................463 Anti-Obesity Lipids and Lipid-Related Compounds ....................................................................464 Anti-Obesity Effect of Marine Lipids ...........................................................................................464 Anti-Obesity Through UCP Expression ........................................................................................465 Anti-Obesity Activity of the Edible Seaweed Carotenoid Fucoxanthin.......................................467 Reducing Effect of Fucoxanthin and Fucoxanthinol on Adipocyte Differentiation.....................470 Conclusion......................................................................................................................................472 References ......................................................................................................................................472

INTRODUCTION The rise in the prevalence of obesity is now recognized as a worldwide problem, with ominous implications for public health and health-related costs. It may be the second-most important preventable cause of death, exceeded only by cigarette smoking. Obesity is a potent risk factor for type 2 diabetes, hypertension, and dyslipidemia, comorbidities that markedly increase the risk of cardiovascular disease. The parameters generally considered to explain the rise in obesity include the increase in food availability, greater dietary fat content, increased energy density of foods, and decreased physical activity. The simplicity of the energy balance equation has led to an inappropriate focus on obesity as being either a problem of food intake control or energy expenditure; however, in practice, a rather more holistic and integrative approach is required. Epidemiologic evidence strongly supports the role of exercise. The impact of vigorous physical activity in preventing excess fat accumulation is readily recognized; however, the inﬂuence of modest levels of physical activity is less obvious. Less attention has focused on sedentary behaviors. Both physical activity levels and sedentary lifestyle contribute to the development of obesity. The body has only a limited capacity to adjust metabolic energy expenditure to offset changes in energy intake to maintain body energy stores. Changes in energy expenditure are generally seen as a secondary consequence of alterations in body weight and lean mass. Thus, regulation of total energy intake in the short term has relatively minor effects on energy expenditure. On the other hand, long-term regulation of food intake (more than 1 year) leads to a remarkably good adjustment of energy intake to energy expenditure, as energy imbalances are generally less than 1 to 2% of energy turnover. Changes in dietary composition in the long term can also have a pronounced effect on the fuel mixture burned by the body. This can have important effects on body composition and the regulation of appetite, the interaction of which determines the steady-state body weight maintained by an individual in the long term.

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Ingestion of either protein or carbohydrate is accompanied by a rapid increase in the oxidation of each. By contrast, consumption of dietary fat does not promote its own oxidation. The fat stored in adipose tissue provides an energy reserve. In evolution, the human body has been compelled to develop regulatory mechanisms that give higher priority to the control of its carbohydrate economy than to the control of fat metabolism. Intake levels and the ratio of these macronutrients are very important to control body weight and to prevent obesity. Although lipids can be stored far more efﬁciently than other nutrients, data accumulated from experimental animal and human studies clearly support a beneﬁcial role for dietary lipids and lipid-related compounds in weight management. This chapter is mainly concerned with the anti-obesity effects of marine lipids and seaweed carotenoids. An effort is also made to outline the mechanism responsible for these effects.

ANTI-OBESITY LIPIDS AND LIPID-RELATED COMPOUNDS Based on the nature of fat digestion and absorption, diacylglycerol (DG) with a 1,3-conﬁguration [1,2] and medium-chain triacylglycerol (MCT) [3] have been used for the prevention of obesity. Several studies have demonstrated that conjugated linoleic acid (CLA) reduces body fat accumulation in growing animals but not all CLA isomers contributed to this effect equally [4–6]. Among CLA isomers studied, trans-10,cis-12-18:2 induced body fat loss. The reported mechanism of this CLA action includes stimulation of lipolysis, reduction of lipid synthesis, and direct action on adipocytes [7,8]. Because CLA isomers, as well as other polyunsaturated fatty acids (PUFAs), are recognized as natural peroxisome proliferator-activated receptor (PPAR) ligands, investigating how these isomers modulate transcription factors and their target genes could lead to elucidation of the anti-obesity effect of CLA [9–12]. Caffeine is a naturally consumed substance that is widely contained in beverages. It has thermogenic properties and increases the metabolic rate in humans [13–17]. This effect can be explained by stimulation of the secretion of catecholamines, such as noradrenaline, from the nerve endings. Noradrenaline stimulates β3-adrenergic receptor (β3-AR) and then induces promotion of energy expenditure through uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT) (Figure 36.1) [18–21]. Capsaicin, the major pungent principle of red pepper, also upregulates UCP1 in BAT by the release of catecholamines such as noradrenaline [22–25]. Green tea extract is reported to increase energy expenditure and fat oxidation in humans [26]. The tea extract contains caffeine and catechin. Epigallocatechin gallate, a main tea catechin, promotes fat oxidation and decreases fat synthesis but does not activate β3-AR [27]. The anti-obesity activity of green tea extract can be attributed to the effects of UCP1 upregulation by caffeine and to the lipid metabolism control by catechin.

ANTI-OBESITY EFFECT OF MARINE LIPIDS Eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) are the two typical fatty acids of marine lipids. These two long-chain PUFAs have been shown to cause signiﬁcant biochemical and physiological changes in the body. Most of these changes exert a positive inﬂuence on human nutrition and health [28]. DHA is an important constituent of the membrane phospholipids of the brain and retina that usually occupies the sn-2 position of these phospholipid moieties. The health beneﬁts of EPA and DHA include protection from hypertension, cancer, diabetes, neuropsychiatric disorders, and autoimmune diseases. The role of EPA and DHA in alleviating cardiovascular diseases has been demonstrated in hundreds of in vivo and in vitro experiments, in addition to several clinical trials [29]. The cardioprotective effects of EPA and DHA include modifying serum triacylglycerol levels by increasing lipoprotein lipase [30] and alteration of the catabolism of apo B-containing lipoprotein or chylomicron remnants [31]. The effect of EPA and DHA on lipid metabolism is strongly correlated to the anti-obesity effect of marine lipids. Some papers have described the reducing effect of ﬁsh oil on the abdominal fat pad [32,33]. Parrish et al. [32] reported that lard-fed rats had 77% more fat in perirenal fat pads

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-AR Gs AC

cAMP R Retinoids

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?

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Heat

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mRNA

PGC-1 R PPAR RXR

T3

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Nuclear Brown adipose cell

FIGURE 36.1 Possible mechanism for upregulation of BAT UCP1 by food components.

and 51% more fat in epididymal fat pads compared with ﬁsh-oil-fed rats. The same result was obtained by Kawada et al. [34], who also found that the expression of UCP1 in interscapular brown adipose tissue (IBAT) was signiﬁcantly higher in rats fed the ﬁsh-oil diet compared to the lard-fed group (Figure 36.2). In IBAT mitochondria, substrate oxidation is poorly coupled to adenosine triphosphate (ATP) synthesis because of the presence of UCP1, thereby leading to energy dissipation (i.e., heat production). Kawada et al. [34] suggested that the intake of PUFAs found in ﬁsh oil, such as EPA and DHA, causes UCP induction and enhancement of thermogenesis, resulting in suppression of the excessive growth of abdominal fat pads. PUFAs from vegetable oils also suppressed the excessive accumulation of adipose tissue as compared to animal fats [35,36]; however, the activity of PUFAs from vegetable oils was less than that of EPA and DHA from ﬁsh oil [34]. Our study supports these results in terms of the higher anti-obesity effect of EPA and DHA in ﬁsh oils (Figure 36.3) [37].

ANTI-OBESITY THROUGH UCP EXPRESSION A great deal of interest has been focused on adaptive thermogenesis by UCP families (UCP1, UCP2, and UCP3) as a physiological defense against obesity, hyperlipidemia, and diabetes [38,39]. UCPs are found in brown adipose tissue (UCP1, UCP2, and UCP3), white adipose tissue (UCP2), skeletal muscle (UCP2 and UCP3), and brain (UCP4 and UCP5) [39,40]. UCP2 and UCP3 are members of the mitochondrial anion carrier superfamily with high homology to UCP1, a wellcharacterized uncoupling protein that plays a key role in facultative thermogenesis in rodents [41]. Interest in UCPs increased with the discovery of proteins similar to UCP1, including UCP2 and UCP3. These proteins are expressed in tissues besides BAT and, thus, are candidates to inﬂuence energy efﬁciency and expenditure [39,42]. Metabolic rate, metabolic efﬁciency, and obesity are integrated properties of the whole animal. Researchers have produced mice lacking UCP2 [43] and

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UCP protein (% of control diet)

180 a

160 140 120 100 80 60 40 20 0 Control

Fish oil

FIGURE 36.2 UCP expression in BAT of control and sardine-oil-fed rats. aSigniﬁcantly different from control (p < 0.05). The experimental diets contained 10% of either lard (control) or ﬁsh oil. Main fatty acids of the ﬁsh oil were DHA (27.7%), 16:0 (18.1%), 18:1n-9 (12.0%), and EPA (7.2%). (Adapted from Kawada, T. et al., J. Agric. Food Chem., 46, 1225–1227, 1998.) 120

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FIGURE 36.3 Plasma lipids and abdominal fat weight of rats fed control (soybean oil) and sardine oil. (A) Plasma total cholesterol; (B) plasma triacylglycerol; (C) abdominal fat weight. a,bSigniﬁcantly different from control (a, p < 0.05; b, p < 0.01). (Adapted from Toyoshima, K. et al., J. Agric. Food Chem., 52, 2372–2375, 2004.)

UCP3 [44,45], but, surprisingly, despite a lack of UCP2 or UCP3, no consistent phenotypic abnormality was observed in the knockout mice that were not obese and had normal thermogenesis. These results suggest that UCP2 and UCP3 are not major determinants of metabolic rate under normal conditions but instead have other functions [39,43,46–51]. Indeed, unexpected physiological or pathological implications of UCP2 and UCP3 function (such as possible UCP2 involvement in diabetes and in apoptosis) could also be implicated [39]. UCP3 has a diminished thermogenic response to the drug 3,4-methylene dioxy methamphetamine (MDMA) [51]. Apart from UCP2 and UCP3, it is certain that UCP1 can potentially reduce excess abdominal fat [52].

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Involvement of BAT in cold-induced thermogenesis is well established, and data from rodents have also demonstrated its role in diet-induced thermogenesis [53,54]. Thermogenesis in BAT is due to UCP1. UCP1 is a dimeric protein present in the inner mitochondrial membrane of BAT that dissipates the pH gradient generated by oxidative phosphorylation, releasing chemical energy as heat. UCP1 is exclusively expressed in BAT, where the gene expression is increased by cold, adrenergic stimulation, β3-agonists, retinoids, and thyroid hormone [55]. The thermogenic activity of BAT is dependent on UCP1 expression levels controlled by the sympathetic nervous system via noradrenaline (Figure 36.1) [52,56–58]. As a consequence of noradrenaline binding to the adipocyte plasma membrane, protein kinase (PKA) is expressed, and then cAMP response element-binding protein (CREB) and hormone-sensitive lipase (HSL) are expressed. HSL stimulates lipolysis, and free fatty acids liberated serve as substrates in BAT thermogenesis [58]. They also act as cytosolic second messengers that activate UCP1 as PPARγ ligand. The same activity is expected in dietary polyunsaturated fatty acids [59]. The anti-obesity effect of dietary EPA and DHA may be partly due to their control of PPARγ expression [34]. DHA and EPA inhibit cyclooxygenase, thereby reducing the amount of prostaglandins and increasing the lipoxygenase activity. This in turn results in higher production of hydroxyeicosatrienoic acid (HETE) and leukotriene B4. Eicosanoids can act as transcriptional regulators of UCP. The anti-obesity effect of ﬁsh oil may, in part, be correlated to the regulatory effect of both PUFA on eicosanoid formation. Although regulation of the sympathetic nervous system via noradrenaline is the physiologically most signiﬁcant effect, a series of other factors may inﬂuence UCP1 gene expression [60]. Thyroid hormones are essential for regulated UCP1 expression [55]. Also, activators of PPARγ such as pioglitazone [61] and probably essential fatty acids [62] activate UCP1 gene expression, as do retinoids, probably through both retinoid X receptors (RXRs) and retinoic acid receptors (RARs) [63,64].

ANTI-OBESITY ACTIVITY OF THE EDIBLE SEAWEED CAROTENOID FUCOXANTHIN Uncoupling protein 1 is a key molecule for anti-obesity. UCP1 expression is known to be a signiﬁcant component of whole body energy expenditure, and its dysfunction contributes to the development of obesity. Adult humans, however, have very little BAT, and most of their fat is stored in white adipose tissue (WAT). A potential breakthrough discovery for the development of an ideal therapy for obesity would be the regulation of UCP expression in tissues other than BAT by food constituents. UCP1, usually expressed only in BAT, has also been found in the WAT of mice overexpressing Foxc2, a winged helix gene, with an accompanying change in steady-state levels of several WAT- and BAT-derived mRNAs [65]. This result suggests the possibility of UCP1 expression in human WAT, which would be an increasingly attractive target for the development of anti-obesity therapies. As the key molecular components become deﬁned, screening for food constituents that increase energy dissipation is becoming a more attainable goal. From this viewpoint, the anti-obesity effect of an edible seaweed carotenoid (fucoxanthin) is very interesting, as its activity depends on the protein and gene expressions of UCP1 in WAT [66]. In a study on the anti-obesity effect of fucoxanthin, lipids were separated from the edible seaweed wakame (Undaria pinnatiﬁda), one of the most popular edible seaweeds in Japan and Korea. Undaria lipids, containing 10% fucoxanthin, signiﬁcantly reduced the weight of WAT (perirenal and epididymal abdominal adipose tissues) of both rats and mice (Figure 36.4). Furthermore, the body weights of mice fed 2% Undaria lipid were signiﬁcantly (p < 0.05) lower than those of the control group, although no signiﬁcant differences were observed in the mean daily intake of diet between the both groups. To conﬁrm the active component of Undaria lipids, fucoxanthin and Undaria glycolipids (the main fractions of the lipids) were administered to obese KK-Ay mice. The dietary effects of both fractions on the WAT weight of obese mice is shown in Figure 36.5. The WAT weight of fucoxanthin-fed mice was signiﬁcantly lower than that of control

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a 10

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FIGURE 36.4 Weight of WAT of rats (A) and mice (B) fed Undaria lipids and control diet. aSigniﬁcantly different from control (p < 0.01). A diet was prepared according to the recommendations of the American Institute of Nutrition (AIN-93G). The dietary fats for rats were 7% soybean oil (control), 6.5% soybean oil + 0.5% Undaria lipids, and 5% soybean oil + 2% Undaria lipids. Those for mice were 13% soybean oil (control), 12.5% soybean oil + 0.5% Undaria lipids, and 11% soybean oil + 2% Undaria lipids. (Adapted from Maeda, H. et al., Biochim. Biophys. Res. Commun., 332, 392–397, 2005.)

WAT (g/100g body weight)

20 16 a 12 8 4 0

Control

Fucoxanthin

Glycolipid

FIGURE 36.5 Weight of WAT of mice fed fucoxanthin, Undaria glycolipids and control diet. aSigniﬁcantly different from control (p < 0.01). The dietary fats were 13% soybean oil (control), 12.6% soybean oil + 0.4% fucoxanthin, and 11.2% soybean oil + 1.8% Undaria glycolipid. (Adapted from Maeda, H. et al., Biochim. Biophys. Res. Commun., 332, 392–397, 2005.)

mice; however, no difference was observed in the WAT weight of mice fed the Undaria glycolipids and those fed the control diet. This result indicates that fucoxanthin is the active component in the Undaria lipids resulting in the anti-obesity effect. Because of its capacity for uncoupled mitochondrial respiration, BAT was implicated as an important site of facultative energy expenditure in small rodents. This led to speculation that BAT normally functions to prevent obesity. In mice fed 2.0% Undaria lipids, the BAT weight was signiﬁcantly greater than for the control mice; however, no signiﬁcant difference was observed in UCP1 expression among the three different dietary groups. Thus, the decrease in abdominal fat pad weight found in mice fed Undaria lipids could not be explained only by energy expenditure in BAT mitochondria by UCP1. As shown in Figure 36.6, UCP1 expression was found in the WAT

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Control

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UCP1 / -Actin

(B)

5

15 10 5 0

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0 Control Undaria Undaria (0.5%) (2%)

FIGURE 36.6 UCP1 and UCP2 expression in WAT of mice fed Undaria lipids and control diet. (A) Western blot analysis of UCP1; (B) UCP1 protein expression; (C) UCP1 mRNA expression; (D) UCP2 mRNA expression. aSigniﬁcantly different from control (p < 0.05). (Adapted from Maeda, H. et al., Biochim. Biophys. Res. Commun., 332, 392–397, 2005.)

of mice fed Undaria lipids, although little expression was found in the WAT of the control mice. Expression of UCP1 mRNA was also found in the WAT of mice fed Undaria lipids, but little expression in that of control (Figure 36.6). On the other hand, UCP2 expression in WAT decreased due to feeding Undaria lipids as compared with control (Figure 36.6). These results show that the decrease in WAT weight of mice fed Undaria lipids may not be due to the thermogenesis through UCP1 expression in WAT but through UCP2 expression. UCP1 expression in WAT was also found in fucoxanthin-fed mice, but little expression of UCP1 was found in the WAT of mice fed Undaria glycolipids and control diets (Figure 36.7). This result conﬁrmed the anti-obesity activity of fucoxanthin through upregulation of UCP1 expression in WAT.

a

UCP1/β-Actin

15

10

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0 Control

Fucoxanthin

Glycolipid

FIGURE 36.7 UCP1 expression in WAT of mice fed fucoxanthin, and Undaria glycolipids. aSigniﬁcantly different from control (p < 0.05). (Adapted from Maeda, H. et al., Biochim. Biophys. Res. Commun., 332, 392–397, 2005.)

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HO

OCOCH3

C

O

H O HO

Fucoxanthin

HO

OH

C

O

H O HO

Fucoxanthinol

FIGURE 36.8 Structures of fucoxanthin and fucoxanthinol.

REDUCING EFFECT OF FUCOXANTHIN AND FUCOXANTHINOL ON ADIPOCYTE DIFFERENTIATION Fucoxanthin has a unique structure including an allenic bond and a 5,6-monoepoxide in the molecule (Figure 36.8). It is a major marine carotenoid found in edible seaweeds such as Undaria pinnatiﬁda, Hijikia fusiformis, and Sargassum fulvellum. In Southeast Asian countries, some seaweeds containing fucoxanthin are often used as a food source. As described earlier, fucoxanthin demonstrates an anti-obesity effect through a very interesting molecular mechanism, and it also has also anticarcinogenic effects [67], apoptotic effects in cancer cells [68–70], antiinﬂammatory effects [71], and radical scavenging activity [72]. Fucoxanthin is easily converted to fucoxanthinol in human intestinal cells and in mice [73], suggesting that the active form of fucoxanthin in the biological system would be fucoxanthinol (Figure 36.8). As shown in Figure 36.9, fucoxanthin and fucoxanthinol inhibited intercellular lipid accumulation during adipocyte differentiation of 3T3-L1 cells. Both carotenoids also decreased glycerol-3-phosphate dehydrogenase activity, an indicator of adipocyte differentiation [74]. The effects of fucoxanthinol were stronger than those of fucoxanthin. When 3T3-L1 cells treated with fucoxanthin and fucoxanthinol, PPARγ (a regulator of adipogenic gene expression) was downregulated by both carotenoids in a dose-dependent manner (Figure 36.10). These results suggest that fucoxanthin and fucoxanthinol inhibit the adipocyte differentiation of 3T3-L1 cells through downregulation of PPARγ. This study [74] indicated that fucoxanthinol might be the active compound for the anti-obesity effect induced in vivo by fucoxanthin administration. It is noteworthy that PPARγ levels were downregulated in 3T3-L1 cells treated with fucoxanthinol and fucoxanthin. PPARγ has an important role in the early stages of 3T3-L1 cell differentiation, because it is a nuclear transcription factor that regulates adipogenic gene expression [75]. Regulation of PPARγ would be one of the expected mechanisms underlying the anti-obesity effect of dietary fucoxanthin. Catechin [76], sterols [77], tannic acid [78], phenolic lipids [78], and red yeast rice extracts [80] also inhibit 3T3-L1 differentiation. Retinoids inhibit the early stage of differentiation of 3T3-L1 cells [81]. Some of these compounds, however, have low absorption and have not been fully investigated for their anti-obesity effects in vivo. Because fucoxanthin accumulates as metabolites (including fucoxanthinol) in the white adipose tissue of mice, dietary fucoxanthin might be a useful natural compound for the prevention of obesity.

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FIGURE 36.9 Effect of fucoxanthin (A) and fucoxanthinol (B) on lipid accumulation of 3T3-L1 cells during adipocyte differentiation. 3T3-L1 cells were treated with fucoxanthin or fucoxanthinol in differentiation medium for 120 hr. The intercellular lipid accumulation was determined by oil red O staining. The values (n = 3) are expressed as absorbance at 490 nm. aSigniﬁcantly different from control (p < 0.01). (Adapted from Maeda, H. et al., Int. J. Mole. Med., 18, 147–152, 2006.) 10

PPAR / - Actin

8

6

4

2

0

Pr

ea

p di

oc

yt

e

l ro ) nt yte o c C po di (A

2.5 M

5 M

Fucoxanthin

2.5 M

5 M

Fucoxanthinol

FIGURE 36.10 Expression of PPARγ in 3T3-L1 cells treated with fucoxanthin and fucoxanthinol. The PPARγ protein expression level was normalized to the β-actin level and expressed as the value relative to preadipocyte PPARγ levels. (Adapted from Maeda, H. et al., Int. J. Mole. Med., 18, 147–152, 2006.)

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CONCLUSION In contrast to rodents, humans have only minute amounts of BAT, thus the contribution of BAT to the regulation of energy balance in humans may be less than in rodents; however, if the expression of UCP1, a key molecule for BAT thermogenesis, can be activated in tissues other than BAT by food constituents, then this would be potential anti-obesity therapy for humans. Both protein and mRNA expression of UCP1 in the WAT of fucoxanthin-fed mice along with a reduction in UCP2 mRNA expression have been reported [66]. This ﬁnding could provide new directions for dietary anti-obesity therapy. Although an enormous amount of data exists on thermogenesis in BAT through UCP1 expression, little information is available on UCP1 expression in WAT induced by a diet. An excessive accumulation of fat in WAT induces some diseases such as type 2 diabetes. Direct heat production by fat oxidation in WAT, therefore, will reduce the risk of these diseases in humans. Although fucoxanthin has been reported to have an anti-obesity effect, further investigations are necessary to evaluate the mechanisms. The underlying mechanisms need to be evaluated to understand the relation of fucoxanthin activity to UCP1 expression pathways in WAT. Vegetables have carotenoids that have a structure similar to that of fucoxanthin; hence, comparative studies on the anti-obesity effects of carotenoids with a structure similar to that of fucoxanthin will be of continued interest to researchers working on the dietary effects of carotenoids. The need of the hour is to bring such challenging areas into the research fold and evaluate these carotenoids individually and in combination with other nutrients. Such studies may encourage the development of novel approaches to anti-obesity therapies.

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Foods, Calcium, 37 Dairy and Weight Management Michael B. Zemel CONTENTS Introduction ....................................................................................................................................477 Mechanisms....................................................................................................................................478 Other Dairy Components........................................................................................................480 Modulation of Central Adiposity............................................................................................482 Animal Studies...............................................................................................................................483 Clinical Data ..................................................................................................................................483 Randomized Clinical Trials ...........................................................................................................484 Observational and Epidemiological Studies..................................................................................486 Dietary Calcium Modulation of Obesity-Induced Oxidative Stress .............................................487 Summary and Conclusions ............................................................................................................488 References ......................................................................................................................................489

INTRODUCTION Thermodynamics and energy balance are clearly the core factors involved in our current obesity epidemic, as modest increases in energy intake coupled with reduced physical activity have resulted in a substantial net positive energy balance and progressive weight gain. It is equally clear, however, that we operate with varying degrees of energetic efﬁciency, deﬁned as the conversion of food energy to useful work or energy storage, and that this variability in energetic efﬁciency results in corresponding variability in susceptibility to the consequences of a chronic imbalance between energy intake and expenditure. The consequence of a chronic positive energy balance, obesity, is well understood as a complex genetic trait, with multiple genes interacting to confer relative susceptibility (increased energetic efﬁciency) or resistance (decreased energetic efﬁciency) to a positive energy balance; however, the metabolic pathways operated by these genetic factors may also be modulated by speciﬁc nutrients or dietary patterns. Although there is no doubt regarding the primacy of energy balance in addressing the obesity epidemic, the additional effects of speciﬁc nutrients and foods on modulation of energy efﬁciency may still have substantial impact on weight gain and obesity incidence; for example, a caloric excess of as little as 25 kcal/day could lead to an annual weight gain of 1 kg. This value is well within the caloric range likely to be inﬂuenced by food components. A large number of food components have been proposed to contribute to healthy weight management. These include conjugated linoleic acid, medium-chain triglycerides, green tea, caffeine, and capsaicin [1], but the reported effect for each of these is modest at best, with support limited to a small number of conﬂicting reports [1]. In contrast, a substantial and largely consistent body of data has emerged over the last 6 years indicating that dietary calcium and dairy foods modulate adipocyte lipid metabolism, energy efﬁciency, and energy partitioning between adipose tissue and muscle, resulting in a meaningful anti-obesity effect.

477

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This effect is supported by a clear mechanistic framework, retrospective and prospective epidemiological and observational studies, secondary analysis of past clinical trials originally conducted with other primary endpoints (e.g., skeletal, cardiovascular), and prospective clinical trials.

MECHANISMS A compelling mechanism for the anti-obesity effect of dietary calcium was provided by our studies of the mechanism of action of the agouti gene in regulating murine and human adipocyte metabolism [2–21]. These studies demonstrated a key role for intracellular Ca2+ in the regulation of adipocyte metabolism, resulting in modulation of adipocyte triglyceride stores; intracellular Ca2+ is regulated by calcitrophic hormones which provides the primary mechanistic basis for the anti-obesity effect of dietary calcium. This regulation of adipocyte lipid metabolism by intracellular Ca2+ provides the key framework for the dietary calcium modulation of adiposity. We have found that both parathyroid hormone (PTH) [4] and 1,25-(OH)2-D [22,23] stimulate rapid increases in human adipocyte intracellular Ca2+; accordingly, suppression of these hormones by increasing dietary calcium facilitates repartitioning of dietary energy from lipid storage to lipid oxidation and thermogenesis. Although both PTH and 1,25-(OH)2-D both modulate adipocyte intracellular Ca2+, a growing body of evidence indicates that 1,25-(OH)2-D plays a pivotal role in modulation of lipid metabolism; however, evidence to exclude a signiﬁcant additional role for PTH is insufﬁcient. Human adipocytes possess membrane (non-genomic) vitamin D receptors that transduce a rapid intracellular Ca2+ response to 1,25-(OH)2-D3 [23,24]; consequently, 1,25-(OH)2-D3 treatment of human adipocytes results in the coordinated activation of fatty acid synthase expression and activity and suppression of lipolysis, leading to an expansion of adipocyte lipid storage [22,24,25]. It should be noted, however, that, although these data provide a plausible mechanism of action based on in vitro studies in human adipocytes, the direct effect of calcitrophic hormones on human adipocyte metabolism has not yet been assessed utilizing in vivo techniques, such as microdialysis. Nonetheless, a potential role of 1α,25-(OH)2-D3 in human obesity is suggested by other data. Polymorphisms in the nuclear vitamin D receptor (nVDR) gene are associated with the susceptibility to obesity in humans [26,27], and several lines of evidence demonstrate an alteration of the vitamin D–endocrine system in obese humans, with an increase in circulating 1α,25-(OH)2-D3 levels [28,29]. These observations, coupled with the direct effects of 1α,25-(OH)2-D3 on adipocyte lipid metabolism, strongly implicate the increase in 1α,25-(OH)2-D3 found on low-calcium diets as a contributory factor to excess adiposity. In addition to regulating adipocyte metabolism via a non-genomic membrane receptor (the membrane-associated rapid response to steroid, or MARRS, protein [23,30,31]), 1α,25-(OH)2-D3 also acts via the classical nuclear vitamin D receptor in adipocytes to inhibit the expression of uncoupling protein 2 (UCP2) [32]. Also, suppression of 1,25-(OH)2-D3 levels by feeding highcalcium diets to mice results in increased adipose tissue UCP2 expression and attenuation of the decline in thermogenesis which otherwise occurs with energy restriction [25], suggesting that highcalcium diets may also affect energy partitioning by suppressing 1,25-(OH)2-D3-mediated inhibition of adipocyte UCP2 expression. The role of UCP2 in thermogenesis is not clear, however, and the observed thermogenic effect may be mediated by other, as of yet unidentiﬁed mechanisms. Moreover, the thermogenic effects of dietary calcium and dairy products have not yet been demonstrated in humans. Nonetheless, in addition to inducing a mitochondrial proton leak, UCP2 serves to mediate mitochondrial fatty acid transport and oxidation, suggesting that 1,25-(OH)2-D3 suppression of UCP2 expression may still contribute to decreased fat oxidation and increased lipid accumulation on low-calcium diets [32]. Limited human data support these proposed mechanisms. We have found that increasing dietary calcium via isocaloric substitution of three daily servings of dairy (without changing dietary macronutrient composition) results in signiﬁcant increases in circulating glycerol, reﬂecting an

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increase in net lipolysis, compared to low-dairy diets under both eucaloric and hypocaloric conditions [33,34]. Melanson et al. [35] conducted a randomized controlled crossover study of the effects of low- and high-dairy diets on substrate oxidation in a room calorimeter under conditions of both energy balance and acute energy deﬁcit. The high-dairy diets signiﬁcantly suppressed circulating 1,25-(OH)2-D3 levels but had no effect on substrate oxidation under zero energy balance conditions; however, under energy-deﬁcit conditions, the high-dairy diet resulted in a signiﬁcant increase in 24-hour fat oxidation, from 106 to 136 g/day, without signiﬁcantly affecting protein or carbohydrate oxidation. This suggests that high-dairy diets may augment the effects of energy restriction on fat mobilization and oxidation and thereby increase the effectiveness of energy-restricted diets in successful weight management. Consistent with these ﬁndings, Gunther et al. [36] recently demonstrated that chronic consumption (1-year) of a dairy-rich, high-calcium diet resulted in a substantially greater increase in postprandial fat oxidation following either a low- or high-calcium liquid meal challenge. Interestingly, they noted that the 1-year change in fasting levels of serum PTH was signiﬁcantly correlated with the 1-year change in postprandial fat oxidation, suggesting that dietary calcium suppression of PTH may have permitted increased levels of fat oxidation. Although this evidence is suggestive of a role for PTH, 1,25-(OH)2-D3 levels were not measured, and it is possible that the observed correlation may have resulted from PTH modulation of 1,25-(OH)2-D3 levels. Recent data demonstrate that 1,25-(OH)2-D3 modulation of adipocyte apoptosis may also contribute to the anti-obesity effect of dietary calcium [37]. This effect is mediated, in part, via inhibition of UCP2 expression and a consequent increase in mitochondrial potential, a key regulator of apoptosis, and in part via 1,25-(OH)2-D3 regulation of cytosolic Ca2+ and of Ca2+ ﬂux between endoplasmic reticulum and mitochondria [37;unpublished data]. Consequently, adipocyte apoptosis is signiﬁcantly impaired in association with increased 1,25-(OH)2-D3 levels in mice fed low-calcium diets, while there is a marked increase in adipocyte apoptosis in mice fed high-calcium or highdairy diets [37]. Although this appears contrary to multiple published reports that indicate a proapoptotic effect of 1,25-(OH)2-D3 in other tissues, this apparent discrepancy is the result of dosing differences. The literature that supports a pro-apoptotic effect of 1,25-(OH)2-D3 utilizes supraphysiological concentrations (≥100 nM), and we are able to demonstrate a similar pro-apoptotic effect (resulting from mitochondrial Ca2+ overload) in adipocytes at these very high levels of 1,25(OH)2-D3. In contrast, physiological concentrations exert an anti-apoptotic effect in human adipocytes, primarily due to suppression of UCP2 expression [37;unpublished data]. Figure 37.1 depicts the role of 1,25-(OH)2-D3 in regulating adipocyte apoptosis, and Figure 37.2 provides an integrated summary of 1,25-(OH)2-D3 modulation of adipocyte lipid metabolism. Increasing dietary calcium may also result in increased fecal fatty acid excretion, and, accordingly, it is possible that the resultant increase in fecal energy loss also contributes to the antiobesity effects of dietary calcium. In support of this concept, Papakonstantinou et al. [38] demonstrated that feeding a high-calcium diet to rats produced a substantial increase in fecal fat and energy excretion, and they attributed the observed reduction in adiposity to fecal energy loss, although a marked decrease in circulating 1,25-(OH)2-D3 was found, as well. More recently, Jacobsen et al. [39] reported that a short-term increase in calcium intake from 500 to 1800 mg/day increased fecal fat excretion ~2.5-fold, from 5.9 to 14.2 g/day; however, although such an increase in fecal fat loss would clearly contribute to a reduction in energy balance, it required a larger level of calcium (1800 mg vs. 1200 mg used in clinical trials of calcium and obesity) to produce a quantitatively small effect (8.3 g additional fecal fat, representing a 75-kcal/day loss) which is insufﬁcient to explain the magnitude of the effects observed in clinical trials (discussed later in this chapter). Nonetheless, the modest reduction in net energy balance resulting from this mechanism may have a pronounced effect in maintaining healthy weights and promoting weight loss over an extended period of time, and the contributory role of increased fecal fat loss should not be overlooked. Indeed, we have found that high-calcium and high-dairy diets exert a substantially greater anti-obesity effect in obese mice on a high-fat diet compared to those on a low-fat diet,

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(Low dose) (High dose)

Ca2+ 1 ,25(OH) 2D3

Calcium influx channels

[Ca2+]c

SERCA

Mitochondria [Ca2+]er

ER

UCP2 Ca release channels (RyR/IP)3R 2+

ATP

[Ca ]m

Apoptosis

FIGURE 37.1 1,25-(OH)2-D modulation of apoptosis. Low (physiological) doses of 1,25-(OH)2-D inhibit apoptosis by inhibiting uncoupling protein 2 (UCP2) and thereby restore UCP2-induced lost mitochondrial potential and ATP reduction, protecting adipocytes from apoptotic death. The reduction in mitochondrial calcium levels found with lower doses of 1,25-(OH)2-D may further contribute to this anti-apoptotic effect. In contrast, high levels of 1,25-(OH)2-D cause markedly greater increases in cytosolic [Ca2+]c, probably resulting in increased [Ca2+]er. Because endoplasmic reticulum (ER) can open their Ca2+ release channels in response to elevations in [Ca2+]c and contribute to Ca2+-induced Ca2+ release (CICR), the high Ca2+ levels achieved at these contact sites favor Ca2+ uptake into mitochondria, which is usually located nearby the ER. Calcium overload in mitochondria in turn triggers apoptosis.

and we attribute the additional effect to increased fecal energy loss in the mice on the high-fat diets [40]. Earlier human studies also demonstrated that large increases in dietary calcium (2 to 4 g/day) result in statistically signiﬁcant, but modest, increases in fecal fat loss [41–43]; for example, a supplement of 2 g calcium increased fecal fat excretion from 6.8 to 7.4% of total fat intake [42]. In contrast, to achieve a clinically meaningful (albeit modest) contribution to weight loss, the pancreatic lipase inhibitor orlistat must produce approximately a 30% inhibition of total dietary fat absorption vs. the approximately 1 to 2% found with dietary calcium. Thus, while calcium inhibition of fat absorption appears to contribute to an anti-obesity effect, this effect is too small to solely explain the observed effects. Dairy products have also been proposed to impact energy balance and obesity risk by affecting satiety, and whey-derived peptides do appear to exert a satiety effect [44], although increased satiety with milk or dairy-based meals has not been consistently found [44–47]. The increased satiety of dairy products has also been attributed to the satiating effect of protein; however, clinical trials that have demonstrated the effects of calcium and dairy on adiposity and weight loss have been primarily conducted at a ﬁxed level of protein intake. Moreover, the animal studies that have demonstrated these effects have not found measurable differences in energy intake between lowand high-calcium diets or between low- and high-dairy diets (discussed in a subsequent section of this chapter).

OTHER DAIRY COMPONENTS Although the aforementioned mechanisms explain dietary calcium inhibition of adiposity, data from clinical trials, rodent studies, and population studies all indicate a substantially (~twofold) greater effect of dairy vs. supplemental sources of calcium in attenuating adiposity. Accordingly, it is

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Ca2+ 1,25(OH)2D3-MARRS

[Ca2+]i Nucleus nVDR

RXR DR3 UCP2

Metabolic Efficiency

de novo lipogenesis

lipolysis

Mitochondria

Apoptosis

FIGURE 37.2 Role of 1,25-(OH)2-D and dietary calcium in modulating adipocyte lipid metabolism. Calcitriol (1,25-(OH)2-D) acts via the membrane vitamin D receptor (MARRS protein) to stimulate Ca2+ inﬂux. Increased Ca2+ inﬂux exerts lipogenic and antilipolytic effects. Calcitriol also acts via the nuclear vitamin D receptor (nVDR) to suppress the expression of uncoupling protein 2 (UCP2). Reduced UCP2 levels lead to increased mitochondrial potential, increased metabolic efﬁciency, and reduced adipocyte apoptosis. Dietary calcium inhibits each of these mechanisms by suppressing 1,25-(OH)2-D levels.

important to identify the additional components of dairy that may be responsible for this augmentation. Our preliminary studies in mice isolate a portion of this additional dairy-derived bioactivity to the whey fraction [48]. Likely candidates for this additional bioactivity include the branchedchain amino acid content of dairy protein and speciﬁc bioactive whey-derived peptides. Dairy contains a number of bioactive compounds, which may act either independently or synergistically with calcium to affect lipogenesis, lipolysis, lipid oxidation, or energy partitioning. Among these, the signiﬁcant angiotensin-converting enzyme (ACE) inhibitory activity contained in whey protein may be relevant to adipocyte lipid metabolism. Angiotensin II upregulates adipocyte fatty acid synthase expression [49], and ACE inhibition mildly attenuates obesity in both mice and in hypertensive patients. Consequently, because adipose tissue has an autocrine renin–angiotensin system, it is possible that a whey-derived ACE inhibitor may contribute to the anti-obesity effects of dairy. In support of these concepts, a whey-derived ACE inhibitor signiﬁcantly augmented the effects of dietary calcium on weight and fat loss in energy-restricted mice [48]; however, the combination of the calcium and ACE inhibitor was markedly less potent than either milk or whey in reducing body fat. Moreover, milk and whey both substantially preserved skeletal muscle mass during energy restriction while calcium and the calcium/ACE inhibitor combination were without effect. Although calcium plays a signiﬁcant role in weight management, and this effect is enhanced by whey-derived ACE-inhibition, these factors are not sufﬁcient to fully explain the effects of dairy. An evaluation of whey-derived mineral mix vs. calcium carbonate indicates that the other minerals contained in whey do not contribute to the anti-obesity effects of whey, as the milk-derived mineral mix exerted an effect comparable to that of calcium carbonate [48; unpublished data]. Although it may be tempting to speculate that the protein content of dairy may play a role in mediating the anti-obesity effect, studies demonstrating an anti-obesity effect of dairy products in both rodents and humans have maintained constant levels of protein intake. Accordingly, the protein content of dairy and whey per se cannot be responsible for the additional bioactivity; however, the

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amino acid composition of dairy protein may play a role. Dairy proteins have a high protein quality score and contain a high proportion (~26%) of branched-chain amino acids (BCAAs) [50,51]. In addition to supporting protein synthesis, the BCAAs (leucine, isoleucine, and valine) play speciﬁc metabolic roles as energy substrates and in the regulation of muscle protein synthesis, and their potential to participate in these additional metabolic processes is limited by their availability, with ﬁrst priority provided to new protein synthesis [50]. Accordingly, only diets that provide leucine at levels that exceed the requirements for protein synthesis can fully support the intracellular leucine levels required to support additional signaling pathways [50]. The abundance of leucine in both casein and whey is of particular interest, as it plays a distinct role in protein metabolism and a pivotal role in the translation initiation of protein synthesis [52]. Accordingly, the high concentration of BCAAs, and leucine in particular, in dairy products may be an important factor in the repartitioning of dietary energy from adipose tissue to skeletal muscle [53–55]. This suggests that an interaction between the high levels of calcium in dairy in combination with the BCAA content of dairy protein, possibly in concert with other dairy-derived bioactive compounds, may work in synergy to minimize adiposity and maximize lean mass. We have recently demonstrated that calcium-depleted milk retains approximately half of the anti-obesity bioactivity of intact milk and that most of the non-calcium/non-ACE-inhibitory bioactivity can be recapitulated by increasing the BCAA content of the low-calcium/non-dairy diet to the level found in milk [unpublished data]. Although the role of BCAA in the preservation of muscle mass is clear, the effects of leucine and other BCAAs on adipose tissue metabolism are unclear and are currently under investigation; at present, we propose that the effects of BCAA on adiposity are likely to represent the additional energetic cost of BCAA-stimulated protein synthesis. Notably, in addition to stimulating muscle protein synthesis via the mammalian target of rapamycin (mTOR) pathway, leucine has recently been demonstrated to stimulate hypothalamic mTOR signaling, resulting in decreases in food intake and body weight [56]; this suggests that leucine may play a role in satiety as well as in protein synthesis and energy partitioning between fat and muscle.

MODULATION

OF

CENTRAL ADIPOSITY

Both rodent and human studies demonstrate a shift in the distribution of body fat loss on high- vs. low-calcium diets during energy restriction. In rodents, high-calcium and high-dairy diets produce a preferential loss of visceral adipose tissue [22,25], and clinical trials demonstrate a preferential loss of fat from the trunk region (i.e., an increase in trunk fat loss as a percentage of total fat loss) [7,34,35,58]. Recent studies describing the role of autocrine production of cortisol by adipose tissue provide a likely mechanism for this effect, as well. Human adipose tissue expresses signiﬁcant 11β-hydroxysteroid dehydrogenase-1 (11β-HSD-1), which can generate active cortisol from cortisone, and visceral adipose tissue exhibits greater 11β-HSD-1 expression than does subcutaneous adipose tissue [59,60]. Further, selective overexpression of 11β-HSD-1 in the white adipose tissue of mice results in central obesity [61,62], while homozygous 11β-HSD-1 knockout mice exhibit protection from features of the metabolic syndrome [63]. We have recently found 1,25-(OH)2-D3 to exert both short-term and long-term regulation of 11β-HSD-1 in human adipocytes, resulting in an ~twofold increases in 11β-HSD-1 expression and up to sixfold increases in net cortisol production [64]. Thus, the increase in 1,25-(OH)2-D3 found on low-calcium diets is likely to cause selective expansion of visceral adipose tissue, and the observed selective loss of central adiposity on high-calcium and high-dairy diets appears to be attributable to a reduction in cortisol production by visceral adipocytes [64]. We have recently conﬁrmed this in aP2-agouti transgenic mice. When mice were fed low-calcium diets, 11β-HSD-1 expression was markedly higher in visceral vs. subcutaneous adipose tissue; however, a high-calcium diet suppressed 11β-HSD-1 expression such that no difference was observed between visceral and subcutaneous adipose tissue 11β-HSD-1 expression in the mice fed a high-calcium diet [65].

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ANIMAL STUDIES We have conﬁrmed the anti-obesity effect of dietary calcium and dairy products in a series of studies conducted in transgenic mice that express the agouti gene in adipose tissue under the control of the aP2 promoter, similar to the human pattern of expression of agouti and other obesityassociated genes [22,25,41,49,66,67]. These mice are not obese when fed standard chow diets but are susceptible to adult-onset diet-induced obesity. They respond to low-calcium diets with accelerated weight gain and fat accretion, while high-calcium diets markedly inhibit lipogenesis, accelerate lipolysis, increase thermogenesis and adipocyte apoptosis, and suppress fat accretion and weight gain in animals maintained at identical caloric intakes [22]. Further, low-calcium diets impede body fat loss, and high-calcium diets markedly accelerate weight and fat loss in transgenic mice subjected to identical levels of caloric restriction [25,41,49,66,67]. One report, however, indicates a lack of effect of increasing calcium intake on body weight and body fat in rats and mice [68]. The reason for this difference is not apparent but may be related to the use of older animals with more fully established obesity, as well as the lack of an energy restriction protocol. Studies in other animal models (Zucker lean and obese rats, Wistar rats, and spontaneously hypertensive rats) conﬁrm the observation that increased calcium intake lowers body weight and fat content [8,69,70]. Dietary calcium and dairy also alter the partitioning of dietary energy during refeeding following weight loss in aP2-agouti transgenic mouse model [71]. Although post-obese mice fed a lowcalcium diet rapidly regained all of the weight and fat that had been lost, refeeding high-calcium diets prevented the suppression of adipose tissue lipolysis and fat oxidation that otherwise accompanies post-dieting repletion and markedly increased indices of skeletal muscle fat oxidation [71]. Consequently, although animals refed low-calcium diets rapidly regained all of the weight and fat that had been lost, animals refed high-calcium diets exhibited a 50 to 85% reduction in weight and fat gain. Moreover, dairy exerted markedly greater effects than supplemental calcium on fat oxidation and fat gain [71]. These data are supported by both clinical trials and observational data, as described in the next sections.

CLINICAL DATA The original concept of calcium and dairy modulation of body composition and weight management emerged from data from a hypertension clinical trial, with subsequent corroboration via secondary analysis of other clinical trials originally conducted with skeletal outcomes and ﬁnally prospective clinical trials to evaluate the effects of calcium and dairy on adiposity. In the hypertension study, dietary calcium was increased from ~400 to ~1000 mg/day in obese African Americans without altering dietary energy or macronutrient content. Although body weight did not change, a 4.9-kg reduction in body fat was observed [22], which led to the subsequent mechanistic investigations already described. Heaney and colleagues [72–74] reanalyzed a series of calcium intervention studies originally designed with primary skeletal endpoints but which support a calcium–body weight linkage. In an analysis of nine studies, including three controlled trials and six observational studies, a signiﬁcant negative association between calcium intake and body weight was noted for all age groups studied (third, ﬁfth, and eighth decades of life), the odds ratio for being overweight was 2.25 for young women below median calcium intake compared to those above median calcium intake [72], and the controlled trials supported this relationship [72–74]. Overall, increased calcium intake was consistently associated with reduced indices of adiposity (body weight, body fat, or weight gain); the aggregate effect was that each 300-mg increase in daily calcium intake was associated with a 3-kg lower weight in adults and a 1-kg decrease in body fat in children. In contrast, a secondary analysis of three 25-week randomized clinical trials originally conducted to evaluate skeletal outcomes during weight loss did not demonstrate an effect of increased

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calcium intake on body weight or fat loss in subjects counseled to follow an energy-restricted diet; however, the authors noted that the calcium groups consistently lost more weight and fat, and they suggested that these studies did not have sufﬁcient statistical power to detect these small effects [75]. Similarly, Reid et al. [76] assessed the results of a study originally designed to assess the effects of calcium on fracture incidence and found no effect of supplementary calcium on body weight or body composition, although they observed a trend toward greater weight loss with calcium supplementation in those with the lowest baseline calcium intakes (<600 mg/day). Notably, both of the aforementioned secondary analyses [75,76] evaluated the effects of supplementary calcium. In contrast, Lin et al. [77] conducted a retrospective analysis of a 2-year prospective study of 54 normal-weight Caucasian women originally conducted to assess the impact of exercise on skeletal outcomes. They found the dietary calcium-to-energy ratio and the dairy calcium-to-energy ratio to be signiﬁcant negative predictors of changes in both body weight and body fat [77]; however, the reported effects appeared to be speciﬁc to dairy sources, as dairy calcium predicted changes in body weight and body fat, but nondairy calcium did not [77]. Thus, the failure to ﬁnd a signiﬁcant effect in retrospective analysis of calcium supplementation trials may result, in part, from the use of calcium supplements rather than dairy sources. Indeed, we have found dairy sources of calcium to be substantially more effective than supplementary sources in controlling adiposity in prospective studies of both mice and humans, as discussed earlier in this chapter. Lin et al. [77] also noted an important interaction between dietary calcium and energy intake in predicting changes in body fat, as calcium (but not energy) intake predicted changes in body weight and body fat for women below the median energy intake (1876 kcal/day), and energy intake alone predicted changes in weight and fat in women at higher levels of energy intake. This is consistent with the concept that energy balance is the predominant predictor of adiposity, with calcium and dairy effects being evident primarily when the energy balance is controlled; clinical trial data (discussed in the next section) further support this concept. An inverse relationship between energy-adjusted dietary calcium intake and body mass index was also reported in lactose-tolerant, but not lactose-intolerant, African-American women [78]. Although the reason for the lack of effect in the lactose-intolerant group cannot be deﬁnitively inferred from this cross-sectional study, the lactose-intolerant group exhibited a uniformly low calcium intake, presumably due to an aversion to dairy products, and the lack of women with adequate calcium intakes in this group therefore precluded a clear relationship emerging as it did for the lactose-tolerant women.

RANDOMIZED CLINICAL TRIALS We have conducted several clinical trials to evaluate the effects of dietary calcium and dairy on adiposity; to date, all available randomized clinical trial data available are from adults. In the ﬁrst trial [58], 32 obese adults were maintained on balanced caloric-deﬁcit diets (500 kcal/day deﬁcit) and randomized to (1) the control group (0 to 1 serving per day and 400 to 500 mg calcium per day supplemented with placebo), (2) a high-calcium diet (control diet supplemented with 800 mg calcium per day), or (3) a high-dairy diet (3 to 4 servings of milk, yogurt, and/or cheese per day for a total calcium intake of 1200 to 1300 mg/day). Control subjects lost 5.4% of their body weight over a 24-week study; this loss was increased to 8.6% on the high-calcium diet and to 10.9% on the high-dairy diet (p < 0.01). Fat loss (determined via dual-energy x-ray absorptiometry [DEXA]) followed a similar trend, with the high-calcium and high-dairy diets augmenting the fat loss found on the low-calcium diet by 38% and 64%, respectively (p < 0.01). This was accompanied by a marked change in the distribution of body fat loss [58], as fat loss from the trunk region represented 19% of the total fat lost on the low calcium diet. This was increased to 50% of the fat lost on the high-calcium diet and 66% on the high-dairy diet; this effect has now been explained via calcium/1,25-(OH)2-D modulation of adipose tissue cortisol production [64,65], as discussed earlier in this chapter. These ﬁndings demonstrate that increasing dietary calcium from suboptimal

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to adequate levels can enhance the efﬁcacy of an energy-restricted diet in weight and fat loss, while a markedly greater enhancement is found when dairy foods are used compared to calcium supplements [58]. The effects of dairy in augmenting weight and fat loss secondary to caloric restriction have been conﬁrmed in additional clinical trials. A recent follow-up clinical trial of 34 obese subjects consuming a diet supplemented with three servings of yogurt (total calcium intake of ~1100 mg/day) compared to a placebo control group (calcium intake of 400 to 500 mg/day) on a balanced caloriedeﬁcit diet (–500 kcal/day) for 12 weeks supports these ﬁndings [33]. Both groups lost weight, but the yogurt group lost 61% more fat (4.43 vs. 2.75 kg) and 81% more trunk fat (3.16 vs. 1.74 kg) than the control group (p < 0.001). Similar to the ﬁrst clinical trial, the fraction of fat lost from the trunk was markedly higher on the yogurt diet vs. control (60.0 vs. 26.4%). Moreover, a signiﬁcant 31% reduction in the loss of lean tissue mass during energy restriction was observed in the yogurt group compared to the control group. No adverse effects on any serum lipid fraction were observed in either of these trials, and both trials demonstrated an improvement in insulin sensitivity, glucose tolerance, and blood pressure in the dairy groups [33,58]. These ﬁndings have been extended in a multi-center trial of 105 overweight and obese adults conducted at the University of Tennessee, Purdue University, the University of California–Davis, and Ohio State University [61]. The design was similar to the ﬁrst clinical trial, with subjects randomized to low-calcium, high-calcium, and high-dairy groups on a balanced deﬁcit (–500 kcal/day) diets for 12 weeks. Although the calcium supplement exerted little effect, the high-dairy diet resulted in signiﬁcant, marked (~twofold) increases in fat loss and trunk fat loss, similar to that seen in the ﬁrst trial [58]; however, in contrast to the ﬁrst clinical trial, the calcium supplement was without signiﬁcant effect. We have also replicated these ﬁndings in a 6-month clinical trial in obese African-Americans [34], with essentially similar ﬁndings. Inclusion of three daily servings of dairy into a balanced deﬁcit diet with no alterations in dietary macronutrients resulted in an approximately twofold increase in weight, fat, and trunk fat loss vs. those maintained on a low-dairy diet. These ﬁndings were extended to a 6-month study of obese African-American adults in the absence of an energy deﬁcit [34]. Isocaloric substitution of three daily servings of dairy products into the diets of obese African-American adults maintained on eucaloric diets for 6 months resulted in a 5.4% reduction in total body fat and a 4.6% decrease in trunk fat (p < 0.01 for both) in the absence of any change in body weight, while the control group maintained on a low-calcium/low-dairy diet with identical macronutrient composition exhibited no signiﬁcant changes in total body fat or trunk fat [34]. Summerbell et al. [79] conducted a 16-week, randomized, placebo-controlled weight-loss trial evaluating three isoenergetic diets: a conventional balanced deﬁcit diet, a milk-only diet, or a milk diet with a single designated food added. They reported markedly greater weight loss in both milkbased diets (9.4 and 7.0 kg) compared to the conventional diet (1.7 kg) despite all subjects being prescribed the same level of energy restriction. Although the authors attributed the observed differences to the novelty of the milk-based diets possibly contributing to a greater level of compliance [79], there was no evidence to support that hypothesis and, in light of the data presented here, it is proposed that the increased weight loss was, in part, due to the effects of the milk on adiposity. Bowen et al. [80] reported that dairy failed to enhance weight loss during 12 weeks of energy restriction in subjects on high-protein diets; however, that work utilized a much higher level of protein intake than that used in the aforementioned trials (34% of energy vs. 18%), making a direct comparison difﬁcult, as higher protein intakes have been shown in some studies to be associated with greater weight loss. Indeed, the weight loss found by Bowen et al. was approximately twice as high (9.7 vs. 4.99 kg) as that found in the control group in the 12-week study discussed earlier in this chapter [34]. At this higher rate of weight loss (0.8 kg/week), a maximal rate of fat mobilization may already be approached, making additional increments due to dairy (or other factors) unlikely. Moreover, the baseline calcium intakes in the Bowen study were considerably higher (899 and 787 mg/day for men and women, respectively, assigned to the dairy protein diet,

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and 935 and 737 mg/day, respectively, for those assigned to the mixed protein diet) than in the aforementioned clinical trials [34,58], in which baseline calcium intakes were <600 mg/day. This was considered critical to ensure that the effects of correcting suboptimal intakes were studied rather than the effects of supplementing near-adequate intakes. Thompson et al. [81] conducted a 48-week trial comparing the effects of a moderate-dairy diet (two daily dairy servings) and a high-dairy diet (four daily dairy servings) on weight and fat loss in energy-restricted obese subjects. Although all groups lost weight and fat, no treatment-speciﬁc effects were observed; however, the energy prescription was periodically readjusted for those subjects who were not demonstrating adequate weight loss. After accounting for these adjustments, among subjects who adhered to the study protocol, those on the high-dairy diet achieved their weight loss while consuming a statistically signiﬁcant 100 to 150 kcal/day more than those on the low-dairy diet. The outcome of this study may have also been affected by the threshold effect, as previous clinical trials had evaluated the effects of increasing dairy and calcium from clearly inadequate levels (less than one daily dairy serving and less than 600 mg calcium per day), but this study utilized relatively low calcium and dairy intakes of 800 mg/day and two dairy servings per day. Nonetheless, among adherent subjects, comparable weight loss was attained by the highdairy group despite consuming signiﬁcantly more energy than the low-dairy group [81]. Harvey-Berino et al. [82] reported no effect of dairy on weight or fat loss in 44 overweight and obese adults for one year using a design comparable to that for our previous clinical trials (low dairy/400 to 500 mg calcium per day vs. high dairy/1200 to 1400 mg calcium per day). Although all subjects were prescribed a 500-kcal/day daily deﬁcit, the high-dairy group reported only a 314kcal/day deﬁcit (calculated from presented data as energy intake at baseline minus energy intake at months 3 and 12 of intervention) at 3 months and a 224-kcal/day deﬁcit at 12 months, while the low-dairy group achieved a 442-kcal/day deﬁcit at 3 months and a 402-kcal/day deﬁcit at 12 months. Thus, although no statistically signiﬁcant difference in energy intake was reported between the low- and high-dairy groups, the low-dairy group had a 41% greater energy deﬁcit at 3 months and a 79% greater energy deﬁcit at 12 months while achieving similar weight and fat loss as the high dairy group. Finally, preliminary data demonstrate that a eucaloric high-dairy diet markedly attenuates regain of body weight following successful weight loss compared to a low-dairy diet (3.03 vs. 1.02 kg weight regain on low- vs. high-dairy diet; p < 0.05) [83]. Similarly, the high-dairy diet attenuated the regain of body fat (1.959 vs. 0.773 kg on low- vs. high-dairy diet; p < 0.01), and trunk fat (1.546 vs. 0.218 kg on low- vs. high-dairy diet; p < 0.01), indicating that dairy-rich diets attenuate short-term (12-week) weight, fat, and trunk fat regain following weight loss. Longer term assessments are needed to fully evaluate this phenomenon and are currently in process.

OBSERVATIONAL AND EPIDEMIOLOGICAL STUDIES Although only a limited number of clinical trials have been performed to date, these clinical data are supported by multiple lines of evidence, including observational data noting an inverse relationship between dietary calcium and/or dairy and body weight and/or body fat in children and adolescents [84–88], younger and older women [77,78,89], and African-American women [78], as well as by epidemiological data from NHANES I [89], NHANES III [22], NHANES 1999–2000 [90], the Continuing Study of Food Intake of Individuals (CSFII) [90], the HERITAGE study [91], the Quebec Family Study [92], the CARDIA study [93], and the Tehran Lipid and Glucose study [94]. Although most studies reporting the relationship between dietary calcium and dairy and indices of adiposity are in adults, a few studies have been done on children and adolescents [84–88,95–97]. Although one study recently reported no relationship between dietary calcium or dairy consumption in a longitudinal assessment of adolescent females [95], the authors noted that dairy consumption was signiﬁcantly higher for their study cohort compared to that reported

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by CSFII for a nationally representative survey of the same age group (428 vs. 269 g/day of milk and milk products). Moreover, the overall reported median dairy intake was 2.9 servings of dairy and 827 mg of dairy-derived calcium per day. Accordingly, it is possible that this cohort represented a relatively high dairy-consuming population and therefore was sufﬁciently above a yet-to-be determined threshold of dairy intake to observe an effect on indices of adiposity. In contrast, several other studies of children and adolescents suggest a protective effect of dairy [84–88,96]. A signiﬁcant inverse relationship between dietary calcium and body fat was reported in a 5-year longitudinal study of preschool children studied from 2 months of age (R2 = 0.51) [84]. The group subsequently extended these longitudinal ﬁndings to 8 years of age [85]. Overall, in predictive equations that explain 26 to 34% of the variability in body fat, variations in dietary calcium explained 7 to 9% of the variability in adiposity [85]. Notably, these longitudinal data strongly suggest that dairy and calcium intake within the ﬁrst year of life are signiﬁcant inverse determinants of body fat levels at age 8 [84,85]. Consistent with these ﬁndings, longitudinal data from the Framingham Children’s Study indicate that higher intakes of calcium early in life (ages 3 to 5) were associated with decreased gain of body fat over time (early adolescence), with dairy servings being more strongly correlated to reduced body fat than dietary calcium per se [96]. It is important to interpret such ﬁndings within the context of overall energy balance; for example, Berkey et al. [97] recently reported that adolescents who consume excess calories from milk exhibit higher gains in body mass index than those who do not; however, when adjusted for energy intake, this effect was not evident. The associations between dairy intake and incidence of the major components of the insulin resistance syndrome (IRS), including obesity, was evaluated in a 10-year population-based prospective study of 3157 African-American and Caucasian adults [93]. Overweight individuals who consumed the most dairy products had a 72% lower incidence of IRS compared to those with the lowest dairy intakes. Moreover, the cumulative incidence of obesity in those who started the study in the overweight category was signiﬁcantly reduced from 64.8% in those consuming the least amount of dairy foods to 45.1% in the highest dairy-food-consuming group. Notably, the inverse relationship between dietary calcium and either IRS or obesity incidence in the CARDIA study was explained solely by dairy intake and was not altered by adjustment for dietary calcium, indicating the presence of an additional effect of dairy beyond the mechanisms already cited for dietary calcium in modulating adiposity and obesity risk; this is consistent with both the experimental animal and clinical trial data which also suggest that other dairy components, in addition to calcium, contribute to an anti-obesity effect.

DIETARY CALCIUM MODULATION OF OBESITY-INDUCED OXIDATIVE STRESS Reactive oxygen species (ROS) production is increased in obesity [98–101]. In the past, the expanded adipose tissue mass that characterizes obesity has been principally considered as a simple fuel reservoir to supply nonesteriﬁed fatty acids (NEFAs) to meet the energy requirements of peripheral organs. This simplistic concept has been modiﬁed, however, following the discovery that adipose tissue also functions as an endocrine organ and produces a variety of bioactive proteins (adipokines) and is a signiﬁcant source of reactive oxygen species. ROS and systemic oxidative stress are implicated as causative factors in systemic inﬂammation and in tissue damage resulting from obesity, diabetes, and atherosclerosis and are recognized as key factors contributing to the physiological processes of aging. We have shown that adipocyte ROS production is modulated by mitochondrial uncoupling status and cytosol Ca2+ signaling, and 1,25(OH)2-D3 regulates ROS production in cultured murine and human adipocytes [102]. Thus, we have proposed that increased 1,25(OH)2-D3 contributes to

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Positive effect 1, 25(OH)2D 3

Negative effect

adipocyte nucleus UCP Ca 2+

Ca 2+

Ca 2+

?? ROS Mitochondria

FIGURE 37.3 Schematic illustration of effects and mechanisms of calcitriol (1,25-(OH)2-D3) on reactive oxygen species (ROS) production and adipocyte proliferation. Physiological doses of calcitriol increase ROS production by inhibiting UCP2 expression and stimulating intracellular calcium inﬂux. Dietary calcium inhibits ROS via suppression of calcitriol.

systemic oxidative stress by inhibiting adipocyte uncoupling protein 2 (UCP2) expression and increasing cytoslic Ca2+ signaling, thereby increasing ROS production. Accordingly, because dietary calcium suppresses 1,25(OH)2-D3, high-calcium diets would be anticipated to correspondingly decrease adipose tissue ROS production and systemic oxidative stress (Figure 37.3). In support of this concept, we have recently reported that high-calcium diets inhibited adipose tissue NADPH oxidase expression (a key source of intracellular ROS) and resulted in a striking 64% reduction in visceral adipose tissue ROS production in mice [65]. A similar pattern was evident in skeletal muscle, which exhibited a signiﬁcant increase in UCP3 expression and a corresponding decrease in NADPH oxidase expression [65]. These ﬁndings indicate a potentially important role of dietary calcium in attenuating obesity-induced oxidative stress and suggest that, in addition to exerting an anti-obesity effect, calcium may play a signiﬁcant role in suppressing a key mediator of obesityinduced morbidity [65].

SUMMARY AND CONCLUSIONS An anti-obesity effect of dietary calcium and dairy foods is evident from animal studies, observational and population studies, and randomized clinical trials. Moreover, a strong theoretical framework is in place to explain the effects of dietary calcium on energy metabolism. The supporting mechanisms include dietary calcium supplementation correcting suboptimal calcium intakes and thereby preventing the endocrine (PTH and 1,25-(OH) 2-D) response, which favors adipocyte energy storage and inhibits adipocyte loss via apoptosis. Dietary calcium appears to further promote energy loss via formation of calcium soaps in the gastrointestinal tract, thereby reducing net energy absorption. Dietary calcium appears to be responsible for ~50% of the antiobesity bioactivity of dairy. The additional dairy bioactivity has not been fully identiﬁed, but major components are the ACE inhibitory activity of dairy and the high concentration of BCAA in dairy. Animal studies indicate that the BCAA content of dairy is largely responsible for the repartitioning of dietary energy from adipose tissue to skeletal muscle during weight loss, resulting in greater preservation of skeletal muscle and accelerated loss of adipose tissue during negative energy balance. Finally, high-calcium diets suppress obesity-induced oxidative stress and may thereby contribute to a reduction in obesity comorbidity independently of the direct anti-obesity effect.

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Phillips, S.M., Bandini, L.G., Cyr, H., Colclough-Douglas, S., Naumova, E., and Must, A., Dairy food consumption and body weight and fatness studied longitudinally over the adolescent period, Int. J. Obes., 27, 1106–1113, 2003. Moore, L.L., Singer, M.R., Bradlee, M.L., and Ellison, R.C., Dietary predictors of excess body fat acquisition during childhood [abstract], paper presented at the 44th American Heart Association Annual Conference on Cardiovascular Disease Epidemiology and Prevention, 2004. Berkey, C.S., Helain, R.S., Willett, W.C., and Colditz, G.A., Milk, dairy fat, dietary calcium and weight gain: a longitudinal study of adolescents, Arch. Pediatr. Adolesc. Med., 159, 543–550, 2005. Furukawa, S., Fujita, T., Shimabukuro, M., Iwaki, M., Yamada, Y. et al., Increased oxidative stress in obesity and its impact on metabolic syndrome, J. Clin. Invest., 114, 1752–1761, 2004. Atabek, M.E., Vatansev, H., and Erkul, I., Oxidative stress in childhood obesity, J. Pediatr. Endocrinol. Metab., 17, 1063–1068, 2004. Lin, T.K., Chen, S.D., Wang, P.W., Wei, Y.H., Lee, C.F. et al., Increased oxidative damage with altered antioxidative status in type 2 diabetic patients harboring the 16189 T to C variant of mitochondrial DNA, Ann. N.Y. Acad. Sci., 1042, 64–69, 2005. Sonta, T., Inoguchi, T., Tsubouchi, H., Sekiguchi, N., Kobayashi, K. et al., Evidence for contribution of vascular NAD(P)H oxidase to increased oxidative stress in animal models of diabetes and obesity, Free Radic. Biol. Med., 37, 115–123, 2004. Sun, X.C., Morris, K., and Zemel, M.B., 1,25(OH)2D3 and reactive oxygen species interactively stimulate angiotensinogen expression in differentiated 3T3-L1 adipocytes [abstract], FASEB J., 19, A70, 2005.

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from the Use 38 Lessons of Ephedra Products as Dietary Supplements Madhusudan G. Soni, Kantha Shelke, and Rakesh Amin CONTENTS Introduction ....................................................................................................................................495 History of Ephedra.........................................................................................................................496 Chemistry .......................................................................................................................................496 Variations in Alkaloid Content ......................................................................................................496 Pharmacological Action of Ephedra ..............................................................................................497 Contraindications of Ephedra Constituents ...................................................................................498 Pharmacokinetics ...........................................................................................................................498 Human Observations......................................................................................................................499 Clinical Studies .......................................................................................................................499 Case Reports and Adverse Event Reports..............................................................................499 The Story and Lessons...................................................................................................................501 References ......................................................................................................................................503

INTRODUCTION Sales trends of herbal products in the United States suggest a dramatic increase in the use of these products. According to industry reports, consumers spend approximately $14 billion a year on dietary supplements. It has been estimated that as many as 2 to 3 billion doses of dietary supplements containing ephedrine alkaloids are consumed each year in the United States [3,27]. Among the products containing ephedrine alkaloids, Ephedra sinica (Ma huang) is the most commonly used plant source. Ephedrine and related alkaloids found in ephedra can also be produced synthetically. Ephedra products have been extensively used for weight loss, weight management, and energy enhancement. Dietary supplements containing ephedra extract generally contain 6 to 8% ephedrine alkaloids. Beginning in the 1990s, concerns over the safety of ephedra and products containing ephedra began to be publicly raised in the United States. The U.S. Food and Drug Administration (FDA) received over 1000 reports of adverse effects (including over 100 deaths) related to the consumption of ephedra-containing dietary supplements. Because of continued and growing health concerns over the years, on February 6, 2004, the FDA issued a ﬁnal rule prohibiting the sale of dietary supplements containing ephedrine alkaloids (ephedra), and the rule became effective 60 days from the date of publication. Many advocates for the use of ephedra maintained that it was safe in low doses. The proponents of ephedra use challenged the FDA prohibition, and a federal district judge limited

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the scope of the FDA’s ban; however, the FDA is arguing to try to restore the ban. The objective of this review article is to highlight the controversy surrounding the safety in use of ephedra as a dietary supplement and the lessons learned.

HISTORY OF EPHEDRA Ephedra sinica is an herb that has been used in traditional Chinese medicine for over 5000 years and is considered the world’s oldest medicine. It is used as a stimulant and for the management of bronchial disorders [4]. Ancient Aryans from India discovered that ephedra or the Soma plant could be used as an energizer cum euphoriant. The use of ephedra juice for longevity has been mentioned in the Rigveda (the oldest of sacred Sanskrit Vedas) [45,46]. Historically, ephedra has been recommended for colds and ﬂu, coughing, wheezing, nasal congestion, fever, chills, headaches, edema, hyperhydrosis, and bone pains. Ephedra, also known as Ma huang, is an evergreen perennial herb native to central Asia and is now widely distributed and cultivated throughout the temperate and subtropical zones of Asia, Europe, and the Americas. The Ephedra genus includes more than 40 species. The majority of these Ephedra species contain the alkaloid ephedrine [15,43]. In 1885, its active ingredient, ephedrine, was isolated from the ephedra plant and was also chemically synthesized. Because of the pharmacological activity of ephedra, ephedrine was recommended as the treatment of choice for asthma. Currently, standardized ephedrine/pseudoephedrine preparations are commonly used around the world in the treatment of asthma [15].

CHEMISTRY The primary compound of interest in commercially cultivated Ephedra plant species is the alkaloid ephedrine. In addition to ephedrine, ephedra plants also contain other alkaloids. The yield of alkaloids in ephedra plants ranges from 0.5 to 2.5%, of which 30 to 90% is ephedrine. In some ephedra species, pseudoephedrine has also been found. Generally, ephedrine and pseudoephedrine constitute more than 80% of the alkaloid content of the dried herb [44]. Additional alkaloids found in ephedra include N-methylephedrine, N-methylpseudoephedrine, norpseudoephedrine, and norephedrine. Ephedrine in its natural form exists as the L isomer (laevorotatory), but the synthetic compound is generally a racemic mixture of L and D isomers. Generally, the fruits and roots of the ephedra plant are devoid of alkaloids. The astringent taste of ephedra products is due to the large amounts of tannins present in the plant.

VARIATIONS IN ALKALOID CONTENT The alkaloid content of the commercially available ephedra products varies considerably and depends on the Ephedra species, geographical location, parts used (aerial, stem, leaf, or a combination of stem and leaf), and harvesting and extraction techniques. Because of the natural variations in the alkaloid contents of the Ephedra plant, signiﬁcant inter-product and intra-product variability has been reported in ephedra products [6,28,29,32]. In a series of studies, Gurley et al. [28–32] investigated the quantitative variations in alkaloid contents in commercially available ephedra products. The alkaloid content in these products varied by as much as ﬁvefold, with different brands exhibiting lot-to-lot variations ranging from 44 to 260%. These investigators also noted that several commercially available ephedra products do not report the amount of ephedrine on the label [31,32]. The total alkaloid content in ephedra products varied considerably and ranged from 0.0 to 18.5 mg/dosage unit. Gurley et al. [32] reported that the ephedrine and pseudoephedrine levels in these products also varied and ranged from 1.1 to 15.3 mg and 0.2 to 9.5 mg/unit dose, respectively. In addition to their variable alkaloid content, ephedra products may also contain intentionally added

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ingredients, such as guarana, St. John’s wort, chromium picolinate, kola nut, White Willow bark, diuretics, or cathartics. Additionally, herbal supplements have been shown to contain undeclared pharmaceuticals, toxic herbs, or heavy metals [32,58]. Thus, it is likely that the differences in the alkaloid content, other ingredients, and contaminants found in ephedra products affect the pharmacological and toxicological action of these products.

PHARMACOLOGICAL ACTION OF EPHEDRA For over 2000 years, ephedra has been used to treat bronchial asthma, cold and ﬂu, chills, fever, lack of perspiration, headache, aching joints and bones, nasal decongestion, and cough and wheezing [7,43]. Ephedra is approved by the German Commission E for the treatment of respiratory tract diseases with mild bronchospasms [7]. The use of ephedra preparations for the treatment of nasal decongestion due to hay fever, common cold, rhinitis, and sinusitis and as a bronchodilator in the treatment of asthma is also recognized by the World Health Organization [68]. The pharmacological action of ephedra is dependent on its chemical composition and particularly on the levels of ephedrine. As ephedrine is the primary alkaloid present in the majority of Ephedra species, the effects of ephedrine can represent the expected pharmacological action of ephedra. The pharmacological action of ephedrine has been extensively investigated in human and animal studies. Although the individual alkaloids have similar pharmacological activity, they vary signiﬁcantly in potency [13] and thus alter the net effect. Lee et al. [41,42] reported that the potency of adrenergic activity and the cytotoxicity of ephedra extracts correlate with the ephedrine content; however, the cytotoxicity of all ephedra extracts could not be completely accounted for by their ephedrine content alone. Both ephedrine and pseudoephedrine have been shown to target the adrenergic receptors, the same receptors targeted by adrenaline. The pharmacological action of ephedrine is comparable to amphetamine but at about one ﬁfth the potency. As a mixed sympathomimetic agent, ephedrine enhances the release of norepinephrine from sympathetic neurons and stimulates α- and β-receptors. Ephedrine stimulates heart rate and thus increases cardiac output. It causes peripheral constriction, leading to an increase in peripheral resistance. Ephedrine is known to relax bronchial smooth muscle; hence, it is used as a decongestant and for the temporary relief of shortness of breath caused by asthma. The onset of the pharmacological effects of ephedrine is generally evident within an hour of ingestion. The alkaloids from ephedra are known central nervous system stimulants; oral administration of a 50-mg dose of ephedrine has been shown to stimulate the central nervous system [10]. In a number of studies, various cardiovascular effects attributed to ephedrine have been reported. In a double-blind study, Tashkin et al. [59] reported that in patients with obstructive airway disease ephedrine at a dose of 25 mg produces a signiﬁcant increase in speciﬁc airway conductance 1 hour following ingestion. Heart rate was signiﬁcantly increased at 2 to 5 hours, and the bronchodilatory effect lasted for over 4 hours. Hoffman and Lefkowitz [35] reported that ephedrine stimulates the heart rate and cardiac output and variably increases blood pressure. In a double-blind study, Nuotto [49] investigated the psychophysiological effects of ephedrine in healthy volunteers. A single oral dose of ephedrine (25 mg) increased the heart rate and systolic blood pressure and reduced diastolic blood pressure without affecting psychomotor performance. Drew et al. [21] reported that ingestion of a single dose of 60 to 90 mg of ephedrine produced a diastolic blood pressure of 90 mmHg and higher in healthy volunteers. A maximum change in heart rate of 12 beats/min was noted after ingestion of 90 mg ephedrine. A signiﬁcant increase in blood pressure was noted at two to three times the recommended dose of 15 to 30 mg of ephedrine [13]. Based on results from several single-oral-dose studies, Chau and Benrimoj [14] attributed the discrepancies in cardiovascular effects to the varying methodologies of the studies with respect to the parameters analyzed and the time intervals assessed.

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CONTRAINDICATIONS OF EPHEDRA CONSTITUENTS Ephedrine, the active ingredient of ephedra, is contraindicated for individuals with heart disease, hypertension, coronary thrombosis, impaired circulation of the cerebrum, glaucoma, diabetes, thyroid disease, autonomic insufﬁciency, pheochromocytoma, chronic anxiety or psychiatric disorders, or enlarged prostate [19,36]. Ephedrine is also contraindicated for patients treated with monoamine oxidase (MAO) inhibitors, as the combination may cause severe, possibly fatal, hypertension [18,36]. Special populations, such as neonates and breast-fed infants, pregnant women, children, and the elderly, may be at increased risk of toxicity from ephedrine and related agents because of increased sensitivity to the effects of sympathomimetic stimulation. Anastario and Haston [2] reported increased fetal heart rate and beat-to-beat variability following intramuscular administration of ephedrine for the treatment of maternal hypotension.

PHARMACOKINETICS Ephedrine, the primary active ingredient of ephedra, is completely absorbed from the gastrointestinal tract within 2 to 2.5 hours [69,70]. In humans, ephedrine is primarily excreted via urine; within 24 hours of administration, approximately 95% of the ephedrine may be excreted unchanged (55 to 75%) or as metabolites [19]. The serum half-life of ephedrine is reported to be 2.7 to 3.6 hours [52]. Available studies suggest that the biotransformation of ephedrine takes place through aromatic hydroxylation, N-demethylation, and oxidative deamination pathways. Approximately 8 to 20% of the administered ephedrine is metabolized by N-demethylation to norephedrine, and 4 to 13% undergoes oxidative deamination resulting in the formation of 1-phenylpropan-1,2-diol and further side-chain oxidation to benzoic acid and hippuric acid [56,69,70]. The pharmacokinetics of other ephedrine-related alkaloids in ephedra, including pseudoephedrine and phenylpropanolamine, are similar to ephedrine. As ephedrine contains ionizable groups, its urinary excretion depends on pH, with excretion increasing in acidic urine and decreasing in alkaline urine [48,69,70]. Following oral ingestion, large inter-individual variations in plasma levels of ephedrine have been reported. White et al. [67] reported that absorption of ephedrine in normotensive subjects is much slower when it is given as a component of an ephedra product compared to its pure form. Comparative absorption of ephedrine following ingestion of pure ephedrine or ephedra products revealed that ingestion of an ephedra product had approximately twice the Tmax (time to maximum plasma concentration). In a subsequent study by the same group, pharmacokinetic parameters for botanical ephedrine were found to be similar to those for synthetic ephedrine [30]. Haller et al. [34] studied the pharmacokinetics and pharmacodynamics of a dietary supplement containing ephedra and guarana. In this study, 80 healthy adults orally ingested a single dose of a dietary supplement containing 20 mg ephedrine alkaloid and 200 mg caffeine. Following the administration, plasma and urine levels of ephedrine alkaloids and caffeine, heart rate, and blood pressure were monitored for 14 hours. The Tmax for ephedrine and pseudoephedrine were similar (2.4 hours), but the Tmax of caffeine was shorter (1.5 hours). The half-life of ephedrine was determined to be 6.1 hours. The plasma clearance and elimination half-lives of ephedrine, pseudoephedrine, and caffeine from this study were similar to values reported for drug formulations. The half-life of ephedrine and pseudoephedrine in one subject with a high urinary pH was prolonged. At 90 minutes after the ingestion, a signiﬁcant increase in mean systolic blood pressure was observed, and at 6 hours after the ingestion the heart rate reached a maximum change of 15 beats/min above baseline. The investigators concluded that the disposition characteristics of botanical products are similar to their synthetic pharmaceutical counterparts.

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HUMAN OBSERVATIONS CLINICAL STUDIES In several clinical studies, ephedrine has been extensively investigated alone or in combination with caffeine, particularly for its effect on body weight reduction. Ephedrine is taken along with caffeine, as the combination has been shown to result in greater body weight decrease compared to ephedrine alone. Reductions in body weight following the combined intake of ephedrine and caffeine have been attributed to both decreased food intake and increased energy expenditure [5,7,22,23,47,62]. None of the studies reported any serious, unanticipated toxicity. In a multi-center, randomized, double-blind, placebo-controlled trial, Boozer et al. [9] studied the safety and efﬁcacy of an herbal supplement. In this trial, 167 subjects were randomized to placebo (84) or herbal treatment (83). Herbal treatments composed of Ma huang (90 mg/day ephedrine) and kola nut (192 mg/day caffeine) were given to subjects for 6 months for weight loss. Alterations in blood pressure, heart function, body weight, and body composition were monitored. Signiﬁcant beneﬁcial effects of the herbal supplement on body weight, body fat, and blood lipids were noted. The herbal supplement produced no adverse events, and only minimal side effects, consistent with the known pharmacological action of ephedrine and caffeine, were noted. In a previous study by these authors, ingestion of a herbal dietary supplement containing 72 mg/day ephedrine alkaloids and 240 mg/day caffeine resulted in short-term weight and fat loss [8]. In both the studies, small persistent increases in heart rate without any evidence of cardiac arrhythmias were noted. In other studies, the increase in heart rate was also noted following acute treatment with ephedrine and caffeine [5] or with ephedra [67]. In another 8-week study with an ephedra formulation (dose not speciﬁed), Kaats et al. [38] also reported weight reduction without any signiﬁcant changes in blood pressure or resting heart rates; however, the details of the study were limited. In a 2-week double-blind trial, Kalman et al. [39] investigated the cardiovascular effects of an ephedra/caffeine supplement in 27 overweight healthy adults. In this study, the subjects were given ephedra (335 mg standardized for 20 mg ephedrine alkaloid), guarana (910 mg containing 200 mg caffeine), and bitter orange (5 mg synephrine). Ingestion of the supplement did not produce any noticeable cardiovascular adverse effects. Contrary to these observations, but based on adverse events reports, Haller and Benowitz [33] and Samenuk [55] speculated that a link might exist between the consumption of low levels of ephedra alkaloid and arrhythmias. In a recent report, Shekelle et al. [57] evaluated 52 controlled clinical trials of synthetic ephedrine or botanical ephedra used for weight loss or athletic performance. A meta-analysis was performed in which weight-loss clinical trials with at least 8 weeks of follow-up data were included. Studies of athletic performance were not included, as these studies used a wide variety of interventions. The use of synthetic ephedrine, ephedrine plus caffeine, or ephedra plus botanicals containing caffeine was found to be associated with two to three times the risk of nausea, vomiting, psychiatric symptoms such as anxiety and change in mood, autonomic hyperactivity, and palpitations, as compared with placebo.

CASE REPORTS

AND

ADVERSE EVENT REPORTS

Case reports on ephedra are available in the published literature. Several cases of psychiatric illness have been reported following the consumption of ephedra [11,20,37,40,61]. In addition, Zaacks et al. [71] reported hypersensitivity myocarditis associated with ephedra use in a 39-year-old male. Powell et al. [53] reported nephrolithiasis in a 27-year-old male using an energy supplement containing ephedra extract. Warner and Lee [65] reported a case of Leber hereditary optic neuropathy in a patient using ephedra alkaloids at the time of onset. Vahedi et al. [64] reported an ischemic stroke in a 33-year-old male who consumed ephedra extract together with creatinine monohydrate

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for bodybuilding. A Naval reservist taking high doses of Ephedra sinica was found to have high blood pressure [66]. Theoharides [60] reported the sudden death of a 23-year-old male that was related to ingestion of an ephedra-containing drink. Autopsy revealed myocardial necrosis and cellular inﬁltration. Other case reports have described ventricular arrhythmias or myocardial infarction in individuals consuming supplements containing ephedrine [50,51,72]. The case reports in the literature do not allow for determination of the overall incidence of different adverse events possibly associated with the use of ephedrine or for all of the patient populations that might be at risk from the use of these types of products. The available case reports support the notion that the use of ephedrine is contraindicated for individuals with a history of cardiovascular diseases, as ephedrine has been shown to have a pharmacologically stimulatory effect on heart rate and cardiac output. Few case reports, however, have been published describing serious adverse events in individuals without preexisting medical conditions. As ephedra-containing products may also contain other stimulants or may be consumed with other stimulants, the exact role of ephedra or the ephedrine alkaloids in these adverse events has been difﬁcult to determine. In addition to the published case reports, thousands of adverse reports were submitted by consumers and healthcare workers to the FDA or manufacturers of ephedra products. To determine the risk to consumers posed by products containing ephedra, at least four groups have independently reviewed adverse event reports ﬁled with the FDA or the manufacturers related to the use of supplements containing ephedra alkaloids. In an initial investigation, Haller and Benowitz [33] reviewed 140 reports of adverse events of ephedra that were submitted to the FDA between 1997 and 1999. Among these reports, 31% were “deﬁnitely” or “probably” related to the use of supplements containing ephedra alkaloids, and another 31% were deemed to be “possibly” related. Approximately, 47% of the events involved the cardiovascular system and 18% were related to the central nervous system. The adverse events included hypertension, palpitations and/or tachycardia, stroke, and seizures. Ten events resulted in death, and 13 events produced permanent disability. The investigators determined that the use of ephedra products might pose a health risk to some individuals. Samenuk [55] also assessed adverse event reports ﬁled with the FDA from 1995 to 1997. Of the 926 cases of possible ephedra-related toxicity, these investigators identiﬁed 37 serious cardiovascular events. In these cases, the use of ephedra was temporally related to stroke (16 reports), myocardial infarction (10), or sudden death (11). The use of ephedra was reported to be within the manufacturers’ dosing guidelines in all serious cardiovascular events but one case. The investigators concluded that the use of ephedra is temporally related to stroke, myocardial infarction, and sudden death. The Council of Responsible Nutrition [16] also investigated a total of 1173 adverse events ﬁled with the FDA. The database identiﬁed 69 reports of death following ephedra use. From the total of 1173 reports, 121 were selected for further evaluation, and 47 were considered to contain serious adverse events that included cases of stroke and stroke-like symptoms (15), seizures (13), cardiac arrest (15), and 2 individuals who collapsed. Among the 121 cases, 8 were reports of death: 6 were cardiovascular, 1 occurred in an automobile accident, and 1 was a spontaneous abortion. Four of the six cardiovascular subjects were using ephedra with other performance-enhancing products, such as caffeine. Autopsy results revealed that one patient had atherosclerotic cardiovascular disease and another had myocardial disease due to chronic catecholamine use. Of the six patients, one individual suffered from asthma. The report concluded that, based on the available information, it was not possible to determine whether or not any unexpected toxicological effects occurred due to the ephedra-containing dietary supplements. The Texas Department of Health received reports of over 500 adverse events, including 7 deaths due to myocardial infarction or stroke in patients who consumed supplements containing ephedrine [12]. One of the makers of ephedra-containing weight loss supplements has turned over nearly 1500 consumer complaints to the FDA. These complaints included 14 alleging serious adverse events (10 strokes, 2 heart attacks, and 2 seizures).

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The authors of the RAND [54] report reviewed 1820 case reports provided by the FDA, more than 18,000 consumer complaints reported to a manufacturer of ephedra-containing dietary supplements, and 71 cases reported in the published literature. The authors stated that the majority of the cases were not well documented and hence decisions could not be made about the potential relationship between the use of ephedra-containing dietary supplements or ephedrine and the adverse events. Of the available reports, 241 cases from the FDA, 43 cases from a manufacturer, and 65 cases from the published literature were analyzed. From these reports, adverse events with prior ephedra consumption included 2 deaths, 3 myocardial infarctions, 9 cerebrovascular/stroke events, 3 seizures, and 5 psychiatric cases; adverse events with prior ephedrine consumption included 3 deaths, 2 myocardial infarctions, 2 cerebrovascular/stroke events, 1 seizure, and 3 psychiatric cases. Approximately 50% of the events were noted in individuals 30 years of age or younger. Of the remaining cases, 43 cases were identiﬁed as possible events with prior ephedra consumption and 7 cases as possible events with prior ephedrine consumption. The ﬁndings of this analysis raise concerns about the risks posed by ephedra supplements; however, the majority of the case reports were not documented sufﬁciently to support an informed judgment about the relationship between the use of dietary supplements containing ephedra or ephedrine and the adverse event in question.

THE STORY AND LESSONS As early as 1995, the FDA convened a special working group to evaluate the potential health effects associated with dietary supplements containing ephedrine alkaloids [24]. Based on the group’s recommendations, on June 4, 1997, the FDA proposed a rule to: (1) limit the total daily intake of ephedrine alkaloids to 24 mg/day or 8 mg/6-hour period; (2) have the label state that the product should not be used for more than 7 days; (3) prohibit the use of ephedrine alkaloids with substances known to have a stimulant effect; and (4) require a speciﬁc warning label [25]. The proposed rule was based on “serious illnesses and injuries, including multiple deaths, associated with the use of dietary supplement products that contain ephedrine alkaloids.” The FDA received over 15,000 comments in response to its proposed rule. The quality of scientiﬁc information and adverse event reports supporting the rule was challenged by industry groups and the Small Business Administration’s Ofﬁce of Advocacy. The House Committee on Science asked the General Accounting Ofﬁce (GAO) to examine: (1) the scientiﬁc basis for the FDA’s proposed rule, and (2) the Agency’s adherence to the regulatory analysis requirements for federal rulemaking [27]. Following its investigations, the GAO concluded that, although the FDA had justiﬁable concerns, the legitimacy of the adverse events reports to form the basis for the FDA’s recommendation was questionable. Following the criticism, on April 3, 2000, the FDA withdrew certain provisions of the proposed rules, such as limiting the ingredient level and duration of use for these products [26]; however, the FDA did not withdraw the proposed prohibition on the use of other ingredients with stimulant effects with dietary supplements containing ephedra alkaloids. Subsequent to the FDA’s withdrawal, additional reports of adverse events and case reports on ephedra safety continued to appear (see Human Observations section). Bent et al. [73] found that the sale of products containing ephedra accounts for only 0.82% of herbal product sales; however, their reported adverse events represent 64% of all adverse reactions to herbs in the United States. The investigators concluded that the use of ephedra poses a greatly increased risk of adverse reactions compared with other herbs. Because of increasing concerns that the use of dietary supplements containing ephedrine alkaloids (ephedra) presents an unreasonable risk of illness or injury, on February 6, 2004, the FDA issued a ﬁnal rule prohibiting the sale of supplements containing ephedra. Advocates for ephedra challenged the ability of the FDA to ban ephedra completely without conclusively demonstrating danger at low doses. Based on inadequate safety data at lower doses, on April 14, 2005, a federal district court in Utah struck down the FDA ban on ephedra. The court determined that the use of a risk–beneﬁt analysis by the FDA was against the intent of Congress

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in passing the Food, Drug, and Cosmetic Act [1]. Although the ruling is speciﬁc only to Utah, it calls into question the FDA ban in general. The ruling places the FDA in a unique situation. The majority of evidence regarding ephedra risks is based on higher use levels or its use in combination with other stimulants. Because the FDA placed a universal ban, it would be unethical to conduct human studies of lower doses in order to establish safety. The clinical trials of ephedra and its principle alkaloid, ephedrine, support the safety of ephedra, but studies investigating adverse event reports and case studies raise concerns about the risks associated with the use of ephedra [33,55]. The adverse event studies do not establish a direct causal relationship between the injuries reported and the intake of ephedra. The adverse event reports are voluntary and anonymous, thus making the reporting system somewhat unreliable. Although some genuine adverse events may be underreported, false reports can be included, creating erroneous information in the database. The differential conclusions drawn from the results of clinical studies and from the adverse events analysis raise important question. Given that some of the adverse events probably reﬂect real problems, it is important to understand the other contributing factors. The adverse events of ephedra may be affected by other factors such as the dosage, duration, underlying sensitivity, simultaneous use of other stimulants, contaminants, inconsistent potency, or a combination of these factors. Some of these factors are discussed below: •

•

•

•

Dosage, duration, and user demographics — Overuse (both dosage and duration) of this dietary supplement because of its conceived beneﬁts is quite possible; thus, ephedra has a potential for abuse. User characteristics such as sex, age, and race or ethnicity can also affect the action of ephedra. Several reports of adverse events suggest the possibility of ephedra overuse. Gurley et al. [32] concluded that the increased incidence of ephedra toxicity results from accidental overdose, often prompted by exaggerated off-label claims and a belief that “natural” products are inherently safe [32]. Speciﬁcations — Marketed ephedra products are subject to variations because of differences in plant species (strain) and varying growth, harvest, and storage conditions. These variations are likely to yield markedly different quantities of the active alkaloids, making it difﬁcult for consumers to ﬁnd standardized products. In one study, the total alkaloid content of ephedra products varied from 0 to 18.5 mg/dosage unit [32]. Available information also demonstrates discrepancies between label claims for the ephedrine content and the actual amount of ephedrine, as well as lot-to-lot variations in ephedrine content. These variables are likely to add to the differential pharmacological effects of ephedra. Recently, the U.S. Pharmacopoeia (USP) has initiated a service to test and certify dietary supplements for ingredient contents and concentrations per label claim. Individual sensitivity — Inter-individual differences in the response to ephedra have been reported. It is likely that some individuals may have inherent sensitivity to ephedra. It is also possible that peoples with special health challenges may react differently to ephedra. White et al. [67] reported wide variations in the blood pressure of individuals taking ephedra. Drug and other product interactions — Because of the known pharmacological interactions between ephedra and other products, individuals with a history of a psychiatric illness, especially if being treated with monoamine oxidase inhibitors or other prescription drugs, must consult a qualiﬁed healthcare provider before taking supplements. People with underlying heart conditions, hypertension, diabetes, or thyroid disease should avoid ephedra use, as the combination of ephedra and caffeine or caffeine-containing herbs may lead to an increased heart rate and blood pressure [63].

In summary, as a result of several well-publicized adverse events and the FDA action, dietary supplements containing ephedra has generated controversy. The ﬁndings that led to the FDA banning the use of ephedra-containing dietary supplements and challenges by the manufacturers offer some

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lessons for the scientiﬁc community, regulatory agencies, healthcare practitioners, consumer advocates, marketers, and the civil courts. As a plant product, the content of its pharmacologically active constituents may be inﬂuenced by differences in species and strain, as well as in growth, harvest, and storage conditions. In an effort to enhance its perceived weight-loss and body-building effects, ephedra products are subject to the addition of a variety of adulterants, both economic and efﬁcacious. Simultaneous use of drugs, dietary supplements, alcohol, illicit substances, and certain foods (caffeine-containing products) can also inﬂuence the desired physiologic outcome. The adverse events of ephedra appear to be affected by such factors as overuse, inconsistent potency (speciﬁcations), individual sensitivity, interactions with drugs and other products, and contaminants. Contrary to the analysis of adverse events, preclinical and clinical studies support the safety of ephedra products. The FDA ban on the sale of all ephedrine-alkaloid dietary supplements, its challenge, and the court ruling to limit the scope of the ban affect FDA procedures for creating rules and its enforcement powers. The controversy still continues to swirl around ephedra, as the FDA is arguing in trying to restore the ban.

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Supplementation 39 Dietary in Weight Loss: A Dietitian’s Perspective Betty Wedman-St. Louis CONTENTS Introduction ....................................................................................................................................507 Food vs. Dietary Supplements.......................................................................................................507 RDA and Weight Loss ...................................................................................................................508 Making Wise Food Choices...........................................................................................................508 Biochemical Individuality..............................................................................................................508 Environmental Factors ...................................................................................................................509 Nutrition Protocols.........................................................................................................................509 Nutritional Supplements ................................................................................................................509 Why Dietary Supplements .............................................................................................................510 Guidelines for Supplements in Weight Loss .................................................................................510 Weight-Loss Surgery......................................................................................................................510 Evidence-Based Dietetics Practice ................................................................................................511 References ......................................................................................................................................511

INTRODUCTION Over the past 30 years in dietetics practice, many diets and weight-loss schemes have come and gone. During this period, it has become increasingly apparent that healthy and effective long-range programs for weight loss should combine a nutritious diet, dietary supplement use, and lifestyle changes. Reduced food intake due to inactive lifestyles make dietary supplements an important adjunct in a world of less than perfect food choices.

FOOD VS. DIETARY SUPPLEMENTS Food is not the sole source of nutrients that the human body can use to meet its dietary requirements, as schools of dietetics have taught for the past 50 years. Science has provided structure and function data on vitamins, minerals, and numerous phytonutrients so they can be produced to supplement diets when individuals cannot eat or do not choose food wisely. As a dietitian with over 30 years of experience, I have yet to plan the perfect diet for a person that meets all the daily nutrient requirements modiﬁed for that individual’s health needs and food preferences. Randolph [1] stated it best when he described the difference between analytical vs. biological dietetics. Foods can be analyzed for nutrient content and organized into a meal plan, but that does not mean that the same food meets the biological needs of the person consuming it. Food storage, food preparation, drug–food interactions, and individual genetic differences mean the menu and food choices must 507

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be customized to the individual. Dietary supplements can be added to ensure adequacy until dietetics research can provide more deﬁnitive answers.

RDA AND WEIGHT LOSS Dietetics has relied on the Recommended Dietary Allowances (RDA) and government guidelines for assessing nutritional adequacy of diets. Using the RDA is not good science for an individual weight-loss regime. As Williams [2] pointed out: “Nutrition is for real people. Statistical humans are of little interest.” The “average” person on which the RDA is based does not exist in weightloss clinics.

MAKING WISE FOOD CHOICES Inadequate research has been done on whether most individuals can routinely select a healthy diet. Dietetics training emphasizes cultural and lifestyle practices as determinants of food selection. If wise food choices are learned from example at the family dinner table, then what happens when families do not sit down to dinner or lunch or breakfast? Eating habits learned as children affect eating patterns throughout life. As children have become less active, obesity has resulted from their selection of highly processed foods mass produced from white ﬂour and sugar which, according to Haas [3], provide useless calories with few nutrients. Haas also believes that, “We require more food on this kind of diet to obtain all our needed nutrients.” The selection of foods in the standard American diet (SAD) generates “a diet rich in reﬁned sugars such as high-fructose corn syrup, saturated fat, and trans-fatty acids and low in ﬁber, legumes, nuts, fruits and vegetables, essential fatty acids, essential nutrients, and phytonutrients” [4]. Unfortunately, many individuals in weightloss programs are unable to signiﬁcantly or permanently change their eating habits or alter their dependence on convenience foods. The self-selection of foods was studied in the 1940s before the days of television and mass media advertising. At that time, most people ate because they were hungry; they selected what they liked and stopped eating when they were full [2]. That is not the case today for the thousands of weight-loss clients I have counseled. Alcohol and sugar calories are a major factor in many obesity cases. Williams [2] reported several examples of rat studies and their desire for alcohol with and without diets supplemented with vitamins. Rats supplemented with vitamins did not consume alcohol like the depleted animals. In other experiments by Williams, rats on nutrient-depleted diets consumed more sugar than when their nutritional needs were better met. How much we can infer in human nutrition from these rat studies is subject to debate, but when trying to establish dietary supplement protocols for individuals it is worth keeping the animal studies in mind.

BIOCHEMICAL INDIVIDUALITY Williams [2] broadened the perspective of nutrition requirements with his simple thesis that all human beings are biochemically unique; therefore, we metabolize nutrients differently. Recent scientiﬁc advances in the study of individual genetic variations have conﬁrmed Williams’ hypothesis of many years ago. We now know that individual nutrient needs are a function of not only genetic differences but also differences in genetic expression, as inﬂuenced by many environmental and lifestyle factors. Such variations may also be contributors to weight management issues, as no two humans have the same genes — not even identical twins. Williams emphasized that chemical reactions in the body and in speciﬁc organ systems vary in efﬁciency from person to person, and these reactions are inﬂuenced by the nutritional status of every cell in the body [2]. A personalized diet and nutrition supplementation program is needed for each individual based on that person’s genetics, environment, and lifestyle.

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ENVIRONMENTAL FACTORS Contradictory diet and nutrition advice for weight loss appears daily in print and electronic media. Not long ago, an individual came into my ofﬁce raving about buying “healthy” margarine instead of butter as her weight-loss goal of the week. When I asked why she had decided to do so (because the caloric differences are insigniﬁcant), her reply was that a television ad had stated that it was healthier and she thought she could use more on her baked potato. As Nestle [5] stated, “Making a high-fat, high-calorie table spread appear to be a health food seems a pessimistic approach to dietary change; it assumes that consumers will ignore advice to cut down on high-calorie table fats.” Nestle further discusses the economic impact of these margarines with a quotation from The London Times [6]: “Eating four daily teaspoons of Finnish wood pulp [Benecol®] disguised as a margarine may lower cholesterol, but it will cost as much as the rest of your breakfast.”

NUTRITION PROTOCOLS As a registered dietitian, I lacked the nutrition protocols for counseling weight-loss patients until I met Dr. Jeffry Bland, founder and board chairman of the Institute for Functional Medicine. Bland provided the nutrition guidelines necessary for identifying and following biomarkers in weightmanagement cases. In addition to helping me recognize the extent to which chronic symptoms (i.e., inﬂammation, food sensitivity, and metabolic syndrome) can affect weight management, the institute provided a framework for understanding the importance of the mind–body relationship in promoting healthy weight loss [4]. Protocols are important in guiding the nutrition counselor in making assessments with appropriate treatment plans. It has been my experience that individuals seeking weight-loss counseling do not care about how many scientiﬁc studies promoting or not promoting dietary supplements have been done and the outcomes. They just want to know if they can be helped. They do not care to read the science. They only want to know that their healthcare provider has read it and what the treatment plan involves.

NUTRITIONAL SUPPLEMENTS Traditional clinical nutrition and dietetics resources fail to provide nutrition supplementation protocols, but Functional Medicine symposiums provide the needed resources to develop nutrition protocols in assisting weight-loss clients. Weight issues are usually a factor in cases of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and ﬁbromyalgia, as well as hyperlipidemia, metabolic syndrome, and premenstrual syndrome. All of these conditions, and numerous others, need to be evaluated for possible nutrient deﬁciencies that could assist in the clinical management of these patients [7]. As examples, when obesity was a major nutritional factor for two multiple sclerosis cases, high doses of linoleic acid (almost 10 times the Dietary Reference Intake) were recommended [8]. A lupus patient who wanted to lead a normal life without dialysis challenged all the nutritional biochemistry available in standard dietetics manuals until a librarian found a journal article describing high levels of pantothenic acid and vitamin E being used for the treatment of lupus erythematosus [9]. Nutritional supplementation is not the standard of care, despite increasing medical literature citations. Vanadium (vanadyl sulfate) has rarely been mentioned as an adjunct to weight loss in syndrome X. As a result of a study by Boden et al. [10] of the effect of vanadyl sulfate on carbohydrate and lipid metabolism, its use has become a standard of practice for non-insulin-dependent diabetes mellitus (NIDDM) cases with elevated triglycerides. These are only a few examples of how dietary supplements have been used to assist weightloss clients. As one individual boldly stated during a counseling session, “I came here to get your professional opinion on what dietary supplements to take and how much. I’m not interested in what the FDA or pharmaceutical studies say. I am paying you for your expertise because I don’t have 10 or 20 years until they decide nutrition may be helpful.”

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WHY DIETARY SUPPLEMENTS Five key reasons given to clients for recommending dietary supplements as part of their weightloss regime are: • • • • •

Food intake in the standard American diet does not meet dietary recommendations for numerous nutrients. Dietary supplements are safe within a broad range of doses. Science had demonstrated the health beneﬁts of high levels of some nutrients such as folic acid and vitamin D. Criticism of supplement doses in excess of the RDA are overstated; “expensive” urine and feces may result, but that is of little relevance in disease management. Herbs and botanicals were the original sources of pharmaceutical drugs, and they generate many orders of magnitude fewer unplanned side effects.

A healthy diet is the keystone of good health because food provides many substances not yet identiﬁed or available as dietary supplements. In weight-loss regimes, however, individuals may need the placebo effect of dietary supplements [11], in addition to the enhanced nutrient beneﬁts.

GUIDELINES FOR SUPPLEMENTS IN WEIGHT LOSS Individualization of meal plans and nutrient supplement regimes is helpful for many tackling body fat issues. Many people need a handy guide to selecting dietary supplements so they can evaluate whether they are getting too high a dose when they combine different capsules, bars, and drinks. A general guideline offered in our weight-loss clinic is provided in Table 39.1.

WEIGHT-LOSS SURGERY Weight-loss surgery for extreme obesity is often an option for those with life-threatening chronic diseases. An extreme diet is used to force the body to reduce excess fuel stored as body fat; however, the surgery creates serious nutritional disorders postoperatively that are often overlooked by both physicians and surgery survivors. The dramatic increase in bariatric surgeries from 63,000 in 2002 to 103,000 in 2003 and over 150,000 in 2004 requires that dietetics professionals be assertive in meeting the nutritional needs of these patients [12]. Many insurance companies require nutrition counseling before surgery but fail to see the importance of postsurgery counseling until malnutrition becomes life-threatening. Bariatric surgery costs $25,000 to $50,000, so a reasonable use of dollars would be to cover nutrition counseling after surgery to be sure that adequate dietary supplementation is being followed. Presurgery nutritional supplementation reduces mortality rates. Flum et al. [13] studied gastric bypass surgery patients for 15 years and found that 88.2% were more likely to be alive if they had the surgery compared to 83.7% of those who did not have the surgery; thus, gastric bypass surgery is a cost-effective means of reducing overall mortality among the obese [14]. After the surgery, patients consume a clear liquid diet for the ﬁrst week, and liquid dietary supplements are recommended to maintain lean muscle mass and improve immune function [12]. By week two, they are taking chewable nutrient supplements and eating soft protein foods. Crushed prenatal supplements are highly recommended for the next 6 months, but many individuals get too interested in how much weight they are losing to stay healthy with nutrition choices. By the eighth week, each weight-loss surgery patient should be evaluated for anemia; additional iron, folic acid, and vitamin B12 may be necessary [12]. Unfortunately, within 6 months many people begin to regain weight because they are adding highcalorie foods back into their diet. Beverage consumption also increases calorie levels. Bariatric surgery patients who continue to overeat postoperatively seldom reach a healthy weight and suffer nutritional deﬁciencies because inadequate attention is being given to dietary supplementation.

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TABLE 39.1 Dietary Supplements For Weight Loss Ingredient Vitamin A Beta-carotene Vitamin D Vitamin E Vitamin K Thiamine (B1) Riboﬂavin (B2) Niacinamide (B3) Pantothenic acid Pyridoxine (B6) Pyridoxal 5 phosphate Cobalamin (B12) Folic acid

Amount

Ingredient

2000–5000 IU 10,000–20,000 IU 800–1000 IU 400–800 IU 200–300 µg 75–150 mg 50–100 mg 75–150 mg 250–500 mg 50–100 mg 100–200 mg 500–1000 µg 800–1000 µg

Biotin Vitamin C Bioﬂavonoids Calcium Chromium Copper Iron (women) Magnesium Manganese Selenium Zinc CoQ 10 Omega-3 fatty acids (EPA and DHA)

Amount 500–1000 µg 2000–5000 mg 250–500 mg 800–1200 mg 400–500 µg 2–3 mg 15–25 mg 400–800 mg 5–10 mg 200–400 µg 20–50 mg 30–100 mg 1000–12000 mg

EVIDENCE-BASED DIETETICS PRACTICE As Dr. Sidney Baker stated in 1993 at the Symposium on Man and His Environment in Health and Disease, each healthcare practitioner must determine whether “you see what you believe or believe what you see” [15]. Nutrition counseling has given me the opportunity to believe what I see, and dietary supplements really can make a difference in weight loss, as well as in other chronic disease management. Dr. Mark Hyman described nutrition as being a young science: “The view of nutrition as simply a source of energy or calories to prevent malnutrition and micronutrients to prevent deﬁciency diseases is being supplanted by a new conception of nutrition in health and disease” [4]. The calories-in vs. calories-out model of weight management is too simplistic to explain the obesity crisis. Both macro- and micronutrient components of the diet need to be evaluated with regard to their inﬂuence on thermodynamics because calorie counting is obsolete as far as changing eating habits. Science has shown that dietary supplements can help upgrade the metabolic processes of detoxiﬁcation and toxic overload found in many chronic diseases such as obesity [4]. The food industry and researchers need to focus more on these uses of nutrients rather than on reducing calories through sugar substitutes and fat replacers. Evidence-based guidelines for additional nutrient use among Americans who spend more than $20 billion annually on herbal and dietary supplements [16] is greatly lacking. The argument that dietary supplements lack safety and efﬁcacy data does not make a difference to those individuals in weight-loss programs who seek increased energy to get physically active plus the enhanced health and sense of well-being that they believe comes from using them. Choosing quality manufacturers with outstanding safety and efﬁcacy records is essential when recommending nutritional supplements in weight-loss programs [17].

REFERENCES [1]

Randolph, T.G., Human Ecology and Susceptibility to the Chemical Environment, Charles C Thomas, Springﬁeld, IL, 1962. [2] Williams, R.J., Biochemical Individuality: The Basis for the Genetotropic Concept, Keats Publishing, New Canaan, CT, 1956. [3] Haas, E.M., Staying Healthy with Nutrition: The Complete Guide to Diet and Nutritional Medicine, Celestial Arts, Berkeley, CA, 1992, pp. 375–383.

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512 [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]

[16] [17]

Obesity: Epidemiology, Pathophysiology, and Prevention Jones, D.S., Ed., Textbook of Functional Medicine, Institute for Functional Medicine, Gig Harbor, WA, 2005. Nestle, M., Food Politics: How the Food Industry Inﬂuences Nutrition and Health, University of California Press, Los Angeles, 2002, pp. 330–333. Rumbelow, H., Food that cuts cholesterol has a fat price, The Times (Lond.), March 30, 1999, p. 8. Levin, B., Environmental Nutrition: Understanding the Link Between Environment, Food Quality, and Disease, HingePin, Vashon Island, WA, 1999, pp. 58–61. Bates, D., Fawcett, P.R.W., Shaw, D.A. et al., Polyunsaturated fatty acids in treatment of acute remitting multiple sclerosis, Br. Med. J., ii, 1390–1391, 1978. Welsh, A.L., Lupus erythematosus: treatment by combined use of massive amounts of pantothenic acid and vitamin E, Arch. Dermatol. Syph., 70, 181–198, 1954. Boden, G., Chen, X., Ruiz, J. et al., Effects of vanadyl sulfate on carbohydrate and lipid metabolism in patients with non-insulin dependent diabetes mellitus, Metabolism, 45, 1130–1135, 1996. Lipton, B., The Biology of Belief: Unleashing the Power of Consciousness, Matter and Miracles, Mountain of Love/Elite Books, Santa Rosa, CA, 2005. Scheier, L., Bariatric surgery: life threatening risk or life-saving procedure?, J. Am. Diet. Assoc., 104(9), 1338–1340, 2004. Flum, D.R., Salem, L., Elrod, J.A, et al., Early mortality among Medicare beneﬁciaries undergoing bariatric surgical procedures, JAMA, 294, 1903–1908, 2005. Craig, B.M. and Tseng, D.S., Cost effectiveness of gastric bypass for severe obesity, Am. J. Med., 113, 491–498, 2002. Baker, S.M., The relationship of chemical interaction on the nutritional chain, in Proc. of Symp. on Man and His Environment in Health and Disease, Human Ecology Research Foundation, Dallas, TX, 1993. Anon., Natural Supplements: An Evidence-Based Update, Scripps Center for Integrative Medicine, LaJolla, CA, 2006. Poston, W.S.C. and Haddock, C.K., Eds., Food as a drug, Drugs Soc., 15(1/2), 1, 2000.

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Part VII Child Obesity and Prevention

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and Prevention 40 Treatment of Childhood Obesity and Associated Metabolic Diseases Michael I. Goran, Jaimie N. Davies, and Louise A. Kelly CONTENTS Introduction and Scope of the Problem.........................................................................................515 Primary Prevention Trials ..............................................................................................................516 Studies Using Physical Activity for Secondary Risk Reduction ..................................................517 Dietary Approaches for Secondary Risk Reduction .....................................................................519 Pharmacological Approaches.........................................................................................................521 Summary and Implications: Concept of Multiple Targets for Treatment and Prevention ...........521 References ......................................................................................................................................523

INTRODUCTION AND SCOPE OF THE PROBLEM Over the past 20 years, the percentage of overweight adolescents in the United States has increased more than threefold, from 5% to 16%, and the percentage of overweight in children ages 6 to 11 years increased from 5% to 15% [67]. The prevalence of overweight is even more striking among certain ethnic groups. In the United States, for example, recent data show that 44% of Latino and 40% of African-American adolescents (ages 12 to 19 years) are considered overweight (above the 85th percentile for age and gender as deﬁned by the Centers for Disease Control and Prevention), which is approximately double the prevalence in Caucasians [67]. The rise in childhood obesity has been associated with an increase in the incidence of type 2 diabetes in children and adolescents [27,65,69,78], as well as other metabolic diseases such as the metabolic syndrome [15,16,18,57,71], polycystic ovarian syndrome [39], and nonalcoholic fatty liver disease [33,72]. The increased prevalence and incidence of pediatric overweight over the last 15 to 20 years and its association with metabolic diseases early in life have prompted health organizations and scientiﬁc associations to advocate for increased attention, resources, and research to address this emerging health crisis through prevention and treatment initiatives. Major health-related organizations have released policy statements and calls for action related to pediatric obesity over the last few years, including the U.S. Institute of Medicine [51], the World Health Organization [2], and the American Academy of Pediatrics [17,52]. In addition to these policy reports, numerous reviews have been published highlighting promising research and underscoring the need for additional study of pediatric overweight prevention and treatment strategies [19,73,86]; however, very few intervention studies have been designed to speciﬁcally address the underlying metabolic abnormalities. As reviewed below, most typical weight-management programs for youth have been based on the traditional energy-balance model

515

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and have utilized restrictive diets, behavior modiﬁcation techniques, physical activity, and drugs, but these approaches have generally not been successful and do not necessarily address insulin resistance and the underlying risks beyond weight loss. In addition, a recent study shows that dieting approaches are generally ineffective in children and adolescents and may actually promote weight gain [32]; thus, as was concluded in a recent Cochran review, conventional approaches targeting weight management in children have not been effective. Currently, only limited quality data on the effects of obesity treatment programs are available, so no generalizable conclusions can be drawn with conﬁdence [87]. The purpose of the discussion that follows is to review intervention studies that have addressed metabolic abnormalities related to the primary prevention of obesity and a reduction in obesity-related chronic disease risk beyond weight reduction.

PRIMARY PREVENTION TRIALS Very few primary prevention trials targeting obesity in children have been conducted, but several recent studies conducted in the United States are reviewed here. Planet Health is a school-based intervention developed and tested by investigators at the Harvard School of Public Health [38]. The school-based intervention was based around four simple health themes integrated into physical education (PE), language, arts, math, science, and social studies classes in a sixth- to eighth-grade curriculum. The program encourages active, inquiry-based learning; emphasizes literacy across the curriculum; addresses national learning standards; and incorporates staff training, classroom lessons, PE curriculum, and incentives to teachers. The curriculum was studied in a 2-year randomized trial in 10 public middle schools [38]. The study found an overall signiﬁcant treatment effect for obesity reduction in girls, but not boys. A signiﬁcant reduction in television viewing was observed (0.6 hr/day for girls, p < 0.001; 0.4 hr/day for boys, p < 0.001) but no signiﬁcant change in moderate to vigorous activity in either boys or girls (as measured by the Youth Activity Questionnaire). Some signiﬁcant dietary changes in girls were found, including an improvement in fruit and vegetable intake of 0.32 servings/day, a 575-kcal/day reduction in reported energy intake, and a marginal improvement in percent calorie intake from fat. Another study by Robinson et al. [77] focused exclusively on a curriculum for promoting reduced television viewing in children. A randomized pilot trial conducted in 192 third- and fourthgrade children from two schools provided 18 classroom-based lessons over 6 months. The intervention led to a signiﬁcant reduction in television viewing, from 14.5 hr/wk to 8.8 hr/wk, with no change over time in control children as measured by questionnaire. The reduction in television viewing was associated with a small but signiﬁcant reduction in body mass index (BMI) over 6 months in treatment relative to control children (18.4 to 18.7 kg/m2 in intervention vs. 18.1 to 18.8 kg/m2 in control; adjusted difference, –0.45 kg/m2; p = .002). Similar patterns were noted for triceps skinfold thickness (adjusted difference, –1.47 mm; p = 0.002) and waist circumference (adjusted difference, –2.30 cm; p < 0.001). Although the two studies reviewed above used conventional curriculum strategies (paper and pencil), the use of novel multimedia teaching approaches has been recognized as one of the most important ways to improve the status of nutrition education in children [1], and computer-assisted behavioral counseling has been shown to be effective in various studies in high-school students [11], undergraduate students [56], and fourth-grade children [7]. Interactive multimedia, therefore, offers tremendous potential as a medium to develop for the delivery of school-based health promotion and education tools; such an approach can also incorporate family involvement and can be designed around effective models of behavior change. One previous study developed a multimedia game called “Squire’s Quest” and focused on improving fruit and vegetable intake in fourth-grade children. The intervention was delivered in 10 classroom sessions over 5 weeks and led to a signiﬁcant increase in total fruit and vegetable consumption by 1 serving per day ( p < 0.05) [7]. A family-based Internet intervention [98] has

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also been used to promote weight loss in overweight African-American girls (11 to 15 years) and their parents. Also, among adults an Internet weight-loss intervention was shown to be more effective when supplemented by e-mail-based counseling [89]. A childhood obesity prevention trial by Goran and Reynolds [36] evaluated the use of a novel interactive CD-ROM for promoting increases in physical activity and reducing obesity in young U.S. children. The Interactive Multimedia for Promoting Physical Activity (IMPACT) curriculum was based on an interactive, animated cartoon adventure that was based on social learning theory and designed for fourth- and ﬁfth-grade children. It consisted of eight weekly sessions, each featuring two to three interactive computer-based games that were supplemented by classroom and take-home activities. A randomized trial was conducted in four schools with before and after measures that included height, weight, and physical activity by accelerometry and a psychosocial questionnaire related to physical activity. No signiﬁcant treatment effects on total physical activity by accelerometry were observed, and, contrary to the hypothesis, a treatment effect was observed with regard to a reduction in the percent of time spent in moderate-intensity activity (16.5% of time in moderate intensity was reduced to 15% of time). A signiﬁcant gender by treatment interaction was observed for the percentage of time spent in light-intensity activities (reduction in boys from 78% to 75% and an increase in girls from 78% to 81%). Signiﬁcant overall improvements in behavioral outcomes related to physical activity were found, including self-efﬁcacy (“I can do it”), social norms (“It’s cool”), and outcome expectancies (“It’s good for me”). These subtle changes in physical activity were related to signiﬁcant gender by treatment interactions for BMI z-score (p = 0.016) and percent body fat (p = 0.009), such that there was a signiﬁcant treatment effect for obesity reduction in girls but not boys. This latter study [36] shows that even very subtle changes in both the qualitative and quantitative aspects of physical activity can be beneﬁcial for obesity prevention. The increase in light-intensity activity in girls translated to approximately 24 minutes per day (approximately 36 kcal/day assuming that the light activities averaged 1.7 METS), and this subtle change was sufﬁcient to reduce obesity indices, even though it was counteracted by a reduction in moderate-intensity activities in the region of 8 minutes per day (approximately 20 kcal/day assuming moderate activities are 2.5 METS). The small net increase in energy expenditure of ~16 kcal/day, or almost 1000 kcal over the 8-week intervention, can potentially explain small changes in body weight over time [37].

STUDIES USING PHYSICAL ACTIVITY FOR SECONDARY RISK REDUCTION In adults, regular physical activity and high levels of physical ﬁtness are associated with reduced chronic disease risk [35,44,49,53,54]. Cross-sectional studies in children have shown a positive inﬂuence of activity and ﬁtness on disease risk [55,81], but others have shown no effect [6,42]. Unfortunately, few randomized controlled trial (RCT) intervention studies have been conducted in youth to examine the effects of physical activity or exercise on obesity reduction and chronic disease risk reduction. A summary of ﬁndings is presented here with a focus on effects on reducing chronic disease risk. Controlled intervention studies suggest that exercise intervention in children may or may not have beneﬁcial effects on obesity, depending on the nature and intensity of the intervention. Project SPARK was a large-scale study that randomly assigned seven U.S. elementary schools to receive physical education via the usual mechanisms, trained teachers, or specialized instructors [80]. A nonsigniﬁcant trend was observed for children exposed to specialized physical education to have lower total body fat after 2 years. Results from other school-based studies that included physical education are controversial, with some showing no changes in obesity indices [12] and others showing improvements [50,74,93].

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Other physical activity interventions have been conducted outside of the school setting. Ferguson et al. [31] reported that 4 months of intensive aerobic-type exercise training without dietary intervention (5 days a week for 4 months; 40-minute training sessions at a heart rate of >150 beats per minute) in obese boys and girls (n = 79) resulted in signiﬁcant decreases in percent body fat (by DEXA) as well as fasting insulin and triglyceride levels over control children (p < 0.05). Although the authors were unable to determine whether reductions in insulin and triglyceride levels were a result of parallel decreases in body fat, these ﬁndings support the notion that increases in moderately vigorous physical activity can lead to improvements of metabolic risk proﬁle in overweight children. In contrast, another study from the same group [41], a comparison of 10-week programs for 7- to 11-year-old obese African-American girls, found that neither aerobic training (n = 12) nor lifestyle education (n = 10) led to improvements in fasting insulin levels. Although some other investigations [48,97] in youth provide evidence that increased moderately vigorous physical activity can lead to improvements in the metabolic and cardiovascular risk of overweight children, the mechanisms of these improvements remain largely unclear. Furthermore, whether improvements in risk proﬁle lead to decreases in future diabetes or cardiovascular disease outcomes has yet to be determined. Although most studies in pediatrics have implemented aerobic training as a modality of exercise, evidence from adults [13,14,79,91] suggests that incorporation of strength training (resistance training) may be important for improving insulin sensitivity, body composition (increased muscle mass and decreased fat mass), and fat redistribution (reduced visceral fat and intramyocellular lipid [IMCL]). Resistance training has also been shown to improve insulin sensitivity and glucose regulation in adults with impaired glucose tolerance or type 2 diabetes [20,23,83]; however, further studies are necessary to identify whether these effects are mediated through changes in body composition or other mechanisms. One previous adult study, for example [70], showed that improvement in insulin sensitivity after resistance training disappeared once the data was normalized for fat-free mass, suggesting that the increased glucose disposal rate was due to a mass effect rather than an alteration in the intrinsic properties of the skeletal muscle. Resistance training may, therefore, be an important exercise modality for overweight youth. Several organizations, including the American Academy of Pediatrics, have recently endorsed resistance training (with appropriate supervision and instruction) as a safe activity for children and adolescents that provides a means of improving strength and decreasing the risk of sports-related injuries [29]. To date, however, most resistance training studies in younger populations have focused on issues related to safety, strength improvements, and musculature changes [28,30]. One prior study [88] examined a 6-week program that combined a dietary intervention (low energy, 20 to 25% calories from fat, high in complex carbohydrate) with strength training in obese children. The main outcomes in this study focused on lipid proﬁle, which improved after the intervention (6% reduction in total cholesterol). We have published reports on a resistance training trial with 12 overweight Caucasian girls [91,92]. This study showed that resistance training (20-minute sessions, 3 days/wk for 5 months) led to increased strength and improvement in visceral fat. Small improvements in glucose tolerance and insulin levels (determined using an oral glucose tolerance test) were noted, but these changes did not achieve statistical signiﬁcance. In another study recently published [82], 16 weeks of twice-per-week progressive resistance training in Hispanic males (15.2 ± 1.7 years; Tanner stage, 3 to 5; BMI percentile, 97.7 ± 2.8) led to a signiﬁcant increase in insulin sensitivity in the training group by 45.1 ± 24.2% vs. no change in the control group (–0.8 ± 40.7%). The between-group difference in change score was highly signiﬁcant (p < 0.001) even after controlling for changes in body composition. Given the increasing prevalence rates of pediatric obesity and related metabolic diseases, the use of resistance training seems to offer good potential to improve metabolic health, and further studies using this approach seem warranted. Moreover, resistance training may be a practical form of exercise, especially for very overweight children who may be extremely challenged by the difﬁculty in performing typical aerobic exercise interventions. In contrast, it seems very likely that

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resistance training may be a form of exercise that overweight children will succeed at, and they should be able to see quick results that will encourage them to continue in an intervention. Given the additional beneﬁts of aerobic exercise, interventions combining both cardiovascular and resistance training could be hypothesized to have maximal beneﬁts; however, only two studies to our knowledge have incorporated both aerobic exercise and strength training. The Physical Activity for Total Health (PATH) study [63] developed and evaluated the health effects of an 11-week circuittraining intervention that consisted of 30-minute classes ﬁve times a week; the subjects (346 minority students, 14 to 17 years of age) alternated between aerobic exercise stations and strengthtraining equipment. The female students in this study had signiﬁcant improvements in cholesterol (a 10% reduction) and cardiovascular ﬁtness (a 15% increase in VO2max) compared to controls, whereas results for the male students were not signiﬁcant. A study by Watts et al. [95] found that an 8-week circuit-training intervention, consisting of three 1-hour sessions per week, signiﬁcantly decreased abdominal and trunk fat and improved ﬁtness and muscular strength in obese adolescents. In summary, current research suggests that physical activity interventions in overweight youth are efﬁcacious for improving overall body composition [58]; however, studies are often difﬁcult to interpret and compare due to the diversity of methodological approaches used to assess physical activity, differences in data analysis and reporting, and the adoption of varying deﬁnitions for what constitutes an appropriate level of activity, all of which makes a summary and comparison of ﬁndings difﬁcult. Perhaps more importantly, however, physical activity interventions in overweight youth may improve the disease risk proﬁle of overweight children [31,40,48,90,96]. Further research is warranted to address the many questions that remain regarding the optimal frequency, intensity, duration, and mode of activity necessary to invoke risk proﬁle improvement.

DIETARY APPROACHES FOR SECONDARY RISK REDUCTION The most successful long-term studies of obesity reduction in children have been reported by Epstein et al. [26]. The dietary component of these successful family-based behavioral interventions have used what is called the “Trafﬁc Light Diet,” which is based on the Food Guide Pyramid; the diet differentiates food choices based primarily on fat content. Other expert dietary recommendations for children have been nonspeciﬁc and have promoted well-balanced, healthy meals based on the Food Guide Pyramid [9], nutritionally balanced meals to support growth [17], and a general emphasis on a reduction in dietary fat intake rather than on types of fat or carbohydrate in the diet. Current clinical treatment guidelines are therefore generally based on empirical evidence and expert opinion [8]. Remarkably few good-quality RCT studies have examined nutritional approaches for reducing obesity and chronic disease risk factors in children. Most studies have focused on diet and weight loss and have been conducted primarily in Caucasian children. In terms of risk reduction, most previous studies have examined dietary intervention for lipid improvement in children. The Dietary Intervention Study in Children (DISC) examined the effects of nutrition education on lipid proﬁles in 663 mostly Caucasian children (8 to 10 years of age at baseline) over 3 years [66]. A small but signiﬁcant 8% reduction in low-density lipoprotein (LDL) cholesterol was sustained 2 years after the intervention ended; however, both control and intervention groups showed a general trend of increasing triglyceride levels, indicating that other dietary combinations may be required to have beneﬁcial effects on multiple risk factors. The Child and Adolescent Trial for Cardiovascular Health (CATCH) sought to improve diet and physical activity in a national study involving 5000 children (mean age, 8.8 years at baseline) from almost 100 schools. Despite improvements in self-reported diet and physical activity in schools, effects on overall dietary intake and physical activity were very limited, and no signiﬁcant changes were observed in obesity measures, blood pressure, or cholesterol [61]. Based on our review of the literature, we conclude that more speciﬁc, targeted, and individualized dietary approaches are needed for risk reduction in overweight children. Speciﬁcally, good evidence suggests that modiﬁcation of the types and quality of carbohydrates in the diet may be

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effective for improving insulin sensitivity and reducing insulin secretion and may also contribute to weight loss. This dietary strategy may be more effective than previous interventions to reduce calories or the proportion of calories from carbohydrate in the diet [43]. In particular, diets enriched with whole-grain carbohydrates, foods that elicit a lower glucose response, and foods higher in ﬁber have been shown to have beneﬁcial effects. In a cross-sectional study in adolescents, wholegrain intake was associated with a lower BMI as well as improved insulin sensitivity [84]. In addition, epidemiological studies show that the intake of whole grains is associated with protection from type 2 diabetes [64], as well as coronary artery disease [85]. Dietary ﬁber, especially soluble ﬁber (e.g., psyllium), has beneﬁcial effects on blood glucose control and blood lipids [21,45,59]. Fiber intake also has beneﬁcial effects on regulating food intake (induces satiation and satiety) and can improve glycemic control and reduce lipids [60]. These carbohydrate effects may work through improvement in the glycemic load (a measure of how much glucose is released into the blood after ingestion of a particular food). Foods with low glycemic values have been hypothesized to be beneﬁcial for reducing the risk for type 2 diabetes because they reduce the demand for high levels of insulin secretion [43]. In both short-term [25] and long-term [24] studies in obese children, a low glycemic index has been shown to reduce plasma glucose and improve insulin resistance. An additional beneﬁt is that voluntary food intake tends to be lower after consumption of foods with low glycemic index values [76]. A recent 12-month intervention in obese children showed that promotion of a diet with a low glycemic index led to greater weight loss and improvement in insulin resistance than did promotion of a typical low-fat diet [24]. Another study in children has shown that a low-glycemic-index breakfast meal led to a reduced calorie intake at lunch [94]. The low-glycemic-index approach also tackles the issue of soda and juice intake. Replacement of sugary drinks with water or lower sugar versions may also result in improved glucose control. In fact, a recent school-based intervention over 3 years in Native American youth that promoted water intake and reduced consumption of sugared beverages led to signiﬁcant improvements in fasting glucose and insulin response [75]. Very few studies have designed and tested culturally tailored nutrition-based interventions. Among Hispanics, evidence suggests that utilizing foods with lower glycemic index values while retaining a Hispanic-style diet can improve glucose control and lipids in Hispanics patients with type 2 diabetes [46,47]. We have previously shown that overweight Latino children consume approximately 16% of their daily caloric intakes from simple sugars, and 50% of this amount comes from sugary beverages. These high intakes of total and added sugar and sugary beverages were the only dietary components associated with poor beta-cell function, after controlling for adiposity, gender, and Tanner stage [22]; thus, interventions focusing on reducing sugar intake in this population may be prudent. We developed a 12-week nutrition intervention program focused on carbohydrate modiﬁcation (decrease in simple sugars and increase in ﬁber) tailored speciﬁcally for overweight Latina female adolescents. The focus of this intervention was on identifying and promoting dietary exchanges rather than on weight and calorie restriction; the program used a combination of customized recipes and activities and motivational interviewing techniques. We also tested whether delivery of the intervention would be more effective using individualized sessions in the home environment as compared to group classes. The nutrition program resulted in signiﬁcant reductions in added sugar, sugary beverages, and reﬁned carbohydrate intake and signiﬁcant increases in dietary ﬁber intake. Surprisingly, we saw no differences in dietary intake or physiological or metabolic changes between the two intervention groups; thus, the data were pooled for further analysis. As a total sample, BMI percentile signiﬁcantly decreased from before to after the intervention (96.8 ± 4.1 to 96.3 ± 4.1; p < 0.05), and there was a trend for a decrease in BMI (33.2 to 33.1 kg/m2; p < 0.06). These preliminary results suggest that an extremely intensive individualized home-based program is no more effective than a group-classroom-based format, and that the 12-week program focusing on improving the quality of carbohydrate intake can signiﬁcantly reduce obesity.

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PHARMACOLOGICAL APPROACHES Although no medications are currently approved for the management of pediatric overweight due to safety concerns, pharmacotherapy may be appropriate for overweight youth who possess comorbidities (e.g., pre-diabetes, sleep apnea), and several studies have been reported. In a randomized and controlled study [68], orlistat (a gastrointestinal lipase inhibitor) decreased BMI in obese adolescents to a greater degree in the experimental group vs. control group (–4.09 ± 2.9 kg/m2 vs. +0.11 ± 2.49 kg/m2, respectively; p < 0.001). In another trial [62] of 20 adolescents (mean age, 14.6 years; mean BMI, 44 kg/m2), orlistat was dosed 3 times daily (120 mg) with a multivitamin and behavioral program (not a randomized study). Similar gastrointestinal side effects were observed as has been observed in adults, and these decreased with time. The main outcomes were also similar, as has previously been shown in adults (4% weight loss; 21-mg/dL reduction in cholesterol; 17-mg/dL reduction in LDL cholesterol; 14-µU/mL reduction in fasting insulin; 15-mg/dL reduction in fasting glucose). In the concluding words of the authors, “Short-term treatment with orlistat, in the context of a behavioral program, is well tolerated and has a sideeffect proﬁle similar to that observed in adults, but its true beneﬁt versus conventional therapy remains to be determined in placebo-controlled trials.” The other U.S. Food and Drug Administration (FDA)-approved drug for obesity, sibutramine, has also been tested in adolescents in a randomized double-blind study (n = 82; 13 to 17 years old). This study compared 6 months of behavior intervention with placebo vs. behavior intervention and the drug [10]. Weight loss with the drug was signiﬁcantly greater than control (8% vs. 4%), but the medication had to be reduced or discontinued in 33 patients to manage increases in blood pressure or other symptoms. In the concluding words of the authors, “Until more extensive safety and efﬁcacy data are available, medications for weight loss should be used only on an experimental basis in adolescents and children.” Thus, these studies show that the general responses in terms of safety and efﬁcacy to these drugs are similar in children compared to adults, although more longer term safety and efﬁcacy data are needed. Few pharmacological studies have targeted the underlying insulin resistance associated with obesity. In one study, metformin, an insulin-sensitizing drug used for the treatment of type 2 diabetes in both adults and children, was used to treat overweight youth with a family history of type 2 diabetes and hyperinsulinemia. In a double-blind controlled trial in 29 obese adolescents [34], metformin (500 mg twice a day for 6 months) resulted in signiﬁcant improvements in BMI and fasting insulin but not insulin sensitivity. In another study [5], metformin was shown to improve insulin sensitivity and lower plasma total and free testosterone in obese adolescent girls with polycystic ovarian syndrome. Other agents that may prove beneﬁcial in the treatment of insulin resistance in high-risk youth are the thiazolidinediones, which are much more potent insulin sensitizers than metformin. Thiazolidinediones have been shown to improve insulin sensitivity, glucose tolerance, and cardiovascular risk factors in non-diabetic obese subjects with impaired glucose tolerance [4]. In summary, pharmacotherapy may be indicated in children with comorbidities and in which attempts to improve risk through lifestyle interventions have failed. Well-designed randomized, controlled studies of safety and efﬁcacy of pharmacological agents in pediatrics are needed.

SUMMARY AND IMPLICATIONS: CONCEPT OF MULTIPLE TARGETS FOR TREATMENT AND PREVENTION Most prior interventions for treating and preventing obesity in children have traditionally targeted body weight and BMI through conventional approaches based on the energy-balance model (Figure 40.1). Several arguments against this approach can be made, especially in children; for example, it may take generations to reverse the population BMI trend, short-term weight loss may be effective

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Whatʼs the Target? Food intake Conventional energy balance approach to reduce body fat

Physical activity

Energy balance

Increased body fat

Alternative targets worth considering

Ectopic fat

Insulin resistance/disease risk

FIGURE 40.1 Conventional vs. alternative targets for reducing obesity and obesity-related metabolic diseases.

but not usually sustainable, and weight loss per se does not necessarily address health and metabolic risk factors. Finally, evidence suggests that a focus on body weight in children and adolescents is not effective. In a large cohort study, children who reported more dieting attempts were more likely to gain weight over a 3-year period [32]; thus, the risks of a focus on weight loss in children and adolescents include greater weight gain, lower self-esteem (due to repeated failures), and body image and eating disorders. Rather than focus on weight loss through energy imbalance, the pediatric model focuses more on the notion of growing into a healthy weight; thus, weight stability in a growing overweight child may actually be a very beneﬁcial outcome. Moving beyond the traditional energy-balance model, interventions designed to target speciﬁc metabolic factors and health outcomes may be more effective, especially in high-risk groups with elevated metabolic risk factors (Figure 40.1). One approach based on the centrally mediating role of insulin resistance, for example, is to identify interventions for improvement in insulin sensitivity and reducing insulin secretion. Improvement in insulin resistance as an intervention strategy may be an efﬁcient strategy, as this addresses multiple risk factors targeted through one common mechanism. It remains to be tested, for example, whether or not improvement of insulin resistance can lead to a reduced risk of type 2 diabetes and cardiovascular disease over and above any effects on risk reduction through weight loss. Alternative strategies using diet and exercise strategies can be designed around this concept; for example, traditional dietary approaches (reduced calorie, low fat, low carbohydrate) have generally been designed to lead to weight loss and have failed to recognize the data suggesting that the quality and type of fats and carbohydrates are more important than the amount in affecting metabolic outcomes and thereby potentially improving risk factors associated with obesity. For fat, replacing foods high in saturated fat and trans-fatty acids with foods rich in plant-based fat sources (mono- and polyunsaturated fatty acids, nuts, ﬁsh, soy) may be effective. With regard to carbohydrates, data are beginning to show that replacing sugary foods based on simple or unprocessed carbohydrates with foods high in whole-grain or processed carbohydrates and ﬁber that have low glycemic index values may be effective, not only for weight loss but also for disease risk reduction. Based on published studies, evidence is beginning to mount that demonstrates the power and potential effectiveness of childhood obesity prevention efforts that focus on subtle changes in the physical activity aspects of health behavior and in particular on reductions in sedentary behavior and increases in light-intensity activities. This approach may partly address the obvious need to target the role of the media in childhood obesity prevention [3]. Cross-sectional and intervention studies support the evidence that increased television viewing is associated with childhood obesity.

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Children on average now are exposed to about 40,000 television advertisements a year (double that of 1970), including 11 food commercials per hour on Saturday mornings, primarily for candy (32%), cereal (31%), and fast food (9%). It is thus no surprise that a recent study showed that children who watch more television tended to choose less healthy choices in a controlled trial [3]. Despite the evidence presented, there is a lack of unequivocal support for any particular treatment or intervention, and pediatric obesity interventions still rest on expert committee recommendations rather than evidence from clinical trials. The limited evidence available suggests that simple strategies (reductions in television and sugar) may be just as effective as more complex interventions. Smaller scale, proof-of-concept studies are greatly needed to develop the case for larger scale, more complex and expensive trials. Interventions should be designed using an integrated and uniﬁed approach based on behavioral theories to affect change. Strategies should think beyond weight and energy balance, focusing more on target physiological outcomes (risk reduction). Because of ethnic differences in metabolic and physiologic pathways, interventions may have to be tailored to different groups (and probably individualized as well). A major limitation impeding progress perhaps lies in the dissonance that exists between the simplicity of the obvious obesity solutions (eat less and move more) and the reality of the complexity of the underlying physiology, the inherent variation between individuals and subgroups of the population, and the difﬁculty in translating simple health messages to actual behavioral changes. The complexity and diversity of the problem are not being helped by the fragmented effort that is occurring in response to this public health crisis, and a more uniﬁed effort at the national level is necessary to tackle the childhood obesity problem.

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Part VIII Bariatric Surgery in Weight Management

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Surgery in 41 Bariatric Obesity and Reversal of Metabolic Disorders Melania Manco CONTENTS Introduction ....................................................................................................................................531 Malabsorptive or Restrictive Procedures .......................................................................................532 Weight Loss and Energy Expenditure ...........................................................................................534 Normalization of Metabolic Inﬂexibility.......................................................................................534 Insulin Action and Secretion .........................................................................................................535 The Gut and Resolution of T2DM ................................................................................................536 Resolution of Hypertension ...........................................................................................................537 Resolution of Dyslipidemia ...........................................................................................................538 Polycystic Ovary Syndrome and Endocrine-Related Diseases .....................................................538 Resolution of Nonalcoholic Steatohepatitis ..................................................................................538 Conclusion......................................................................................................................................539 References ......................................................................................................................................539

INTRODUCTION Bariatric surgery is increasingly regarded as a treatment of morbidly obese patients who have serious comorbidities or fail on medical and behavioral weight reduction therapies. In 1991, the National Institutes of Health Consensus Conference made a recommendation for surgery in patients having a body mass index (BMI) of >40 kg/m2 and exhibiting a strong desire for substantial weight loss to improve quality of life or in patients with a BMI of >35 kg/m2 plus serious comorbidities [1]. So far, several surgical procedures have been developed. The history and descriptions of the main bariatric procedures developed to date are available at the website of the American Society of Bariatric Surgery [2]. In particular two of them — the Roux-En-Y gastric bypass (RYGB) (Figure 41.1A) [3] and the biliopancreatic diversion (BPD) (Figure 41.1B) [4] — seem at the present to be the most effective in the achievement of a long-term weight loss and in the resolution of obesityrelated morbidities. Comorbidities include diabetes, hypertension, dyslipidemias, nonalcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), sleep apnea and obesity–hypoventilation syndrome, cardiac dysfunction, reﬂux esophagitis, pseudotumor cerebri, arthritis, infertility, stress incontinence, and venous stasis ulcers. The Consensus Development Panel endorsed only vertical banded gastroplasty and RYGB [1]; however, in Europe and, particularly, in Italy, BPD is very frequently performed. In this chapter, attention is mainly focused on both BPD and RYGB, as these two techniques share a common remarkable feature. They impressively ameliorate obesity-related insulin resistance and diabetes, very early after surgery and independently of weight loss [5–19]. We strongly believe 531

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A

B

FIGURE 41.1 Schematic representation of the Roux-en-Y gastric bypass (A) and biliopancreatic diversion (B). (Figure courtesy of the American Society for Bariatric Surgery.)

that operative risk and postoperative and late complications must be measured against the medical beneﬁts of massive weight loss, despite the fact that the exact mechanism explaining early diabetes resolution has not yet been identiﬁed. Operative risk is reported to be approximately 1%, but it may be further lowered by experienced surgeons. Postoperative complications (Table 41.1) occur in approximately 10% of patients. Colecistectomy is strongly recommended to avoid gallstone formation with rapid weight loss [18–20]. In our experience with post-BPD patients, operative and late complications may be prevented by close surveillance and follow-up of patients. To further support the emerging role of bariatric surgery as a therapeutic option in severe obesity, it is remarkable that overall annual mortality is lower in obese patients who undergo bariatric surgery than in morbidly obese people who do not undergo surgery for personal reasons [14,21]. We must point out, however, that no standard criteria exist for judging the best surgical option for each patient or for evaluating the success of surgery for morbid obesity in terms of weight loss. Also, no consensus has been reached on the management, therapy, and follow-up required after surgery. Thus, the success of each surgical procedure in terms of weight loss and low incidence of complications depends greatly on the ability of the surgeons, physicians, and nurses taking care of patients after surgery.

MALABSORPTIVE OR RESTRICTIVE PROCEDURES Surgery can induce weight loss by two obvious mechanisms: intestinal malabsorption or gastric restriction. The types of operations are traditionally categorized based on which of these changes they induce. Both restrictive (RYGB) and malabsorptive (BPD, with or without duodenal switch) bariatric techniques aim at a stable reduction in total caloric assimilation. Purely restrictive bariatric operations cause weight loss by restraining the capacity of the stomach to contain food and constricting the ﬂow of ingested nutrients. Gastroplasty involves placing a horizontal staple line; a small, proximal pouch is separated from the large distal remnant, and the two parts are connected through a narrow stoma [22]. To avoid dilation of the stoma and proximal pouch or dehiscence of the horizontal gastroplasty, Mason [23] modiﬁed this procedure to develop vertical banded gastroplasty (VBG), in which the partitioning line extends upward from the angle of His. A polypropylene band supports the stoma. Although VBG effectively limits the amount of food that can be consumed

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TABLE 41.1 Main Surgical Complications of Roux-en-Y Gastric Bypass (RYGB) and Biliopancreatic Diversion (BPD) Complication Deep venous thrombosis Anastomotic leaks Internal hernias Gastrointestinal bleeding Intestinal obstruction Wound complications Staple-line disruption Ulcers Torsion or volvulus of the roux limb Stomal stenosis Biliopancreatic limb obstruction and pancreatitis Closed loop obstruction

RYGB

BPD

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes — Yes

Yes Yes Yes Yes Yes Yes Yes Yes — — Yes —

at one sitting and causes a 30 to 50% reduction of excess body weight within the ﬁrst 1 to 2 years, long-term results are disappointing, showing a nearly 80% failure rate after 10 years [19,24]. Patients often accommodate to gastric restriction by frequently eating small meals and calorie-dense foods [20]. Laparoscopical adjustable gastric banding (AGB) is used extensively worldwide. This approach involves placement of a prosthetic band around the upper stomach to partition it into a small, proximal pouch and a large, distal remnant, connected through a narrow constriction [25,26]. Weight loss after either type of gastric banding is usually less than that expected from RYGB [19]. Roux-en-Y gastric bypass is the most effective restrictive procedure to induce and maintain weight loss [27–31]. The stomach is divided into a small, proximal pouch and a large, distal remnant. The upper pouch is joined to the proximal jejunum through a narrow gastrojejunal anastomosis. The storage capacity of the stomach is reduced to approximately 5% of its normal volume, and ingested food bypasses approximately 95% of the stomach, the entire duodenum, and a small portion (15 to 20 cm) of the proximal jejunum. Patients can lose 35 to 40% of total body weight, and most of this effect is maintained for at least 15 years [8,18,19]. Bypassing the stomach and duodenum impairs the absorption of iron, calcium, thiamine, and vitamin B12; thus, supplements of these micronutrients and periodic monitoring for deﬁciencies are required. After the failure of jejunoileal bypass, which was plagued by severe and life-threatening consequences [2], BPD is the only malabsorptive procedure currently being performed. It allows patients to eat as much as they want, as it primarily acts through lipid malabsorption. Malabsorption occurs because pancreatic and biliary secretions are diverted to the distal approximately 50 cm of the ileum. Some surgeons do not perform BPD because of the increased likelihood of life-threatening complications [19], even though they believe that this procedure promotes durable weight loss as effectively as any bariatric procedure does, in particular RYGB. Severe complications include protein malnutrition, hypocalcemia and metabolic bone disease, foul-smelling diarrhea, and deﬁciencies of iron, vitamin B12, and fat-soluble vitamins [20]. In the authors’ opinion, the metabolic effects of BPD may largely outweigh its complications. Again, we recommend very close surveillance of both BPD and RYGB patients to obtain the best results in terms of weight loss and the lowest rate of complications. Patients are admitted to the care unit monthly during the ﬁrst 6 months of follow-up, every 3 months during the next 6 months, and then every 6 months after a year. A dietary recall diary is required so we can check their daily energy intake. Patients are prescribed oral supplementation of sulfate iron (525 to 1050 mg/day), calcium carbonate (1 g/day), multivitamins, and ergocalciferol (400,000 to 1600,00 UI i.m.

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monthly). Despite ergocalciferol supplementation, the prevalence of hypovitaminosis D ranges from 89 to 91% in women 10 years after BPD [32]. Intravenous iron supplementation may be required, primarily in fertile women. BPD patients are instructed to eat freely and frequently, as compared with post-RYGB patients, who must restrain their consumption of calorie-dense foods, including fats, concentrated carbohydrates, ice cream, and sweetened beverages. BPD patients should consume proteins at least twice a day.

WEIGHT LOSS AND ENERGY EXPENDITURE Bariatric surgery is the most effective method to obtain major, long-term weight loss [19,20]. In individuals genetically prone to develop obesity, any attempt to reduce body fat stores by conventional weight-loss programs triggers compensatory changes in appetite and energy expenditure that resist weight change [33]. Physiological regulation of body weight developed as a mechanism to defend against malnutrition in times of famine; therefore, the adaptive responses to weight loss seem to be stronger than those in response to weight gain. Nonsurgical methods are notoriously ineffective at achieving major, long-term weight reduction. In contrast, surgery can effectively alter this physiological system. The so-called “adipostat” regulates body weight in a manner analogous to that by which a thermostat controls ambient temperature. No more than 5 to 10% of body weight is lost through dieting, exercise, and the few available anti-obesity medications (e.g., sibutramine and orlistat). Recidivism after dietary weight reduction is very common [34–37]. Bariatric surgery is able to reduce body weight by 35 to 40%. Most of this effect is maintained for at least 10 years or longer [8,18–19]. Surgery imposes a ﬁxed reduction in energy intake, and energy requirements decline as subjects lose largely fat mass, as well as (to a lesser extent) fatfree mass. The decline in body weight after surgery is a nonlinear function of time [38]. The resting energy expenditure (REE) is a function of the fat-free mass, which represents the mass of metabolically active tissues [39]. The total amount of energy expenditure (EE) results basically from REE; energy expenditure related to physical activity (PA); non-exercise activity thermogenesis (NEAT), which is the energy required to ﬁdget, to maintain posture, and to perform other activities of daily living [40]; and diet-induced thermogenesis (DIT), which is the energy consumed for absorbing, digesting, processing, and storing nutrients. In dieting obese individuals, the resting energy expenditure decreases [41,42], DIT is blunted, thermogenesis is defective [43–48], and fat oxidation decreases [49–50]. These impairments in metabolism can contribute to weight regain after dieting. In contrast, after surgery, energy intake is constantly reduced or unchanged while energy expenditure and metabolic efﬁciency are both increased. In post-BPD patients, the amount of metabolizable energy per kilogram of fat-free mass (deﬁned as total energy intake minus fecal and urinary losses) is not different before and after surgery [51], but the energy required for absorption and digestion processes is greater [52]. Surgery is also likely to positively inﬂuence NEAT, as body agility is improved after massive weight loss. In post-BPD patients, average 24-hour lipid oxidation is improved from 69% before surgery to 97% of metabolized fats after the procedure [51]. Metabolic efﬁciency in the oxidation of absorbed lipid is signiﬁcantly increased.

NORMALIZATION OF METABOLIC INFLEXIBILITY The higher efﬁciency in substrate oxidation suggests that the metabolic inﬂexibility may partially reverse after BPD. Metabolic inﬂexibility, which characterizes obesity, is deﬁned as the pathological incapacity to utilize lipid and carbohydrate fuels as needed and to switch between them [53]. In obese subjects, inﬂexibility includes: (1) impairment of the cephalic phase of the insulin secretion, (2) failure of muscle tissue to correctly oxidize lipids at fasting and carbohydrate in the insulinstimulated prandial state, and (3) impaired transition of fatty acid efﬂux from storage in response to a meal. Major weight loss following bariatric surgery is able to restore the early phase of insulin

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secretion by type 2 diabetes mellitus (T2DM) patients [16]. Insulin secretion in response to a meal is normalized and post-obese subjects are able to oxidize lipids or carbohydrates as needed [54]. Oxidation of lipid substrates is more efﬁcient in the fasting status, while glucose oxidation is increased in the insulin-stimulated condition as evaluated by the euglicemic hyperinsulinemic clamp [56]. With regard to circulating fatty acids, post-surgery levels of circulating fatty acids are significantly lowered. In post-BPD, this effect is largely due to the massive lipid malabsorption. In RYGB subjects, changes in eating behavior occur for unknown reasons, and these patients voluntarily reduce the intake of calorie-dense foods, including fats [7]. We suggest that the massive reduction in dietary fats induces a dramatic reduction in circulating and intramyocyte fat depots [56] which is associated with the reversal of insulin resistance 6 months after surgery [56]. The elimination of lipotoxicity and normalization in lipid fuel sensing inside the cells translate into amelioration of the action of insulin, accompanied by enhanced glucose oxidation and a shift from lipid to glucose metabolism [57,58]. Insulin sensitivity improves in proportion to weight loss with the use of predominantly restrictive procedures but is completely reversed by predominantly malabsorptive approaches long before normalization of body weight [38,60]. It is not surprising that full normalization of insulin action occurs in parallel with achieving an ideal body weight [5,8], but it is astonishing that normalization also results in patients who do not achieve a normal BMI [55,56]. The amount of weight lost may not be the only determinant of metabolic improvement, and the surgical strategy used to achieve weight reduction may have an independent effect. Although the degree and time course of weight reduction (average weight loss of 53 kg) are almost identical after BPD or RYGB [38], patients who have undergone BPD achieve levels of insulin sensitivity that are double those of patients following RYGB. Normalization of insulin action may be not complete after RYGB, despite substantial weight reduction [59]. After RYGB, the improvement in insulin sensitivity is of the exact magnitude predicted by the general relation between glucose disposal and BMI found in healthy normal-weight individuals [38]. In contrast, in post-BPD patients, the levels of insulin sensitivity are almost normal at 6 months, when their BMIs average 39 kg/m2. A further loss of approximately 15 kg over the following 18 months increases insulin sensitivity to levels higher than those of lean controls [60]. Evidence from molecular studies is consistent with the hypothesis of lowered lipo- and glucotoxicity. After BPD, the expression of acetyl-CoA carboxylase (ACC2) [61], uncoupling proteins 2 and 3 (UCP2 and UCP3) [62,63], and pyruvate dehydrogenase kinase (PDK4) [64] is downregulated, but glucose transporter 4 (GLUT4) mRNA is increased in muscle tissue [56]. The intramyocyte content of malonyl-CoA decreases [51]. After RYGB, muscle expression of insulin receptors increases, lipid depots and the fatty acyl CoA content decreases. After both RYGB and BPD, levels of circulating adiponectin are increased [65–68], and leptin is decreased [51].

INSULIN ACTION AND SECRETION In people with normal glucose tolerance, a decrease in insulin action is accompanied by the upregulation of insulin secretion, and vice versa. A compensatory increase of insulin secretion maintains normoglycemia despite decreased insulin sensitivity. After being algebraically transformed, insulin secretion and sensitivity are commonly represented as a hyperbola describing the acute insulin response (AIR) as a function of insulin sensitivity [69]. The hyperbola reﬂects the natural relationship between β-cell function and insulin sensitivity, taking into the account β-cell compensation for the insulin resistance. The disposition index represents the mathematical product of the insulin action for the β-cell function, and it simpliﬁes the concept of the hyperbola [70]. The disposition index is a way of measuring the ability of the β-cells to compensate for insulin resistance. This compensation is thought to be perfect when the disposition index remains constant in the face of decreasing insulin action; thus, it seems intuitive that β-cell function is modiﬁed for every signiﬁcant change in peripheral insulin sensitivity. Surprisingly, this is true for obese patients

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who undergo malabsorptive bariatric surgery but not for T2DM patients after a hypocaloric diet, for RYGB patients, or for those who undergo gastroplasty [38]. An innate hyperactivity of the β-cell response to feeding seems to be the cause of weight gain rather then the consequence of weight excess. In obese and T2DM subjects, weight loss is followed by an increase in insulin sensitivity and also an increase, rather than a decrease, in β-cell activity [60,71]. The disposition index is unchanged in RYGB patients [72], and it increases after gastroplasty at a time when 25% of the initial weight is lost [73]. Because weight loss is invariably associated with improved glycemic control, the paradoxical rise in insulin secretion is commonly regarded as the result of removing the toxic effect of chronic hyperglycemia on β-cell function [74–76]. Insulin hypersecretion after dieting or RYGB may also suggest that the post-obese state reproduces the primary insulin hypersecretion of the obese state or is a consequence of the secretory system setpoint being reset. In post-BPD patients, insulin hypersecretion is abolished even before achievement of ideal body weight, and the depletion of intramyocyte lipid depots occurs as a consequence of the increased β-cell glucose sensitivity.

THE GUT AND RESOLUTION OF T2DM Resolution of diabetes has been largely demonstrated as an additional outcome of surgical treatment for morbid obesity. The Greenville study [8] demonstrated that 82% of 165 patients with T2DM stably remitted from diabetes after an average 14 years of follow-up. The SOS study [17], which prospectively compared obese patients treated or not treated by surgery, showed that the number of patients not requiring drug treatment to maintain normal glycemia after 2 years in the surgical arm was about double that in the control group. In a recent systematic review and meta-analysis of the data reported in the literature on bariatric surgery, Buchwald et al. [15] found a range of effects, from 98.9% in patients after BPD or duodenal switch to 83.7% for gastric bypass, 71.6% for gastroplasty, and 47.9% for gastric banding. What is impressive is how rapidly the diabetes is corrected after BPD or RYGB, usually in a matter of days. The improvement in diabetes is unrelated to the amount of weight lost and seems to be strictly associated with the surgical manipulation of the small intestine. We have recently observed that the normalization in β-cell function and insulin action that occurs in T2DM patients within one week following BPD does not occur in obese subjects who undergo abdominal surgery for gallstones, despite both groups of patients consuming no foods in the immediate period after surgery [Guidone et al., unpublished data]. This observation eliminates the possibility that the early improvement of diabetes may be related to the diminished meal-induced challenge of β-cells. A more intriguing hypothesis is that manipulation of the small intestine (duodenum and proximal jejunum) may alter the hormone milieu, and the exclusion of its large part from nutrient transit may play a relevant role in the resolution of diabetes, apart from reduced lipotoxicity. In a very elegant review on the mechanisms by which RYGB induces the resolution of diabetes, Cummings et al. [7] proposed a role for ghrelin and glucagon-like peptide 1 (GLP-1). In RYGB, ghrelin secretion is decreased and the 24-hour proﬁle is completely ﬂat [77]. In contrast, in patients who have undergone BPD without duodenal switch, in spite of a ﬂat ghrelin proﬁle circulating levels of the hormone increase, because the main site of ghrelin secretion, the fundus, is preserved in this surgical procedure [78]. Ghrelin, then, does not seem to be a candidate to fully explain the reversion of diabetes observed after either RYGB or BPD. In RYGB, enhanced GLP-1 release is due to the earlier delivery of food to lower segments of the gut. This effect is likely to also occur after BPD; thus, GLP-1 seems to be a more attractive candidate, as well as the glucose-dependent insulinotropic polypeptide (GIP), to explain the amelioration of glucose metabolism after bariatric surgery. GIP is synthesized and released in the duodenum and proximal jejunum, especially in response to glucose and fat ingestion. It acts as an insulinotropic agent with a stimulatory effect on insulin release and synthesis [79]. Defects in its signaling pathways are considered among the most critical alterations underlying T2DM. The

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incretin effect of GIP is characteristically attenuated in T2DM [80], and the expression of glucosedependent insulinotropic polypeptide receptor (GIPR) is also decreased [81]. GLP-1 is released by the L cells of the distal ileum and colon, and it enhances glucose-induced insulin secretion [82]. After RYGB, levels of GIP have been found to be decreased [83] but GLP-1 was increased [84,85] or unchanged [83,86]. Rubino et al. [83] found an exaggerated GLP-1 response following a 420-kcal meal in gastric bypass subjects. They suggest a major role for GIP in the resolution of T2DM and speculate that in susceptible individuals, such as diabetic patients, chronic exaggerated stimulation of the proximal gut with fat and carbohydrates may induce overproduction of an unknown factor that causes impairment of GIPR expression or GIP/GIPR interaction, leading to an insufﬁcient or inappropriate insulin secretion and the development of glucose intolerance. The duodenal–jejunal exclusion may resolve this aberration by restoring normal GIP sensitivity and reducing GIP secretion. Unlike GIP, GLP-1 has been shown to signiﬁcantly improve or even restore normal glucose-induced insulin secretion in diabetic patients [87]. Although the changes in GLP-1 levels did not reach statistical signiﬁcance in the Rubino et al. study [83], the authors do not exclude a role of GLP-1 in restoring glucose homeostastis. In diabetic obese patients one week after BPD, we have observed a signiﬁcant decrease in fasting- and glucose-stimulated GIP secretion during standard oral glucose loads and an increase in fasting- and glucose-stimulated GLP-1 secretion [Guidone et al., unpublished data]. As previously observed, insulin secretion decreases and β-cell sensitivity to glucose is improved [60]. All of the above-mentioned reports in patients after RYGB or BPD and evidence from two elegant animal studies [88,89] suggest that bypass of the duodenum and jejunum, which is performed in RYGB and BPD, can ameliorate T2DM independently of weight loss through mechanisms that remain unclear. In rats, transposition of the ileum [88], a procedure where an isolated segment of the ileum is transposed to the jejunum, results in an intestinal tract of normal length but an alteration in the normal distribution of the endocrine cells along the gut. The procedure is associated with a net increase in insulin sensitivity without any signiﬁcant decrease in adiponectin levels, a rise of glucose-stimulated GLP-1, and signiﬁcant lowering of plasma leptin. The restoration of normal insulin sensitivity with subsequent improvement of β-cell sensitivity is not predicted by the measured variables. In Goto–Kakizaki rats (a spontaneous, non-obese model of T2DM), the effects of RYGB related to the exclusion of duodenum and proximal jejunum are distinct from those related to gastric restriction and bypass. The stomach is left unperturbed, but food is diverted from the pyloric area to the proximal jejunum with a gastrojejunal anastomosis. Experimental animals display food intake and body weight similar to sham-operated controls, indicating that foregut bypass alone is not sufﬁcient to cause weight loss. Noteworthy is that the rats show signiﬁcant improvement in glucose tolerance compared with sham-operated controls, despite equivalent body weights [89]. Consistent with these observations, our working hypothesis is that the exclusion of the entire jejunum, which is characteristic of BPD, might be responsible for the inhibited secretion of an unknown hormone that strongly affects insulin sensitivity. The reduction in food ingestion and absorption suppresses the release of GIP and GLP-1, thereby contributing to the fall in insulin secretion.

RESOLUTION OF HYPERTENSION Even a modest weight loss can lower blood pressure signiﬁcantly. It is commonly assumed that a decrease of 1% in body weight reduces systolic blood pressure by 1 mmHg and diastolic blood pressure by 2 mmHg [90–92]. The reduction of blood pressure seems to be independent of the type of surgery [15]. A recent meta-analysis by Buchwald et al. [15] found that hypertension signiﬁcantly improves in morbidly obese subjects after bariatric surgery. The improvement is independent of the type of surgery. The percentage of patients in the total population whose hypertension fully resolved was 61.8%, and this ﬁgure rose to 78% when resolution and development were both considered.

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RESOLUTION OF DYSLIPIDEMIA Hypercholesterolemia and hypertriglyceridemia are signiﬁcantly improved after bariatric surgery independently of the technique used. The lipid proﬁle improves in at least 70% of the patients. A major improvement is obtained in patients after BPD, duodenal switch, or gastric bypass [15]. Total cholesterol may be decreased by a mean value of 33%, low-density lipoprotein (LDL) by 29.34%, and triglycerides by 79.65%. Surprisingly, high-density lipoprotein (HDL) cholesterol is improved after gastric banding (by 4.63%) or gastroplasty (by 5.02%). Also, after BPD, we have observed a signiﬁcant increase in HDL levels and the reduction of cardiovascular risk [93]. In the late 1990s, two studies suggested that bariatric surgery could be a therapeutic option for severe dislipidemia [5,6]. Two sisters affected by a familial deﬁcit of lipoprotein lipase and T2DM underwent biliopancreatic diversion. Because their BMIs were within the normal range, the rationale for surgery was to reduce the absorption of lipids to achieve normal glucose homeostasis [5].

POLYCYSTIC OVARY SYNDROME AND ENDOCRINE-RELATED DISEASES The etiology of PCOS is still largely unknown. The primary defect consists of increased androgen synthesis and secretion by ovarian thecal cells [94,95], worsened by hyperinsulinism and insulin resistance [96]. Obesity is commonly associated with PCOS and hyperandrogenism [97]. Compared with non-hyperandrogenic women with morbid obesity, PCOS and hyperandrogenic patients with regular menstrual cycles present with similarly increased total and free testosterone levels, but insulin resistance is present only in the PCOS group. In contrast, the prevalence of PCOS is increased six- to sevenfold in women with morbid obesity compared with unselected healthy controls [98]. Diet-induced weight loss ameliorates the clinical signs and symptoms of PCOS, including hyperandrogenism and insulin resistance [99], menstrual dysfunction [100], and oligoovulation [101]. We and others [102,103] have recently showed that massive weight loss due to surgery is also able to ameliorate or resolve signs and symptoms of hyperandrogenism. Moreover, the sustained and marked weight loss achieved either after RYGB or BPD leads to the almost complete resolution of PCOS [15]. PCOS patients recover regular ovulatory menstrual cycles after weight loss in parallel with a marked improvement in the indices of insulin resistance.

RESOLUTION OF NONALCOHOLIC STEATOHEPATITIS Nonalcoholic fatty liver disease (NAFLD) is a common condition that may progress to end-stage liver disease. NAFLD ranges from fat depots in the liver, known as simple steatosis or nonalcoholic steatohepatitis (NASH), to steatohepatitis or fat with inﬂammation and ﬁbrosis, to advanced ﬁbrosis and cirrhosis, when fat may no longer be present. NAFLD is closely associated with obesity and insulin resistance. NALFD is estimated to occur in 30 to 100% of obese adults. The majority of obese patients have ultrasonographic evidence of fatty liver; 30% have histologically proven NASH. Up to 25% of obese patients with NASH may progress to cirrhosis [104]. The exact mechanisms leading to NAFLD or ﬁbrosis are incompletely understood. Hyperinsulinemia and insulin resistance are clearly important, as they act to increase the inﬂux of free fatty acids into the liver and drive hepatic triglyceride production. They promote de novo lipogenesis by upregulating lipogenic transcription factors such as the sterol regulatory element-binding protein 1c (SREBP-1c) and the carbohydrate response element-binding protein [105,106]. Furthermore, insulin-mediated activation of SREBP-1c increases malonyl-CoA which inhibits free fatty acid oxidation, thereby favoring hepatic triglyceride accumulation [107]. Lipid export from the liver may be impaired because of defective incorporation of triglycerides into apolipoprotein B (apoB) or reduced apoB synthesis or excretion [108,109]. Hepatic triglyceride accumulation subsequently leads to hepatic insulin resistance by interfering with tyrosine

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phosphorylation of insulin receptor substrates 1 and 2 [110,111]. Hepatic lipid accumulation does not universally result in hepatocellular injury, indicating that additional secondary insults are important [112]. Day et al. [111] initially proposed a “two-hit” model to explain the progression of NAFLD. The ﬁrst hit constitutes the deposition of triglycerides into the hepatocyte cytoplasm. The disease does not progress unless additional cellular events occur (the second hit), thus promoting inﬂammation, cell death, and ﬁbrosis. To date, surgical solutions for morbid obesity have proven to be effective in the treatment of NAFLD, although some of these studies were confounded by the unexplained progression of disease occurring after surgery in a few patients [113,114]. Recently, Mattar et al. [114] demonstrated signiﬁcant and widespread improvement up to the resolution of NAFLD and NASH after laparoscopic weight-loss procedures, which included gastric bypass, sleeve gastrectomy, and laparoscopic banding in 70 obese patients. More than one third of the patients had postoperative liver biopsies that showed resolution of steatosis and inﬂammation, and 20% of the patients had at least some reversal of ﬁbrosis. No patient experienced a progression of abnormal liver morphology or a deterioration of hepatic function, as indicated by persistently normal liver enzymes. The beneﬁcial effects of weight loss are believed to be mediated primarily via improved insulin sensitivity. After surgery, circulating levels of glucose, insulin, and leptin are decreased, contributing to the decrease in fatty liver inﬁltration and inﬂammation [115]. However, it cannot be ruled out that rapid weight loss may aggravate liver function and histology as a result of increased free fatty acid levels derived from extensive fat mobilization or that additional factors, such as toxins from bacterial overgrowth or nutritional challenge, may represent a second hit in susceptible livers. Luyckx et al [113] conﬁrmed this observation in patients after RYGB. Initially, steatosis improved and inﬂammation transiently worsened, then liver inﬂammation improved over time in accordance with resolution of other metabolic abnormalities [114]. Dixon et al. [112] demonstrated major improvement in liver disease in patients who achieved signiﬁcant weight loss with gastric banding. After BPD, a remarkable reversal of ﬁbrosis and macroscopic liver appearance was found in 60% of cirrhotic patients; in nearly 40%, ﬁbrosis increased, and de novo cirrhosis developed in a few cases [115].

CONCLUSION Both RYGB and BPD are effective in the resolution of metabolic comorbidities of severe obesity. Diabetes, hypertension, dislipidemia, nonalcoholic fatty liver disease, and polycystic ovary syndrome are improved or completely resolved. It must be pointed out, however, that (1) the mechanisms by which bariatric surgery acts to ameliorate metabolic comorbidities are still unclear; (2) severe morbidity is resolved by inducing a different pathological status, which requires a close follow-up and continuous medication; and (3) no consensus has been reached on the treatment and follow-up of these patients, despite the widespread diffusion of surgery as a therapeutic option for severe obesity and metabolic comorbidities. Long-term complications of bariatric surgery must therefore be carefully weighed against the beneﬁcial effects, and surgery must represent the last therapeutic option following the failure of any other feasible treatment.

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NIH Consensus Development Panel, Gastrointestinal surgery for severe obesity, Ann. Intern. Med., 115, 956–961, 1991. The American Society for Bariatric Surgery, www.asbs.org. Schirmer, B., Laparoscopic bariatric surgery, Surg. Clin. North Am., 80, 1253–1267, 2000. Scopinaro, N., Gianetta, E., Civalleri, D., Bonalumi, U., and Bachi, V., Bilio-pancreatic bypass for obesity. II. Initial experience in man, Br. J. Surg., 66, 618–620, 1979. Mingrone, G., Henriksen, F.L., Greco, A.V., Krogh, L.N., Capristo, E. et al., Triglyceride-induced diabetes associated with familial lipoprotein lipase deﬁciency, Diabetes, 48, 1258–1263, 1999.

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Index A abdominal obesity, 5, 10, 22, 43, 45, 124, 126, 141, 142, 143, 220, 240, 366, 388, 464, 465, 466, 468, 482, 519; see also visceral fat acanthosis nigricans, 117 acarbose, 283, 284, 293, 429 acetaldehyde, 363, 366 acetaminophen, 166, 168 acetate levels, serum, 284 acetic acid, 436 acetone, 363, 366 acetylated glucosamine, 414 acetylation, 53 acetyl-CoA, 355, 445 acetyl-CoA carboxylase, 329, 535 N-acetylcysteine, 132, 160 N-acetyl-hexosaminidase (NAH), 170 actin, 160 activational effects, of sex hormones, 34 acute insulin response (AIR), 257, 535 acyl CoA, 535 diacylglycerol acyltransferase 1 (DGAT1), 183–184 monoacylglycerol acyltransferase, 310 acylation, 107 adenosine monophosphate (AMP), 364 adenosine triphosphate (ATP), 201, 364, 366, 465 adhesion molecules, 98 adipocyte-complement-related protein (adipoQ), 47, 179 adipocytes, 35, 47, 49, 50, 52, 54, 57, 87, 90, 96, 143, 144–145, 156, 161, 178, 179, 181, 249, 250, 307, 308, 327, 328, 366, 386, 387, 388–389, 390, 405, 464, 470 apoptosis of, 479, 483, 488 brown-like, 185–188 calcium, and, 478 estrogen and, 36–37 hyperplasia, 36, 37 insulin-induced glucose uptake in, 37 post-mitotic, 36

adipocytokines, 48, 54, 110, 143, 144, 160, 386, 388, 391 adipogenesis, 37, 38, 108, 116, 157, 159, 180, 181, 328, 386, 387, 388, 389, 390 adipokines, 144, 156–157, 178, 179, 269, 328, 386, 389–390, 392, 393, 487 leptin, 93–100; see also leptin adipokinomes, 156–157 adiponectin, 45, 47, 53, 57, 142, 143, 145, 147, 156, 179–180, 257, 388, 391, 535, 537 as risk factor for type 2 diabetes, 257 fragment, recombinant, 180 small-molecule mimetics, 180 adiponectinemia, 385 adipoQ, 47, 179 adipose drug targets, 177–189 adipose tissue, 44, 46, 49, 50, 51, 52, 87, 93, 96, 97, 98, 99, 105, 108, 144, 155, 156, 158, 159, 161, 177–178, 181, 182, 183, 184, 221, 234, 235, 269, 281, 328, 356, 379, 384, 387, 388, 389, 391, 403, 404, 459, 464, 465, 481 adrenoreceptors in, 74 as endocrine organ, 487 branched-chain amino acids, and, 482 brown (BAT), 90, 180, 185, 390, 404, 464, 465, 467, 468, 472 interscapular, 465 human vs. rodents, 185 hydrogen peroxide, and, 48 leptin, and, 116 macrophages, and, 51 NADPH oxidase expression, 488 ob gene in, 83 omental, 328 remodeling, 185–188 superoxide anion exposure, and, 51 UCP2 expression, 478 white (WAT), 49, 97, 105, 156–157, 180, 183, 185, 187, 206, 328, 386, 387, 390, 391, 465, 467, 468–469, 470, 472, 482 caloric restriction, and, 269 adiposity, milk effects on, 485

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546

Obesity: Epidemiology, Pathophysiology, and Prevention

adiposity, central, 45; see also abdominal obesity; visceral fat adipostat, 178, 534 adjustable gastric banding (AGB), 533 adolescents, obesity among, 11–14, 115, 142, 219–220, 233, 250, 423 adrenal insufficiency, 116 β3-adrenergic receptor (β3-AR), 185–188, 373, 379, 464 adrenergic receptors, 116, 187, 241–242 adrenoceptors, 74 adrenocorticotropic hormone (ACTH), 76, 78 adrenocorticotropin, 89, 116 adult respiratory distress syndrome (ARDS), 47, 56 advanced arteriosclerotic vascular disease (ASCVD), 204 Advantra Z™, 379 adventitia, 96 aerobic exercise, 129, 222 for children, 518, 519 afferent signals, 105 Africa, obesity in, 10 age, obesity and, 27 aglycones, 323 agouti, 478, 482, 483 Agouti-related peptide/protein (AGRP), 44, 77, 78, 86, 89, 90, 108, 166 L-alanine, 428 alginate, 438 alkaloids, ephedrine, 495–503 allyl sulfides, 56 alpha-amylase, 281, 282, 286 alpha-amylase inhibition, 423–429 alpha-amylase inhibitors, 280, 281, 282, 283, 284, 285, 288, 293 non-kidney-bean, 287–288 alpha-glucosidase inhibitors, 280, 283, 293 alpha-methyl-para-tyrosine (AMPT), 201 Amadori reactions, 125 American Diabetes Association (ADA), 258 American Heart Association diet, 256 γ-aminobutyric acid (GABA), 75 aminoglycoside antibiotics, 170 aminorex fumarate, 202 AMP-activated protein kinase (AMPK), 94, 96 amphetamine, 74, 201, 203, 204, 497 amphetamine derivatives, 203, 205 amylin, 208 anabolism, 249 anaerobic bacteria, 282

anandamide, 79 anesthesia, 166 Angelman syndrome, 118 angina pectoris, 54 angiogenesis, 156, 157, 158, 160, 161, 211 inhibitors, 158 oxidants as inducers of, 159–160 redox control of, 159–160 -targeted redox-based therapeutics, 155–161 angiogenic factors, oxidants as inducers of, 159–160 angiopoietin-1, 159, 160 angiostatin, 158 angiotensin-converting enzyme (ACE), 130, 481, 488 angiotensin II, 53, 97, 159, 481 angiotensin receptor blockers (ARBs), 130 animal models of obesity, 166 anorexia nervosa, 63, 64, 65, 66, 67, 86, 205, 206 anthocyanidins, 325 anthocyanins, 148, 323, 325, 328 berry, 160, 161 anti-aging caloric restriction, 265–274 antiangiogenic therapeutics, 158–159, 160, 161 antibiotics, aminoglycoside, 170 antihyperglycemia therapy, 130 antiinflammatory adinopectin, 45, 53, 147, 388 arachidonic acid, 454 fucoxanthin, 470 ghrelin, 53 phytochemicals, 53, 56 antioxidant supplementation, 131–132 antioxidants, 54, 55, 56, 160, 161, 271, 311, 322, 331, 384, 392 dietary, 124, 127, 130, 160–161 enzyme, 128, 132 exercise, and, 129 herbs, 326 hypertension, and, 53 metabolic syndrome, and, 127–128 polyphenols, 323 small-molecule, 127 tea, 235 vitamins, 127 antisauvagine-30, 77 antisense oligonucleotides (ASOs), 182, 184 apnea, 141, 142, 220, 322, 423, 521, 531 apochromodulin, 341

3802_C042.fm Page 547 Monday, January 29, 2007 3:41 PM

Index

apolipoprotein B (apoB), 438, 538 apolipoprotein E (apoE), 160 apomorphine, 74 appetite, 105–112 control, 329 defined, 105 low-glycemic-load diet, and, 245–260 regulation, 45 stimulants, 108, 109, 427 neuropeptide Y, 46 suppressants, 155, 202, 252, 331, 356, 365, 366, 443 chitosan, 414 nicotine, 44 apples, 322 arachidonic acid, 392, 454 2-arachidonoylglycerol (2-AG), 79 arcuate nucleus (ARC), 73, 75, 77, 78, 84, 86, 87, 90, 95, 96, 110 arginine, 87 L-arginine, 428 aromatase, 38 aromatic compounds, 55 aromatic L-amino acid decarboxylase, 72, 73 arrhythmias, ephedra, and, 499, 500 ascorbate, 415 astragulus root, 210 atherogenesis, 45, 53–54, 56, 100, 391 atherosclerosis, 47, 48, 49, 52, 54, 55, 57, 93, 98, 99, 126, 128, 143, 144, 145, 148, 159, 182, 339, 385, 386, 413, 487 cholesterol, and, 455 atherosclerotic lesions, 54, 98 Atkins diet, 246, 315–320 metabolic advantage, 316, 317, 318 atorvastain, 131 Australia, childhood obesity in, 14 autonomic nervous system, 404 autoxidation, 51, 125 Ayurveda, 350, 366

B babassu oil, 457 bacteria, antibiotic-resistant, 458 Bardet–Biedel syndrome, 116 bariatric surgery, 146, 226–227, 240, 246, 531–539 nutritional requirements of, 510 basic fibroblast growth factor (bFGF), 54, 156 Behavioral Risk Factor Surveillance System (BRFSS), 8, 142

547

benzo(a)pyrene, 45 benzoic acid, 498 benzphetamine, 203, 204 β-blockers, 130 β-cells, 48, 49, 142, 143, 145, 146, 207, 208, 535, 536, 537 bile acids chitosan and, 414 glucomannan, and, 438 biliopancreatic diversion (BPD), 531–539 binge eating disorder, 64–65, 66, 67, 209 birth weight, 142 bisflavanols, 403 bisphenol A (BPA), 37, 38 bitter orange extract, 371–381, 439, 499; see also Citrus aurantium chemistry, 372–373 bitter principles, 444 blood–brain barrier, 85, 86, 87, 94, 110, 207, 282, 373 blood pressure adipokines, and, 156 adipokinomes, and, 157 antioxidants, and, 131 bariatric surgery, and, 537 caloric restriction, and, 270, 272 Caralluma fimbriata, and, 446 dairy, and, 485 diastolic, 270 Citrus aurantium, and, 375, 377, 379 ephedrine, and, 497 white bean extract, and, 428 diethylpropion, and, 204 ephedrine, and, 497 glycemic load, and, 256, 258, 259 HCA, and, 361 Lean Source™, and, 376 leptin and, 95–96 lipid peroxidation, and, 125 physical activity, and, 129 potassium, and, 364 sibutramine, and, 521 synephrine, and, 373 systolic, 227, 270 chitosan, and, 418 Citrus aurantium, and, 379 ephedrine, and, 497, 498 glucomannan, and, 438 white bean extract, and, 428 TheraSlim™, and, 292 vitamin C, and, 131

3802_C042.fm Page 548 Monday, January 29, 2007 3:41 PM

548

Obesity: Epidemiology, Pathophysiology, and Prevention

blood vessel wall, composition of, 96 Blount’s disease, 117 body mass index (BMI), 4, 5, 9, 10, 12, 13, 21–22, 23, 26, 43, 45, 85, 86, 88, 96, 110, 112, 115, 125, 126, 129, 140, 141, 142, 144, 208, 220, 223, 245, 251, 253, 257, 272, 292, 299, 300–301, 304, 306, 308, 309, 310, 322, 343, 363, 364, 366, 367, 391, 408, 409, 423, 428 bariatric surgery, and, 531 Caralluma fimbriata, and, 446 defined, 219 dietary calcium, and, 484, 487 fiber, and, 434 orlistat, and, 521 television viewing, and, 516 trends in, 141 vitamin E, and, 127 whole-grain intake, and, 520 body weight regulation, 82–83, 105 botanicals, 235–236 branched-chain amino acids (BCAAs), 482, 488 Brazil, obesity in, 10 breakfast, high-protein vs. high-carbohydrate, 308 breast cancer, 258 Brewer’s yeast, 339, 340 BRFSS, see Behavioral Risk Factor Surveillance System brown adipose tissue (BAT), 90, 180, 185, 390, 404, 464, 465, 467, 468, 472 interscapular, 465 bulimia nervosa, 63, 64, 65, 66, 67, 68, 86, 205, 206 bupropion, 206 butter, 283 butyric acid, 436

C caffeine, 203, 325, 329, 331, 372, 375, 377, 378, 379, 380, 381, 402, 403, 404, 405, 407, 408, 424, 439, 464, 477, 498, 499, 500, 502 habitual intake of, 408–409 HCA, and, 361 calcineurin, 388 calcium, 364–365, 367, 477–488 ACE inhibitor, and, 481, 488 anti-obesity mechanisms of, 478–482

body weight, and, 483–484 dairy vs. nondairy, 484–487 intake, in children, 487 oxidative stress, and, 487–488 calcium carbonate, 481, 533 calcium channel blocker, 130, 227 calcium hydroxycitrate, 352 Calorex, 285 caloric restriction, 129, 265–274, 424 causes and effects of, 268–269 effect on blood pressure, 270, 272 in humans, 271–273 life span, and, 265–268 mimetic drugs, 273–274 cAMP response element-binding protein (CREB), 467 cancer, 49, 157, 160, 161, 166, 182, 233, 258, 259, 266, 322, 330, 331, 332, 341, 350, 390, 423, 464, 470 conjugated linoleic acid, and, 385 cannabinoid-1 (CB1), 147 receptor, 206 cannabinoids, 79 Cannabis sativa, 79 capric acid, 458 capsaicin, 329, 464, 477 Caralluma fimbriata, 443–448 carbohydrate digestion inhibitors, 279–294 mechanism of action, 282–283 safety of, 293 metabolism, in small intestine, 327 oxidation, 250, 362, 363, 464, 479 red pepper and, 330 carbohydrates, 65, 66, 146, 307, 309 Atkins diet, and, 315–320 body fat levels, and, 241 complex, 280, 281, 287, 291, 294, 424 depression, and, 66 diabetes management, and, 258 digestion of, 281 forms of, 281 galanin, and, 76 glycemic index, and, 246, 247, 252 glycemic load, and, 249, 253 ketosis, and, 317 malabsorption of, 283, 426 neuropeptide Y receptors, and, 75 refined, 255, 315, 316, 319, 320, 350, 520 simple/complex vs. glycemic load, 255 testing for malabsorption, 283–284

3802_C042.fm Page 549 Monday, January 29, 2007 3:41 PM

Index

Carbolite, 284–285 carboxypeptidase, 166 cardiovascular disease, 3, 5, 50, 52–55, 97, 124, 126, 128, 142, 143, 146, 178, 179, 180, 189, 204, 220, 233, 245, 246, 255–256, 259, 310, 315, 316, 320, 329, 330, 331, 350, 372, 383, 384, 386, 388, 393, 463, 464, 518, 522 caloric restriction, and, 269–271 ephedrine, and, 500 phytochemicals, and, 56 potassium, and, 364 risk markers for, 255–256 cardiovascular incidents, Citrus aurantium and, 372, 373, 374, 377, 380 Caribbean, obesity in, 10 carnitine, 377, 438 β-carotene, 127, 129 carotenoids, 127, 129, 331, 467–469, 470, 472 in tea, 402 casein, 482 caspase-3, 389 catalase, 128, 271 CATCH, 519 catechin derivatives, 160 catechins, 161, 235, 323, 326, 328, 329, 470 tea, 160, 402, 403, 404, 405, 407, 408, 409 catecholamines, 36, 55, 71, 73–74, 75, 185, 241, 401, 404, 405, 464, 500 catechol-O-methyl transferase (COMT), 404 cayenne pepper, 329, 424 CCAAT/enhancer-binding protein (C/EBP), 36, 388, 390 C/EBPα, 36 cell adhesion molecules, 53, 56 cell-surface receptors, 178, 180 cellulose, 415 Centers for Disease Control and Prevention (CDC), 8, 23, 115, 140, 226, 233 centile crossing, 35 central nervous system, 44, 46, 72, 73, 74, 75, 79, 81, 83, 87, 179, 202, 203, 204, 207, 210, 211, 234, 350, 372, 373 ephedra, and, 497, 500 leptin transport into, 85–86 cereal starches, 281 cerebrospinal fluid, 85, 86 chemical toxicities, 165–171 chemokines, 47, 98, 100 Child and Adolescent Trial for Cardiovascular Health (CATCH), 519

549

childhood obesity, 11–14, 25, 43, 66, 127, 142, 165, 219–220, 224–226, 349, 423, 515–523 glycemic load, and, 251, 252 China, obesity in, 10, 14 Chinese medicine, 210, 496 chitin, 414 chitosan, 413–419, 424, 438 mechanism of action, 414 toxicology of, 414 chlorogenic acid, 323, 325, 326, 402 cholecystectomy, 258 cholecystokine, 57 cholecystokinin, 44, 46, 82, 235, 308, 309, 318, 436 food intake, and, 46 cholesterol, 292, 306, 330, 355, 356, 452, 455; see also low-density lipoprotein (LDL), high-density lipoprotein (HDL) absorption, 329 chromium (III), and, 339 fiber, and, 414 Phaseolus vulgaris, and, 426 total, 254, 256, 292, 330, 340, 343, 360, 361, 363, 364, 366, 385, 418, 438, 446, 538 coconut oil, and, 460 cholesteryl esters, 356 chromium, 148, 377, 438 chromium (III), 339–345 bioavailability of, 341 deficiency, 339 dietary sources of, 340 metabolic syndrome, and, 341–344 safety of, 344–345 chromium chloride, 344, 345 chromium nicotinate, 360 chromium picolinate, 341, 343, 344, 345, 376, 497 chromium polynicotinate, 361 chromodulin, 341 chromosome 15q11–q13 region, 118 chronic obstructive pulmonary disease (COPD), 47, 56 chylomicron, 464 cigarette smoke, components of, 45 cigarette smoking, 310 appetite, and, 44–45 Citrus aurantium supplements, and, 377 energy expenditure, and, 44–45

3802_C042.fm Page 550 Monday, January 29, 2007 3:41 PM

550

Obesity: Epidemiology, Pathophysiology, and Prevention

cigarette smoking (cont.) energy homeostasis, and, 45–46 obesity and, 43–57 oxidative stress, and, 47–51 synephrine, and, 378 ciliary neurotrophic factor, 386 cirrhosis, 166, 538 citric acid, 351 Citrus aurantium, 371–381, 424; see also bitter orange extract adverse events, 379–380 as substitue for ephedra, 373 LD50 for, 374 CLA-mediated lipoatrophic syndrome, 385 cocaine- and amphetamine-regulated transcript (CART), 86, 89, 108, 112 cocoa, 325 coconut, 456–458 coconut oil, 452–460 as antimicrobial agent, 458 heart disease, and, 455 coenzyme A, 131 coenzyme Q, 271 coenzyme Q10, 127, 131 coffee, 325, 340 cold sensitivity, 186 colecistectomy, 532 Colombo curing, 350 complementary and alternative medicine (CAM), 439 Comprehensive Assessment of the Long-Term Effects of Reducing Intake of Energy (CALERIE), 273 conjugated linoleic acid, 235, 376, 383–393, 424, 464, 477 c9t11-CLA, 384–385, 387–388, 390, 392 chemical properties of, 384–385 pharmacology/dosage, 385 safety, 385–386 t10c12-CLA, 384–385, 387–388, 390, 392, 464 conjugated linolein acid, 359 coronary artery disease, 53, 142, 143, 144, 321, 386, 520 coronary heart disease, 66, 97, 131, 205, 255, 377, 423 among cigarette smokers, 48 corticosteroids, 82 corticotropin-releasing factor (CRF), 71, 76–77, 80 receptos, 76, 77

corticotropin-releasing hormone (CRH), 76 cortisol, 250, 254, 482, 484 cortisone, 482 cottonseed oil, 455 p-coumaric acid, 323, 326 coumarins, 148, 323 coumarylquinic acid, 402 coumestans, 330 coumestrol, 330 C-peptide, 284, 286, 287, 344, 425, 426 cravings, 65, 66, 67, 345, 366 C-reactive protein (CRP), 50, 53, 55, 56, 96, 97, 99, 144, 179, 255, 256, 391, 392 creatine phosphate, 364 creatinine monohydrate, 499 Crete, childhood obesity in, 12 critical periods, 34, 35, 37 Crohn’s disease, 416 cryptorchidism, bilateral, 117 curcumin, 56, 161 cyanidin, 323, 328 cyanidin-3-glucoside, 328 cyclic adenosine 3′,5′-monophosphate (cAMP), 404 cyclin D, 391 cyclooxygenase, 467 cyclooxygenase-2 (COX-2), 392 cytochrome c, 389 cytochrome P450s, 51, 159, 168, 170, 171, 380 cytokines, 47, 49, 50, 51, 54, 55, 56, 83, 84, 93, 99, 144, 145, 159, 178, 257, 386, 390 adipose-derived inflammatory, 157 inflammatory, 49, 51, 53 proinflammatory, 391, 392

D daidzein, 323, 330 dairy foods, 384, 477–488 damiana, 331 db gene, 84, 85, 87 death rate, effect of obesity on, 165 delphinidin, 323 2-deoxy-D-glucose (2-DG), 273 depression, 67, 68 carbohydrates and, 66 depsides, 402 dexamethasone, 388 dexfenfluramine, 202 dextrins, 281 dextroamphetamine, 201 diabesity, 139

3802_C042.fm Page 551 Monday, January 29, 2007 3:41 PM

Index

diabetes, 5, 14, 15, 16, 22, 43, 49, 50, 54, 55, 57, 82, 84, 93, 117, 124, 128, 139–149, 159, 165, 166, 189, 200, 205, 207, 208, 220, 227, 246, 254, 255, 257, 258, 273, 280, 293, 315, 316, 317, 320, 321, 322, 327, 328, 330, 331, 332, 372, 383, 384, 385, 386, 387, 391, 423, 464, 465, 531, 539 chromium (III), and, 339, 340 diagnostic criteria for, 141 medical costs of, 423 reversal of after bariatric surgery, 536 white bean extract, and, 425 diacylglycerol, 235, 464 diacylglycerol acyltransferase 1 (DGAT1), 183–184, 189 diacylglycerol kinase, 132 diacylglycerols, 235 diadzin, 323 diastolic blood pressure, see blood pressure: diastolic Dietary Intervention Study in Children (DISC), 519 dietary supplements, 132, 235–236, 322, 326, 350, 351, 373, 374, 377, 378, 379, 384, 385, 386, 405, 418, 429, 439, 440, 507–511 carbohydrate digestion inhibitors, 279–294 ephedra, 495–503 diethylpropion, 203, 204 diethylstilbestrol (DES), 37 diet-induced thermogenesis (DIT), 534 dieting, 129 as a risk factor for binge eating, 66 children and, 516, 522 differentiation, 34, 35, 36–37, 38, 47, 52, 53, 156, 180, 181, 187, 328, 387, 388–389, 390, 391, 470 digitalis, 201 diglycerides, 356 dihydrocapsaicin, 329 dihydroxyphenylalanine (DOPA), 73 1,25-dihydroxyvitamin D, 478, 479, 482, 484, 487–488 dinicotinic acid, 340 dinitrophenol, 200–201 dipeptidyl peptidase 4 (DPP-4), 207 disaccharides, 280, 281, 293, 424 disintegrin, 387 dislipidemia, 206, 539 bariatric surgery, and, 538

551

disposition index, 257 of insulin, 535, 536 diuretics, 130, 201, 424 DNA methylation, 115–118 docosahexaenoic acid (DHA), 306, 454, 464–465, 467 dopamine, 71, 73–74, 82, 203, 206, 318, 323 receptors, 73, 74 dorsomedial nucleus of the hypothalamus (DMH), 85, 86, 95 dosing adjustment, for obese patients, 170 drug toxicities, 165–171 dual oxidase, 49 duodenal switch, 532, 538 DUOX, 49 dynorphin, 77 dyslipidemia, 66, 123, 124, 130–131, 132, 143, 145, 178, 179, 180, 182, 188, 189, 207, 386, 391, 463, 531

E eating disorders, 63–69 health effects of, 66–68 leptin, and, 86 medication for, 68–69 prevalence of, 66 eating disorders not otherwise specified, 64–65, 67 effector mechanisms, 105 eicosanoids, 99, 389, 467 eicosapentaenoic acid, 306, 454, 464–465, 467 8-epi-prostaglandin-F2α (8-iso), 125, 126, 129, 130, 131 electrospray ionization (ESI), 353 elephant yam, 435 endocannabinoids, 71, 79, 80 endocrine disruptors, obesity and, 33–38 endogenous glucose output (EGO), 144 endoplasmic reticulum (ER), 51 endorphins, 89, 116 endostatin, 158 endothelial adhesion molecules, 125 endothelial cells, 98, 100, 156, 159, 160, 161 endothelial dysfunction, 49, 50, 52, 96, 97, 98, 144, 391 hypertension, and, 53 endothelial injury, 51, 52, 53, 54, 55, 98 endothelial nitric oxide synthase (eNOS), 49, 50, 52, 53 endothelin-1, 97 endothelin-A (ETA), 97

3802_C042.fm Page 552 Monday, January 29, 2007 3:41 PM

552

Obesity: Epidemiology, Pathophysiology, and Prevention

endothelium-derived relaxing factor (EDRF), 49 endothelium, oxidative stress, and, 52 energetic efficiency, 477 energy balance, 45, 47, 65, 74, 76, 78, 81, 82, 83, 85, 87, 88, 90, 105–112, 157, 223, 233 energy density, 234 energy expenditure, 44–47, 71, 82, 83, 94, 105, 155, 178, 179, 183, 200, 220, 233, 240, 241, 256, 307, 310, 328, 332, 364, 376, 387, 390, 401, 403, 404, 405, 406, 408, 409, 463, 468, 499, 517, 534 fatty acids, and, 459 green tea extract, and, 464 hydroxycitrate, and, 357, 359, 362 medium-chain triacylglycerols, and, 458 resting, 45, 241, 253, 377, 380, 407, 534 total, 241, 534 uncoupling proteins, and, 465 energy homeostasis, 82, 88, 93, 95, 109, 110, 111 cigarette smoking and, 45–46 ghrelin, and, 47 leptin, and, 46 energy intake, 44–47, 234 energy metabolism, 252 energy storage, 44–47 enflurane, 166 enteroglucagon, 207 environmental estrogens, 33–38 enzymes, antioxidant, 128, 132 ephedra, 203, 246, 372, 373, 495–503 adverse events factors affecting, 502–503 reports for, 500–503 alkaloid content variation in, 496–497, 502 caffeine, and, 499, 502 case reports for, 499–501 overuse, 502 pharmacokinetics of, 498 pharmacological action of, 497 sensitivity to, 502 Ephedra sinica, 495, 496, 500 ephedrine, 203, 350, 371, 372, 373, 375, 424, 495–503 botanical vs. synthetic, 498 caffeine, and, 499 half-life of, 498 label claims, 502 pharmacokinetics of, 498

epicatechin, 323, 325, 329, 403 epicatechin gallate, 402, 403, 408 epigallocatechin, 326, 327, 402, 403 epigallocatechin gallate, 326, 327, 328, 329, 402, 403, 404, 405, 407, 408, 409, 464 epigallocatechin-3-gallate (EGCG), 160 epigenetic modifications, of DNA, 34, 35, 37 epinephrine, 73, 241, 242, 250, 251, 328, 330, 377, 401, 403, 404 epitheaflavic acids, 403 ergocalciferol, 533 essential fatty acids, 454, 467 estradiol, 33, 34, 35, 36, 37, 38, 330, 390 cholecystokinin, and, 44 estrogens, 161, 390 adipose tissue, and, 36–37 obesity, and, 33–38 removal of, 35 estrogen receptor, 390–391 estrogen receptor alpha (ERα), 35, 37 estrogen receptor beta (ERβ), 37 estrogen-related receptor α (ERRα), 188 estrogen-related receptor γ (ERRγ), 188 ethanol, 160, 169 ethnicity, obesity and, 8–10, 13, 515 ethylamine, 403 Europe, obesity in, 6–8, 11–12, 23 exenatide, 147, 207 exendin-4, 207 exercise, 129, 219–229 aerobic, 129, 222 for children, 518, 519 gender differences in, 241–242 options, 222–223 prescription, 221–222 weight maintenance, and, 221 extracellular matrix, 53, 54 extracellular signal-regulated kinase (ERK), 117

F FABP aP2 (FABP4), 52 FABPs, see fatty-acid-binding proteins Famoxin, 180 fasting, 65, 85, 110, 132, 240, 256, 257, 258, 270, 340, 362, 425, 535 ghrelin levels, and, 90 fasting plasma glucose (FPG), 141 fat, 44, 246, 306, 307, 309–310 absorption, 413, 415–417, 436 as energy source, 240

3802_C042.fm Page 553 Monday, January 29, 2007 3:41 PM

Index

Atkins diet, and, 315–320 distribution, 45, 240 function of, 453 loss chitosan, and, 417–419 chromium (III) and, 343 mass, plasma leptin concentrations and, 46 monounsaturated, 283, 306, 310 neuropeptide Y, and, 88 obesity, and, 65 oxidation, see fat oxidation partially hydrogenated, 455 physical activity, and, 241 polyunsaturated, 310 satiety, and, 234 saturated, 283, 310, 452, 453 storage, 241 stores, 46 regulation of, 44 subcutaneous, 240, 241, 242, 408, 482 synthesis, 464 table and cooking, 453 unsaturated, 310 utilization, gender differences in, 239–243 visceral, 143, 144, 240, 241, 242, 258, 363, 391, 409, 482, 488, 518 fat oxidation, 250, 309, 362, 363, 366, 367, 401, 405, 406, 407, 409, 534 calcium, and, 479, 483 green tea, and, 464 in white adipose tissue, 472 postprandial, 409 fatty-acid-binding proteins (FABPs), 52 fatty acid synthase, 478 fatty acids, 82, 96, 180, 181, 182, 183, 188, 240, 241, 271, 282, 287, 310, 327, 355, 362, 387, 389, 487; see also free fatty acids categories of, 455 circulating, 535 essential, 454, 467 vs. non-essential, 454–455 fecal volatile, 416 long-chain, 455, 459 marine lipid, 464 medium-chain, 451, 454, 455, 457–458, 459 immune-enhancing properties of, 459–460 milk fat, 385 monounsaturated, 454

553

omega-3, see omega-3 fatty acids omega-6, see omega-6 fatty acids omega-9, see omega-9 fatty acids oxidation of, 387, 389, 459, 478 polyunsaturated, 454, 455 saturated, 283, 310 short-chain, 282, 287, 424, 436 synthesis of, 356 trans, 451, 454, 459, 522 transport of, 478 unsaturated, 455 volatile, 414 fatty liver, 145–146 fecal fat excretion, 414, 415–417, 479–480 fenfluramine, 72, 73, 202, 203, 210 fennel, 428 fermentation by colonic bacteria, 436 of tea, 402 ferrulic acid, 160, 161 fertility, impaired, 116 ferulic acid, 323 fetal basis of adult disease, 35 fetal growth, 35 fetal levels of bisphenol A, 37 fiber, 234, 248, 257, 281, 306, 307, 309, 414, 415, 424, 433, 440, 520; see also glucomannan diabetes, and, 257 supplements, 434 weight reduction, and, 434 fibrosis, 538, 539 fisetin, 160, 161, 328 fish oil, 464–465, 467; see also marine lipids fish-eaters, 300 flavanoids, 327 flavanols, 323, 326, 402, 403 flavanones, 323 flavans, 402 flavocytochrome, 49 flavones, 323, 326 flavonoids, 56, 148, 160, 161, 323, 325, 326, 328, 329, 330, 331, 374, 402, 406 flavonols, 323 fluoxetine, 72, 207, 423 fluvastatin, 131 foam cells, 56, 98 atherosclerotic, 52 macrophage-derived, 54 food choices/preferences, 65–66 Food Guide Pyramid, 248, 315, 350, 519

3802_C042.fm Page 554 Monday, January 29, 2007 3:41 PM

554

Obesity: Epidemiology, Pathophysiology, and Prevention

food intake, 178, 179, 463 adipokines, and, 328 adrenoceptors, and, 74 adrenocorticotropic hormone, and, 79 amphetamine, and, 74 anorexia, and, 65, 66 anti-obesity drugs, and, 74 black tea, and, 403 cannabinoids, and, 79 cholecystokinin, and, 46 cigarette smoking, and, 44 Citrus aurantium, and, 374 compensation effect of, 241 corticotropin-releasing factor, and, 76, 77 cravings, and, 65 dopamine, and, 73 ephedrine, and, 499 epigallocatechin gallate, and, 404 estrogen, and, 35 exendin-4, and, 207 fiber, and, 520 galanin, and, 76 gallic acid, and, 211 gender differences in, 240–241 ghrelin, and, 47, 90, 108, 110, 111, 112 glucagon-like peptide 1, and, 207 glucomannan, and, 435 glycemic index, and, 520 glycemic load, and, 250 HCA, and, 357, 358, 359, 364 histamine, and, 74 histidine, and, 75 insulin, and, 46 leptin, and, 78, 94, 95, 105, 110, 157, 179, 390 long-term regulation of, 463 melanocortin, and, 73, 78, 89, 90 melanocortin-4, and, 116 α-melanocyte-stimulating hormone, and, 76, 78 neuropeptide Y, and, 75, 76, 88 niacin-bound chromium, and, 343 orexins, and, 77 peptide signals, and, 234 proopiomelanocortin (POMC), and, 76, 116 regulation of, 234 regulation of body weight, and, 82 restriction, see caloric restriction SCD1, and, 182 sensory inputs, 82 serotonin, and, 72, 73, 366

sibutramine, and, 74, 205 signaling pathways for the regulation of, 89 thioperamide, and, 75 vs. energy intake, 307 forkhead box protein C2 (FOXC2), 187 formaldehyde, 363, 366 formic acid, 436 FOXC2, 187 free fatty acids, 55, 96, 143, 144, 145, 147, 201, 240, 249, 250, 356, 409, 467, 538, 539 glycemic load, and, 251 hydroxycitrate, and, 358 free radicals, 55, 57, 124, 125, 127, 130, 385 NOS, 49 fructosamine, 254, 255, 438 fructose, 247 fruit juice, 322 fruits, 56, 234 polyphenols from, 321–332 fucoxanthin, 467–470, 472 fucoxanthinol, 470 fumagillin, 158 functional foods, 68, 160, 235, 332, 393, 409, 457 fundus, 536 furosemide, 170

G galanin, 71, 76, 80 gallbladder disease, 66, 82, 220, 233, 322, 350 gallic acid, 211, 326, 329, 403 gallocatechin, 323, 402, 408 gallocatechin gallate, 408 3-galloylquinic acid, 402 gamma-aminobutyric acid (GABA), 75 Garcinia cambogia, 350–353, 358, 360, 361, 362, 366, 424, 427 Garcinia indica, 360 gastric banding, 533, 536, 538, 539 gastric bypass, 207, 510, 536, 537, 538, 539 gastric emptying, 331, 359, 360, 426, 435 gastric inhibitory peptide, 309, 425, 426 gastric inhibitory polypeptide, 282, 284, 286, 287, 288 gastric motility, 282 gastric restriction, 532–534 gastrin, 426 gastrin-releasing peptide, 82 gastrointestinal fat absorption, 413, 415–417 gastroplasty, 108, 532, 536 gender differences, 239–243, 258, 377, 516, 517

3802_C042.fm Page 555 Monday, January 29, 2007 3:41 PM

Index

gene expression, caloric restriction, and, 271 gene regulation, by HCA-SX, 365–366 genes, estrogen-responsive, 33 genistein, 160, 161, 323, 327, 328, 330, 390 genistin, 323 gentamicin, 170 geriatric population, physical activity and, 226 GH-releasing hormone receptor (GHRH-R), 106 ghrelin, 45, 47, 53, 57, 82, 90, 105–112, 148, 209, 308, 309, 318, 536 appetite control, and, 108 central vs. peripheral, 108, 111, 112 food intake, and, 47, 90, 108, 110, 111, 112 gut-derived, 110 levels, regulation of, 109–110 structure of, 106–107 unacylated, 107, 111, 112 ginger, 210, 375 ginkgo, 375 ginseng, 375 glipizide, 273 globesity, 349, 350 glucagon, 36, 74, 82, 249, 250, 251, 284, 344, 362, 426 upregulation of, 308 glucagon-like peptide 1 (GLP-1), 147, 207, 283, 308, 309, 536, 537 glucoamylase, 281, 282 glucocorticoids, 36 glucokinase, 327 glucomannan, 416, 424, 433–440 case study, 438–439 dosage, 437 drug interactions, 437 mechanisms of action, 435–436 pharmacokinetics of, 436 safety of, 436–437 structure of, 435 Glucomannan+®, 438 gluconeogenesis, 143, 188, 317, 327 glucosamine, 414 glucose, 54, 74, 82, 90, 94, 96, 125, 128, 132, 141, 205, 241, 258, 281, 309, 317, 340, 362, 424, 436 absorption, 327, 359 as energy source, 240 caloric restriction, and, 273 control, 520 2-deoxy-D-glucose (2-DG), 273 exercise and, 227 fasting, 207, 521

555

homeostasis, 143, 184, 185, 327, 330, 538 intolerance, 257, 341, 537 metabolism, 45, 47, 178, 184, 535 oxidation, 330, 405, 535 Phase 2®, and, 288, 289 phloridzin, and, 326–327 postprandial levels of, 246, 247, 249–250, 281, 286, 287, 288, 359–360, 425, 426, 427, 446 psyllium, and, 434 sensitivity, 339 tolerance, see glucose tolerance transport, 48 transporter 4 (GLUT4), 37, 535 transporters, 327 uptake, 326–327 glucose-dependent insulinotropic polypeptide (GIP), 536, 537 glucose-dependent insulinotropic polypeptide receptor (GIPR), 537 glucose-6-phosphatase, 327 glucose tolerance, 209, 257, 359, 518, 535, 537 coronary artery bypass surgery, and, 256 dairy, and, 485 factor (GTF), 339, 340–341 impaired, 126, 127, 142, 143, 147, 148, 208, 257, 521 test, 254, 340, 359 glucosides, 330 glucosinolates, 56 glucosuria, 326 glucuronidation, of acetaminophen, 168 GLUT4, 37, 535 glutamine, 87 glutathione (GSH), 54, 127, 130, 132, 166, 171, 340 glutathione peroxidase (GSHPx), 54, 128, 130, 271 glycation, 385 glycemic control, 255, 258, 536 glycemic index, 246–247, 248, 250, 252, 256, 257, 258, 259, 281, 294, 307, 309, 318, 366, 393, 520, 522 alpha-amylase inhibitors, and, 293 lowering of, 282 Phase 2®, and, 289 glycemic load, 245–260, 281, 309, 520 defined, 248 effect on hunger, 250–251 of American diet, 248–249 weight loss, and, 251–254

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556

Obesity: Epidemiology, Pathophysiology, and Prevention

glycerides, 235 glycerol, 96, 235, 240, 362, 453, 478 glycogen, 249, 250, 281, 327, 363, 424 hydroxycitrate, and, 357 stores, depletion of, 317 synthesis, 327 glycogenesis, 249 glycogenogenesis, 207 glycogenolysis, 143 glycolipids, Undaria, 467–469 glycolysis, 250, 273, 327, 366 glycomacropeptide, 235 glycoproteins, 425 glycosides, 323, 326 pregnane, 444 saponin, 444 glycoxidation, 385 gonadotropin-releasing hormone (GnRH), 111 gp91phox, 49 G-protein-coupled receptors, 75, 76, 77, 89, 107, 159 granulocyte-colony-stimulating factor, 84 grapes, 323 grapeseed extract, 328, 375 green tea, see tea: green growth factors, 36, 49, 54, 156, 159, 160, 328 growth hormone, 36, 47, 90, 106, 148, 250, 251, 308 secretion, 107, 111 growth hormone secretagogue receptor (GHS-R), 108, 110, 111, 112 structure of, 106–107 growth hormone secretagogues (GHSs), 106, 108, 110 guar gum, 359, 414, 415, 424, 434, 438, 440 guarana, 331, 376, 377, 407, 439, 497, 498, 499 gymnema, 438 Gymnema sylvestre, 343, 363, 364

H halothane, 166 haptoglobin, 156 HCA-SX, 343, 351–355, 358, 359, 363, 364, 367 gene regulation by, 365–366 heart-valve abnormalities, 202, 204 hemoglobin, 254, 255, 258, 291, 378, 446 hepatic regeneration, 269 hepatic steatosis, 166, 182, 183, 385 hepatitis B vaccinatio, 392 hepatomegaly, 182

herbs, 325–326, 371–372, 497, 499, 501, 502, 510 as obesity drugs, 210–211 HgbA1c, 207 high-carbohydrate vs. high-protein meals, 308 high-density lipoprotein (HDL), 128, 139, 143, 146, 147, 205, 206, 254, 256, 270, 280, 361, 363, 364, 366, 388, 418, 426, 438, 446, 460 bariatric surgery, and, 538 niacin-bound chromium, and, 343 high-fructose corn syrup, 165, 315, 319 high-protein diet, 308 high-sensitivity C-reactive protein (hs-CRP), 255 hippuric acid, 498 Hispanics, glycemic index and, 520 histamine, 71, 74–75, 80 receptors, 75 histidine, 74, 75 L-histidine decarboxylase, 74 histone proteins, 34 homeostasis, 156 energy, 45–47, 82, 88, 93, 95, 109, 110, 111 glucose, 143, 184, 185, 327, 330, 538 lipid, 47 vascular wall, 96–97 homeostasis model assessment (HOMA), 251, 254, 257 hordenine, 373, 377 hormones, 44, 45, 46, 157, 178, 185, 234, 251 adipogenic, 388 adrenocorticotropic, 76, 78 corticotropin-releasing hormone, 76 gastrointestinal, 426 gonadotropin-releasing, 111 growth, 36, 47, 90, 106, 107, 111, 148, 250, 251, 308 insulin-like, 161 luteinizing, 111 melanin-concentrating, 44, 77 melanocyte-stimulating, 76, 78, 79, 89, 90, 116 metabolism, and, 318 parathyroid, 478, 479 sex, 34 suppression of by calcium, 478 thyroid, 36, 44, 185, 200, 201, 467 hormone-sensitive lipase (HSL), 467 human umbilical vein endothelial cells (HUVECs), 97, 157, 160

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Index

hunger caloric restriction, and, 272 glycemic load effect on, 250–251 insatiable, 117 pains, 316 hydrogen breath test (H2BT), 282, 283, 284, 285, 286, 287, 288, 424, 425, 426 hydrogen peroxide, 47, 48, 49, 124, 159, 161 hydrogenated vegetable oils, 384 hydroxy-3-methyl glutaryl CoA (HMGCoA), 329 hydroxybenzoic acid, 323 hydroxycinnamic acid, 323 hydroxycitrate, see (–)-hydroxycitric acid (–)-hydroxycitric acid, 72, 349–367, 377, 427 animal studies of, 355–360 bioavailability of, 353 chemistry, 351–352 clinical studies, 360–364 isolation techniques, 352 NOAEL, 355 pharmacognosy, 351 physicochemical properties, 352 safety of, 354–355 salts, 352–353 hydroxyeicosatrienoic acid (HETE), 467 5-hydroxyindoleacetic acid, 72 11β-hydroxysteroid dehydrogenase-1 (11β-HSD-1), 482 5-hydroxytryptamine (5-HT), 71, 72–73, 80, 205 receptors, 72, 73 5-hydroxytryptophan (5-HTP), 72 hyperactivity, 71, 74 hyperandrogenism, 538 hypercholesterolemia, 52, 128, 131, 418, 438 bariatric surgery, and, 538 hyperglycemia, 51, 123, 124, 126, 127, 130, 132, 158, 209, 250, 327, 328, 385, 536 antioxidant enzymes, and, 128 lipid peroxidation, and, 125 Hypericum perforatum, 331, 375 hyperinsulinemia, 47, 72, 127, 143, 147, 249, 250, 251, 365, 385, 521, 538 hyperleptinemia, 72, 86, 96, 97, 98, 99, 100, 187, 365 hyperlipidemia, 51, 54, 93, 142, 144, 220, 316, 321, 330, 340, 356, 465, 509 hyperlipogenesis, 356 hyperphagia, 65, 66, 68, 72, 73, 75, 78, 85, 86, 90, 117 hyperplasia, 54, 357

557

hypertension, 52, 53, 54, 55, 57, 66, 82, 93, 95, 115, 123, 124, 128, 130, 132, 141, 142, 143, 144, 146, 148, 166, 182, 200, 202, 204, 205, 206, 220, 227, 270, 316, 321, 341, 364, 378, 386, 391, 423, 463, 464, 498, 502, 531, 539; see also blood pressure bariatric surgery, and, 537 calcium, and, 483 lipid peroxidation, and, 125–126 hyperthyroidism, 204 hypertriglyceridemia, 146, 356 bariatric surgery, and, 538 hyperuricemia, 146 hypoadiponectinemia, 142, 144 hypocaloric diets, 129 hypochlorous acid, 124 hypoglycemia, 209, 249, 251, 293, 438 exercise-induced, 227 hypophagia, 73, 77 hypotension, 227 hypothalamic–pituitary axis, 76 hypothalamic–pituitary–adrenal axis, 94, 386 hypothalamus, 44, 45, 53, 72, 73, 74, 76, 77, 78, 81, 83, 84, 86, 87, 88, 89, 90, 95, 99, 105, 106, 107, 108, 110, 184, 201, 206, 234, 390, 444 hypothyroidism, 209 hypotonia, 117 hypovitaminosis D, 534 hypoxia, 157, 159, 160 hypoxia-inducible factor 1 (HIF-1), 157

I ideal body weights, 21 I-kappaB kinase (IκBK), 51 ileal fluids, 283 immunity, impaired, 116 impaired glucose tolerance (IGT), see glucose tolerance: impaired imprinting, 118 incretin mimetics, 147 indoles, 331 inducible nitric oxide synthase (iNOS), 49–50, 392 inflammation, 145, 156–157, 161, 178, 386, 390, 391–392, 393, 487, 539 exercise and, 129 leptin and, 99 obesity and, 43–57 vascular, 148

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558

Obesity: Epidemiology, Pathophysiology, and Prevention

inflammatory cytokines, adipose-derived, 157 inflammatory response, 49, 50, 51, 52, 389 inosine, 364 insulin, 36, 44, 45, 46, 48, 49, 82, 110, 132, 184, 241, 283, 309, 326, 388, 425, 518 adipocytes, and, 47 bisphenol A, and, 37 Brewer’s yeast, and, 340 caloric restriction, and, 273 cancer, and, 161 cholecystokinin, and, 44 chromium (III), and, 340, 341 downregulation of, 308 estradiol, and, 390 fasting, 257, 258 food intake, and, 46 hypersecretion, 209 glycemic load, and, 251, 253 leptin secretion, and, 365 needs, exercise and, 227 postprandial levels of, 247, 249–250, 286, 287, 425, 436 receptor, 341, 535 receptor substrate 1 (IRS1), 184, 327, 390 release of, 44 resistance, see insulin resistance response, 282, 343 to glucose, 249–250, 254 secretion, see insulin secretion sensitivity, see insulin sensitivity insulin resistance, 37, 45, 47, 48, 50, 51, 52, 54, 93, 100, 124, 125, 126, 127, 128, 139, 141, 142, 143, 144–145, 146, 147, 148, 157, 161, 178, 179, 180, 181, 182, 183, 184, 185, 187, 188, 207, 220, 249, 250, 257, 269, 280, 310, 316, 317, 318, 319, 331, 341, 365, 385, 386, 388, 389, 391, 393, 516, 520, 521, 522, 535, 538 antioxidants, and, 127 calcium, and, 365 dairy intake, and, 487 phytoestrogens, and, 330 predictor of in children, 35 insulin secretion, 48, 57, 74, 96, 108, 143, 144, 145, 207, 209, 254, 309, 328, 330, 520, 522, 534, 535–536, 537 glucose-dependent insulinotropic polypeptide receptor, and, 537 glycemic load, and, 251 metabolic inflexibility, and, 534

insulin sensitivity, 96, 143, 144, 145, 157, 158, 178, 181, 183, 184, 208, 252, 254, 257, 273, 308, 309, 327, 332, 339, 340, 341, 388, 424, 518, 520, 521, 522, 535, 536, 537, 539 BPD vs. RYGB, 535 dairy, and, 485 t10c12-CLA, and, 385 insulin-like growth factor, 36, 273 insulin-like growth factor 1 (IGF-1), 57, 308 insulin-like hormones, 161 Interactive Multimedia for Promoting Physical Activity (IMPACT), 517 interleukin 1 (IL-1), 54, 56 interleukin 1β (IL-1β), 47, 156 interleukin 2 (IL-2), 392 interleukin 6 (IL-6), 50, 52, 53, 84, 144, 145, 156, 388, 391, 392 interleukin 8 (IL-8), 56, 156 interleukin 10 (IL-10), 156 International Association for the Study of Obesity (IASO), 16 International Obesity Task Force (IOTF), 7, 11, 12, 15, 16, 17 interscapular brown adipose tissue, 465 intestinal malabsorption, 532–534 intima, 96 intramyocellular lipid (IMCL), 518 inulin, 427 ischemia, 159, 270, 299, 310, 378, 499 3-isobutylmethylxanthine, 388 isoflavones, 323, 330 isoleucine, 482 isorhamnetin, 327 isovitexin, 326

J JAK/STAT pathway, 84, 88, 94, 96 Janus kinase (JAK), 51, 94, 95 Janus kinase 2 (JAK2), 84, 184 Japan, obesity in, 10 jejunoileal bypass, 533 c-Jun N-terminal kinase (JNK), 117, 390, 389

K kaempferol, 160, 161, 323, 326 keratinocytes, 161 ketones, 317 ketosis, 316, 317, 318 kola nut, 497, 499 extract, 378

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Index

konjac, 435, 436 Kreb’s cycle, 327

L lactate, 362 lactic acid, 287 lactone, HCA, 352 lacto-ovo vegetarians, 300, 306 lactovegetarians, 304 lactulose, 283 Lamiaceae, 326 laparoscopic banding, 539 LASIX®, 170 lateral hypothalamus (LH), 85, 86 Latin America, obesity in, 10 lauric acid, 451, 454, 455–457, 458, 459 antimicrobial properties of, 458, 459 laxatives, 201 Lean Source™, 376 Lean System 7™, 376 left ventricular hypertrophy, 98 legumes, 281, 282 LEP gene, 46 leptin, 44, 45, 46, 57, 78, 81, 82, 83–90, 105, 112, 116, 145, 148, 155, 156, 157, 158, 160, 166, 178, 179, 184, 200, 253, 282, 307, 309, 318, 328, 343, 359, 364, 365, 366, 367, 386, 388, 390, 391, 404, 408, 535, 537 action in the brain, 86–87 as a vasoactive adipokine, 93–100 blood pressure, and, 95–96 central effects of, 94–96 -deficient mice, 46 eating disorders, and, 86 food intake, and, 78, 94, 95, 105, 110, 157, 179, 390 gene, mutations in, 116 ghrelin, and, 109–110 HCA, and, 363 inflammation, and, 99 peripheral effects of, 96–99 plasma, 97 proatherogenic effects of, 98 protein, 83–84 recombinant, 116, 179 resistance, 81, 85, 86, 95, 100, 179, 282, 310 obesity, and, 87–88 sensitivity, 183 signaling pathways, 88–90

559

smooth muscle cells, and, 98 sympathoactivation of, 95 transport of into the CNS, 85–86 leptin receptor (Ob-R), 84–85, 87, 94, 116, 157, 179 defects in, 87 gene, 167 gene, mutations in, 116 long form of (Ob-Rb), 85, 86, 88, 89, 94, 96, 97, 98 short form of (Ob-Ra), 85, 94 leptinemia, 385 leucine, 482 leukocyte inhibitory factor, 84 leukotriene B4, 467 life expectancy, decline in, 165 life span, caloric restriction, and, 265–268, 271–272, 273 lignans, 323, 330 lignin, 309 linoleic acid, 235, 376, 454 biohydrogenation of, 385 conjugated, 383–393, 464 high doses of, 509 linolenic acid, 385, 454 lipase, 328, 329, 464 inhibitors, 328, 521 lipid absorption, 328–329, 415–417 homeostasis, 47 malabsorption, 533, 535 metabolism, 45, 52, 156, 157, 328–329, 388, 464, 479, 481, 535 regulation of by calcium, 478 oxidation, 90, 358, 405, 478, 481, 535; see also fat oxidation peroxidation, 48, 49, 53–54, 129, 359, 385 biomarkers of, 125–126 postprandial, 401 peroxides, 55, 132 synthesis, 178, 189, 327, 355, 356, 464 viruses, 458 lipids, 51, 52, 54, 56, 76, 249, 256, 269, 271, 341, 344, 389 dieting, and, 129 glucomannan, and, 437, 438 major classes of, 453–454 marine, 463–472 metabolic inflexibility, and, 534 psyllium, and, 434 Undaria, 467–469

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Obesity: Epidemiology, Pathophysiology, and Prevention

Lipodex-2™, 360 lipodystrophy, 179 lipofuscin, 125 lipogenesis, 35, 36, 96, 148, 249, 328, 355, 356, 357, 359, 389, 390, 424, 458, 481, 483 α-lipoic acid, 127, 130 lipolysis, 74, 96, 148, 188, 203, 211, 240, 242, 249, 250, 328, 330, 364, 371, 379, 387, 390, 403, 404, 405, 464, 467, 478, 479, 481, 483 lipopolysaccharide (LPS), 50, 392 lipoprotein, 464 lipoprotein lipase, 538 activity, 37 lipoprotein(a), 460 liver, 184 disease, 166 nonalcoholic fatty, 141, 145, 515, 531, 538–539 nonalcoholic steatohepatitis, 117, 142, 166, 538–539 fatty, 145–146 steatosis, 166, 182, 183, 385 long-chain fatty acids, 455, 459 long-chain triacylglycerols, 458 long-chain triglycerides, 235 loop diuretic furosemide (LASIX®), 170 lorazepam, 166 lovastatin, 131 low-carbohydrate diet, 246, 281; see also Atkins diet low-density lipoprotein (LDL), 22, 52, 53, 54, 55, 56, 128, 130, 131, 143, 158, 205, 254, 256, 270, 292, 329, 330, 385, 418, 426, 438, 446, 460, 519 bariatric surgery, and, 538 chromium (III), and, 341 exercise, and, 129 HCA, and, 361, 363, 364, 366 niacin-bound chromium, and, 343 oxidation, 126, 391, 408, 460 receptor-related protein 2, 366 low fat consumption, 309, 316, 319, 455 low-glycemic-load diet, 245–260 components of, 260 physiological effects of, 249–250 luteinizing hormone (LH), 111 luteolin, 160, 161 lycopene, 56–57, 129 lypogenesis, 90 L-lysine, 428

M Ma huang, 331, 495, 496, 499 macrophage inflammatory protein 2, 47 macrophages, 45, 46, 49, 50, 52, 53, 54, 55, 56, 98, 178, 386, 392 in adipose tissue, 51 malabsorption, of lipids, 533, 535 malondialdehyde (MDA), 53, 125, 129, 130, 363, 366 malonyl-CoA, 535, 538, 445 maltase, 281 maltose, 282, 424 malvidin, 323 mammalian target of rapamycin (mTOR), 482 mannose, 436 marine lipids, 463–472 mast cells, 74 mastocytes, 386 matrix metalloproteinase (MMP), 52, 158, 387 mead acid, 454 media, 96 Mediterranean diet, 306 Mediterranean islands, obesity rates in, 11 medium-chain fatty acids, 235, 451, 454, 455, 457–458, 459 immune-enhancing properties of, 459–460 medium-chain triacylglycerols, 458, 464 medium-chain triglycerides, 235, 362, 477 melanin-concentrating hormone (MCH), 44, 77 melanin-concentrating hormone receptor-1 gene, 117 melanocortin, 71, 78–79, 80, 82, 89–90, 116, 148 receptors, 78, 89 melanocortin-4 gene mutations in, 116 receptor (MC4R), 116, 166 melanocyte-stimulating hormone (MSH), 116 α-MSH, 76, 78, 79, 89, 90 β-MSH, 78, 89 γ-MSH, 78, 89 membrane-associated rapid response to steroid (MARRS), 478 menopause, 35 metabolic efficiency, 534 metabolic inflexibility, 534–535 metabolic rate, 158, 178, 182, 184, 185, 187, 188, 189, 221, 242, 307, 330, 343, 344, 365, 366, 375, 376, 401, 406, 409, 424, 464, 465, 466 basal, 241, 242

3802_C042.fm Page 561 Monday, January 29, 2007 3:41 PM

Index

dinitrophenol, and, 201 gender differences in, 240 leptin, and, 179 metabolic risk factors, pharmacotherapy for, 146–147 metabolic syndrome, 35, 48, 50, 54, 56, 93, 123–132, 142, 143, 144, 147, 156, 157, 158, 182, 206, 220, 316, 321, 322, 339, 341–344, 386, 388, 391, 393, 482, 509, 515 adinopectin, and, 145 antioxidant defense mechanisms, and, 127–128 biomarkers of oxidative stress, and, 128–132 pharmacotherapy of, 130–132 prevalence of, 124 metabolism, 46–47, 93–100 metacresol, 208 metenkephalin, 106 metformin, 147, 208, 273, 293 use by adolescents, 521 methamphetamine, 201 methoxyflurane, 166 methylation, 115–118, 328 methyl-binding protein 2 (MeCP2), 118 3,4-methylene dioxy methamphetamine (MDMA), 466 N-methylephedrine, 496 N-methylpseudoephedrine, 496 N-methyltyramine, 373, 377 methylxanthine, 203, 375, 378, 402, 404, 405, 409 metronidazole, 282 Micronesia, obesity in, 10 microsomal ethanol-oxidizing system, 169 milk fat, 384 mimetics, caloric restriction, 268, 273–274 mitochondrial dysfunction, 389 mitochondriogenesis, 181, 187, 188 mitogen-activated protein kinases (MAPKs), 117, 328 mitogens, 156 MONICA study, 23 monoacylglycerol acyltransferase (MGAT), 310 monoamine oxidase inhibitor (MAOI), 204, 205, 206, 207, 378, 498, 502 monobutyrin, 156 monocaprin, antiviral action of, 458 monocyte chemotactic protein 1 (MCP1), 47, 49, 98 monocytes, 53, 56, 98

561

monoglycerides, 457, 458, 459 monolaurin, 458, 459, 460 antiviral action of, 458, 459 monosaccharides, 280, 281, 424 monosaturated fat, 522 monounsaturated fat, 283 monounsaturated fatty acids, 182, 454, 455 morbid obesity, 165, 226, 240, 349, 532, 536, 537, 538, 539 morbidity drug-related, 166 obesity-related, 14, 25, 43, 51, 165, 168, 220, 488, 531 smoking-related, 48 type 2 diabetes and, 142 morin, 327 morning anorexia, 68 mortality drug-related, 166 obesity-related, 5, 14, 21, 25–26, 51, 165, 220 reductions in, 15 smoking-related, 48 type 2 diabetes and, 142 motilin, 106, 426 motilin-related peptide (MTLRP), 106 mouse models, 166 multimedia health promotion, 516 muraglitazar, 182 mutations, in leptin receptor gene, 87 myocardial infarction, 54, 377 myricetin, 323, 327

N NAD(P)H oxidase, 49, 50, 53, 54 NADPH oxidase (NOX), 49, 159, 391, 488 naringenin, 327, 328 National Center for Health Statistics (NCHS), 25 Native Americans, obesity and, 9, 13 natural killer (NK), 99 neoplasms, 268 neosynephrine, 379 neovascularization, 98, 158, 160 nerve growth factor (NGF), 391 neurobiology, of obesity, 81–90 neuroleptic malignant syndrome, 207 neuronal nitric oxide synthase (nNOS), 49 neuropeptide Y, 44, 46, 57, 71, 73, 75–76, 78, 80, 82, 86, 88, 90, 108, 148, 365, 367 receptors, 75–76, 77

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562

Obesity: Epidemiology, Pathophysiology, and Prevention

neuropeptides, 75–79, 86, 89, 105, 108, 112, 116, 366, 404 orexigenic, 44, 45 neuropilin-1, 158 neurotensin, 426 neurotransmitters, 71–80, 82, 83, 86, 155, 318 neurotrophins, 386, 391 neutrophils, 45, 49 New Zealand Obese mouse (NZO/HlLt), 148 niacin-bound chromium, 341, 343, 344, 345, 363 nicotinamide adenine dinucleotide phosphate (NADP+), 364 nicotine, 44, 45, 55 food intake, and, 44 nicotinic acid, 340, 341, 345 night eating syndrome, 64, 65, 68, 209 nitric oxide, 45, 50, 52, 96, 97, 98, 99, 100 nitric oxide synthase (NOS), 49–50, 51, 159 nitrite, plasma, 50 nitrogen-bound chromium, 364 nitrolinoleic acid, 392 nitrosative stress, 52–55 nitrotyrosine, 126 nonalcoholic fatty liver disease, 141, 145, 515, 531, 538–539 nonalcoholic steatohepatitis, 117, 142, 166, 538–539 nonesterified fatty acids (NEFAs), 404, 487 non-exercise activity thermogenesis (NEAT), 534 non-insulin-dependent diabetes mellitus (NIDDM), 5, 14; see also type 2 diabetes no-observed adverse effect level (NOAEL), 355 noradrenaline, 201, 202, 203, 205, 404, 464, 467 nordexfenfluramine, 202 norephedrine, 496, 498 norepinephrine, 46, 71, 73, 74, 75, 80, 82, 97, 201, 206, 241, 242, 330, 401, 403, 404, 405, 497 norfenfluramine, 73 norpseudoephedrine, 496 NOX, 49, 159, 391, 488 NT, 210 nuclear factor kappa-B (NF-κB), 51, 161, 391, 392 nuclear factor of activated T (NFAT), 388 nuclear receptors, 52 nuclear transcription factor, 470

nuclear vitamin D receptor (nVDR), 478 nutrient partitioning, 155 nutrigenomics, 332 nutrition transition, 3 nutritional supplements, 509 nuts, 325–326

O ob gene, 81, 83, 84, 85, 157 obese mice, 48, 49, 50, 78, 81, 94, 95, 116, 117, 148, 184 obesity adinopectin, and, 47 age, and, 27 animal models of, 166 carbohydrates, and, 65, 316 cardiovascular disease, and, 52–55 central, 5, 10 chemical toxicities, and, 165–171 cigarette smoking, and, 43–57 comorbidities, 141 costs of, 5, 15, 115, 165, 200 defined, 3, 12, 13, 140, 245, 386, 423 DNA methylation, and, 115–118 drug toxicities, and, 165–171 drugs, safety of, 199–212 early-onset, 116 eating disorders, and, 63–69 endocrine disruption, and, 33–38 energy expenditure, and, 46–47 environmental estrogens, and, 33–38 epidemiology of, 3–17, 21–27 epigenetic mechanisms, and, 35 ethnicity, and, 8–10, 13 factors contributing to, 233 genetic component of, 83 genetics vs. environment, 167 health consequences of, 14 (–)-hydroxycitric acid, and, 349–367 impact on type 2 diabetes, 142 -induced oxidative stress, 487–488 inflammation, and, 50–51 initiatives to combat, 220–221 iNOS, and, 49–50 leptin resistance, and, 87–88 lipid peroxidation, and, 125 marine lipids, and, 463–472 melanocortin-4 receptor, and, 116 metabolism, and, 46–47 molecular genetics of, 116–117 morbid, 165, 166

3802_C042.fm Page 563 Monday, January 29, 2007 3:41 PM

Index

neurobiology of, 81–90 pharmacotherapy for, 146–147 phytochemicals, and, 55–57 polyphenols, and, 321–332 prevalence of, 3, 5–14, 21, 22–25, 115, 140, 155, 219, 233, 239, 349, 423 in children/adolescents, 11–14 race, and, 8–10, 13 regulation, by neurotransmitters, 71–80 sex, and, 27 thrombotic events, and, 54–55 treatment, adipose drug targets for, 177–189 type 2 diabetes, and, 139–149 vegetarian diets, and, 299–311 visceral, 5 obsessive–compulsive disorder, 67, 68 obstructive sleep apnea, 141; see also sleep apnea octopamine, 372, 373, 377, 378 octreotide, 209 oil palm, 457 oleic acid, 182, 454 Olibra™, 235 oligosaccharides, 281 olive oil, 283 omega-3 fatty acids, 148, 249, 306, 310, 451, 454 omega-6 fatty acids, 149, 451, 454 omega-9 fatty acids, 454 omnivores, 300 oolong tea, see tea: oolong oolonghomobisflavans, 403 oolongtheanin, 403 OptiBerry, 160–161 orexigens, 108, 110 orexin, 71, 80, 82, 108 organizational effects, of sex hormones, 34 organogenesis, 35 organotin compounds, 37–38 orlistat, 129, 146–147, 148, 200, 205–206, 211, 328, 380, 416, 423, 480, 534 use by adolescents, 521 Ornish, 316 orocecal transit time, 283 osteoarthritis, 66, 227, 233, 245, 322 osteopontin, 117 osteoporosis, 115, 330, 331, 365, 390 overfed rat model, 166, 167–168, 169, 170 overweight defined, 12, 13, 21, 140, 423 prevalence of, 515

563

oxedrine, 371 oxidants, 159–160 cigarette-smoke-derived, 45 oxidation carbohydrate, 250, 362, 363, 464, 479 red pepper and, 330 fat, see fat oxidation fatty acid, 387, 389, 478 glucose, 330, 405, 535 lipid, 90, 358, 405, 478, 481, 535 low-density lipoprotein, 126, 391, 408, 460 products, increases in, 125–126 protein, 131, 271, 464, 479 oxidative damage, 270–271 oxidative stress, 45, 46, 52–55, 56, 100, 123–132, 159, 327, 331, 391–392 biomarkers, changes in, 128–132 cigarette smoking, and, 47–51 dietary calcium, and, 487–488 exercise, and, 129 pharmacotherapy of, 130–132 oxidized low-density lipoproteins (ox-LDLs), 52, 54, 56, 126 oxygen radicals, 99

P p22phox, 49, 50 palm kernel oil, 454, 455–458 palmitic acid, 454 pancreas, 282 pancreatic β-cells, 48, 49 pancreatic islets, Ob-Rb in, 96 paraoxonase (PON), 131 paraoxonase-1 (PON-1), 128 parasympathetic nervous system, 44, 329 parathyroid hormone, 478, 479 paraventricular nucleus (PVN), 75, 76, 78, 85, 86, 117 partially hydrogenated fat, 455 partially purified white bean products, 286–287, 289 pears, 322 pectin, 414, 416, 424 pelargonidin, 323 peonidin, 323 peptide signals, 234 peptide YY, 426 peptides, 155 peripheral vascular disease, 53 smoking, and, 55 peroxisome proliferation, 182

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564

Obesity: Epidemiology, Pathophysiology, and Prevention

peroxisome proliferator-activated receptor (PPAR), 180–182, 188–189, 388, 389–390, 464 peroxisome proliferator-activated receptor α (PPARα), 182, 188–189, 389–390 peroxisome proliferator-activated receptor β (PPARβ), 389–390 peroxisome proliferator-activated receptor δ (PPARδ), 181–182, 189, 389–390 peroxisome proliferator-activated receptor γ (PPARγ), 36, 38, 47, 52, 145, 180–181, 182, 187, 189, 328, 366, 387, 389–390, 392, 467, 470 coactivator-1α (PGC-1α), 187 peroxisome proliferator-activated receptor γ2 (PPARγ2), mutations in, 116 peroxisomes, 389 peroxynitrite, 45, 53, 98, 124, 126 petunidin, 323 PGC-1α, 187–188 phagocytes, 49 Phase 2®, 288–293, 426–429 Phaseolamin 2250®, 285 Phaseolus vulgaris, 282 α-amylase inhibition, and, 423–429 phendimetrazine, 203, 204 phenethylamine, 204 phenolic acids, 323, 325, 326, 329, 331 phentermine, 74, 202, 203, 204–205 phenylephrine, 373, 379 phenylethanolamine, 373 phenylethylamine, 371, 373, 374, 375, 376, 378 phenylpropanolamine, 202–203, 350, 373, 498 phloretin, 327 phloridzin, 326–327 phosphodiesterase, 404 phosphoinositide 3-kinase (PI3K), 327 phosphoinositol 3-kinase-dependent pathways, 94 phospholipids, 356, 453, 460, 464 phosphorylation, 467 physical activity, 36, 219–229, 366, 463, 534 IMPACT, and, 517 of children, 517–519, 522 Physical Activity for Total Health (PATH), 519 physical education, 225–226, 516, 517 physical inactivity, obesity and, 27, 65, 220 phytoalexin, 160 phytochemicals, 54, 55–57, 66, 68, 311 phytoestrogens, 330, 390 phytopharmaceuticals, 68, 350

picolinic acid, 345 pioglitazone, 181, 182, 467 piperine, 376 pituitary dysfunction, 116 placental blood flow, restriction of, 35 placental growth factor (PGF), 392 Planet Health, 516 plantago, 330, 434 plantain, 330 plaques, 52, 53, 54–55, 98, 99, 339 plasminogen activator inhibitor, 255 plasminogen activator inhibitor 1 (PAI-1), 156 platelet aggregation, smokers and, 55 platelet-derived endothelial cell growth factor, 156 platelet-derived growth factor (PDGF), 54 plum juice, 145 polycarbonate plastic, 37 polycystic ovary syndrome (PCOS), 117, 141, 144, 208, 515, 521, 531, 538, 539 polymerase chain reaction (PCR), 118 real-time, 159, 390 polymerized polyphenols, 403, 407 Polynesia, obesity in, 10 polypeptide N, 118 polypeptides, 288 polyphenol oxidases, 401, 402 polyphenolic compounds, in tea, 402 polyphenols, 160, 161, 273, 311, 321–332, 460 mechanisms of action, 326–330 plant, 323–324 polysaccharides, 281, 324, 424 polyunsaturated fat, 522 polyunsaturated fatty acids, 56, 306, 310, 454, 455, 464, 465, 467 polyvinylchloride (PVC), 37 potassium, 364–365, 367 potatoes, 247, 252, 281, 285, 323 PPARγ coactivator-1α (PGC-1α), 389 Prader–Willi syndrome (PWS), 117–118, 209 pramlintide, 208 preadipocytes, 36, 37, 52, 156, 158, 327, 328, 387, 388–389, 391 pre-B-cell colony-enhancing factor (PBEF), 145 Precose™, 293 pregnane glycosides, 444 preproghrelin, 106 preproorexin, 77 primary dermal irritation index (PDII), 354 primary pulmonary hypertension, 202, 204, 205 proanthocyanidins, 324, 402, 403

3802_C042.fm Page 565 Monday, January 29, 2007 3:41 PM

Index

procyanidins, 324, 327 prohormone convertase 1, 116 proopiomelanocortin (POMC), 76, 77, 78, 83, 86, 89, 108, 116, 166 propionic acid, 436 prostacyclin, 55 prostaglandin D synthase, 366 prostaglandin E2 (PGE2), 392 prostaglandins, 454, 467 protein, 246, 247, 271, 306, 307, 308; see also Atkins diet absorption, 436 conversion to glucose, 317 metabolism, 482 oxidation, 131, 271, 464, 479 pork vs. soy, 308 satisfaction, and, 316 whey, 481 protein kinase, 467 protein kinase C, 50, 132 protein tyrosine phosphatase 1B (PTP1B), 95, 179, 184–185, 189 pseudoephedrine, 496, 497, 498 psyllium, 414, 416, 424, 434, 438, 440, 520 Pu-Erh black tea, 403 purging, 64, 65 pyrrolidine dithiocarbamate, 160 pyruvate dehydrogenase kinase (PDK4), 535

Q quantitative trait loci (QTL), 148, 187 quercetin, 160, 161, 323, 326, 327, 328, 329 quercetin glycosides, 326

R race, obesity and, 8–10, 13, 515 radioprotective effect, of Citrus aurantium, 374 rainbow pills, 201 rat models, 166, 167–168 reactive nitrogen species (RNS), 47 reactive oxygen species (ROS), 45, 47, 48, 49, 51, 53–54, 98, 159–160, 270–271, 391, 487 Recommended Dietary Allowances (RDA), 508, 510 recruitment, 186 red pepper, 329, 330 red sage root, 210 redox-based therapeutics, 155–161 redox ratio, 127 redox recycling, 45

565

regulation, of body weight, 82–83 repaglinide, 130 reserpine, 200, 211 resistance training, 225 among children, 518–519 resistin, 45, 145, 392, 393 restenosis, 97, 98 resting energy expenditure (REE), 45, 241, 253, 377, 380, 407, 534 resveratrol, 160, 161, 273, 329 retina, of diabetics, 160 retinoic acid receptor (RAR), 390–391, 467 retinoic X receptor (RXR), 38, 180, 391, 467 retinoids, 467, 470 rhamnetin, 327 rhubarb, 210 rimonabant, 79, 147, 200, 206 rosiglitazone, 181, 182, 273 rosmarinic acid, 326 Roux-En-Y gastric bypass (RYGB), 531–539 rumenic acid, 384 rupture, 54–55, 99 rutin, 160, 161

S safety, of obesity drugs, 199–212 salicylic acid, 323 Salix matsudana, 330 saponin glycosides, 444 satiation, 250, 366, 520 Satietrol®, 235 satiety, 71, 73, 77, 82, 94, 147, 148, 205, 207, 234–235, 249, 250, 251, 259, 282, 307, 308, 309, 310, 322, 332, 363, 366, 390, 434, 435, 437, 440, 480, 520 index, 250 leucine, and, 482 Satíse®, 235 saturated fat, 283, 452, 453, 522 saturated fatty acids, 454, 455 Scd1 gene, 182, 183 seaweed, 467–469 sedentary lifestyles, 27 seeds, 325–326 selective estrogen receptor modulators (SERMs), 33 selective peroxisome proliferator-activated receptor modulators (SPPARMs), 181, 182 selective serotonin reuptake inhibitors (SSRIs), 68, 72, 205, 207

3802_C042.fm Page 566 Monday, January 29, 2007 3:41 PM

566

Obesity: Epidemiology, Pathophysiology, and Prevention

semivegetarians, 304 sennosides, 211 serotonin, 71, 72–73, 74, 82, 202, 205, 318, 323, 343, 359, 363, 364, 365, 366, 367 serotonin receptor reuptake inhibitors (SRRIs), 365, 366 sertraline, 207 serum amyloid A, 156 Seventh-Day Adventist vegetarians, 300, 308, 309 Seville orange juice, 378 sex, obesity and, 27 shear stress, 49, 52, 97, 159 short-chain fatty acids, 282, 287, 424, 436 sibutramine, 74, 146, 147, 200, 205, 206, 423, 534 use by adolescents, 521 signal transducers and activators of transcription (STATs), 94 signal transduction, 389–390 pathway, 85 signaling molecules, 46–47 simvastatin, 131 single nucleotide polymorphisms (SNPs), 117 sleep apnea, 141, 142, 220, 322, 423, 521, 531 sleep disturbances, 66 sleeve gastrectomy, 539 Slimaluma™, 444 small intestine, manipulation of, 536 small-molecule adiponectin mimetics, 180 small-molecule antioxidants, 127 sodium, 327 sodium-dependant glucose transporters, 327 Solanaceae, 330 Solanum lycocarpum St. Hill, 330 soluble thrombomodulin (sTM), 96 somatostatin, 209 soy, 323, 330 isoflavone extract, 273 protein, 330 SPARK, 517 St. John’s wort, 68, 331, 375, 497 starch blockers, 279–294 starches, 281, 424 digestion of, 424, 425 malabsorption of, 283 Starchex, 285 starvation, 63, 239 statins, 131 stearic acid, 454 ∆9 stearoyl-CoA desaturase, 385, 388

stearoyl-CoA desaturase 1 (SCD1), 182–183, 189 steatohepatitis, nonalcoholic, 117, 142, 166, 538–539 steatosis, 166, 182, 183, 385 stem cells, 268–269 steroids, 453 sterol regulatory element-binding protein (SREBP), 388, 390 1c (SREBP-1c), 96, 538 sterols, 470 stilbene, 323, 329 stomach motility, 282 stool tests, for carbohydrate malabsorption, 284 stress-response genes, 51 stroke, 53, 54, 66, 220, 258, 259, 321, 364, 378, 423, 499, 500 subcutaneous tissue, 240, 241, 242, 408, 482 sucrose, 247, 286 sugar intake, among Latino children, 520 sulfate iron, 533 sulfation, of acetaminophen, 168 sulfonylurea, 208 medications, glucomannan, and, 437 sulfonylureas, 293 Super CitriMax®, 352, 358 superoxide anion, 45, 49, 50, 51, 159 superoxide dismutase (SOD), 54, 128, 130, 271 suppressor of cytokine signaling 3 (SOCS-3), 88, 95 sympathetic nervous system, 44, 53, 74, 97, 178, 185, 329, 401, 405, 467 sympathoactivation, of leptin, 95 syncope, exercise-induced, 378 syndrome X, 123, 144, 316, 364, 366, 386, 509 synephrine, 371, 372, 374, 376, 377, 378, 379, 380, 499 content in fruit, 372 isomers of, 373 LD50 for, 372 systolic blood pressure, see blood pressure: systolic

T tamarind, 350 tannic acid, 470 tannins, 323, 324, 325, 328, 330, 331 tar, in cigarette smoke, 45 tea, 235, 328, 329, 401–409, 439 black, 401, 402, 403 L-theanine content of, 403

3802_C042.fm Page 567 Monday, January 29, 2007 3:41 PM

Index

composition of, 402–403 green, 56, 68, 160, 235, 326, 327, 329, 361, 375, 376, 377, 401, 402, 403, 405, 406, 407, 408, 409, 464, 477 catechins, 160, 464 powder, 403, 404, 405 oolong, 235, 328, 329, 401, 402, 403, 406, 407, 408, 409 catechins, 403 television, obesity and, 220, 225, 516, 522 tendamistat, 287 testosterone, 38 tetrahydrobiopterin, 50 ∆9-tetrahydrocannabinol (THC), 79, 206 thalidomide, 158 The Zone, 316 theaflavins, 235, 403 L-theanine, 403 theanine, 329, 404 thearubigins, 235, 403 theasinensins, 403 theobromine, 402 theogallin, 402 theophylline, 402, 404 therapeutics, angiogenesis-targeted, redoxbased, 155–161 TheraSlim™, 292 thermogenesis, 71, 74, 77, 83, 147, 157, 182, 185, 187, 205, 235, 308, 329, 364, 371, 372, 374, 377, 380, 401, 404, 405, 406, 409, 458, 465, 466, 467, 472, 478, 483, 534 diet-induced, 407, 467 thiazide, 200 diuretics, 130, 211 thiazolidinediones (TZDs), 130, 181, 182, 521 thiobarbituric acid reactive substances (TBARS), 125, 130, 131 thioperamide, 75 thioredoxin reductase, 271 thioridazine, 207 3T3-L1 cells, 49, 327, 328, 387, 388, 389, 390, 405, 470, 37, 391 thrombosis, 55 thrombotic events, 54–55 thromboxane A2, 55 thrombus formation, 99 thyroid hormone, 36, 44, 185, 200, 201, 467 thyroid hormone receptor β (TRβ), 185 thyroxine, 200 tissue regeneration, 268–269

567

TNP-470, 158 α-tocopherol, 53, 127, 129, 131, 271 α-tocopherol quinone, 53 tocopherols, 129 tofu, 308 Tonga, obesity in, 11 topiramate, 209–210 torula yeast, 340 Traffic Light Diet, 519 transcription factors, 49, 187 transcriptome, 366 trans-fatty acids, 451, 454, 459, 522 transferrin, 341 transforming growth factor β (TGF-β), 54, 156 triacylglycerol, 235, 283, 340, 358, 363, 409, 458, 464 accumulation, 37 tea, and, 403 tributyltin, obesity and, 37–38 tricyclic antidepressants, 207 triglycerides, 44, 45, 47, 54, 90, 139, 143, 144, 146, 147, 178, 182, 183, 189, 205, 206, 235, 240, 254, 255, 256, 270, 280, 281, 282, 316, 341, 343, 356, 357, 360, 361, 363, 364, 366, 385, 387, 388, 390, 392, 407, 415, 416, 417, 426, 428, 446, 478, 509, 518, 519, 538, 539 medium-chain, 451–460 white bean extract, and, 428 trisaccharides, 293 troglitazone, 130, 182 trypsin, 425 tryptophan, 72 tryptophan hydroxylase, 72 tumor necrosis factor α (TNFα), 47, 50, 51, 52, 53, 54, 55, 56, 144, 145, 156, 161, 387, 388, 391, 392 tunica adventitia, 96 turmeric, 56, 161, 210 type 2 diabetes, 10, 11, 21, 22, 35, 45, 47, 50, 54, 66, 97, 115, 117, 126, 130, 131, 132, 139–149, 178, 179, 180, 182, 184, 185, 188, 207, 208, 220, 233, 245, 246, 254, 269, 286, 331, 341, 349, 350, 386, 438, 463, 472, 520, 522, 538 bariatric surgery, and, 535 diagnostic criteria for, 141 glycemic load, and, 256–258 impact of childhood obesity on, 142

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568

Obesity: Epidemiology, Pathophysiology, and Prevention

type 2 diabetes (cont.) impact of obesity on, 142 in children, 515, 521 metformin, and, 521 prevalence of, 140, 141, 280 prevention of with weight reduction, 147–148 resistance training, and, 518 the gut, and, 536–537 trends in, 141 tyramine, 323, 372, 373, 377, 378 tyrosine, 73, 84, 378 tyrosine hydroxylase, 73 tyrosine kinase, 144, 157, 327, 328, 341 tyrosine kinase inhibitors, 327 tyrosine phosphorylation, 84, 538

U ubiquinol, 127 ubisemiquinone, 51 Ucn-I/II, 77 uncoupling protein 1 (UCP1), 181, 185, 186–187, 464, 465–467, 468, 469, 472 uncoupling protein 2 (UCP2), 478, 479, 488, 535 uncoupling protein 3 (UCP3), 535 uncoupling proteins, 389, 465–467, 535 Undaria pinnatifida, 467–470 United Kingdom, obesity rates in, 8, 11–12 United States, obesity rates in, 8–10, 13 unpurified white bean products, 284 upregulation of adhesion proteins, 47 of mRNA expression of NADPH, 49 uric acid, 127 urine tests, for carbohydrate malabsorption, 284 urocortin, 76

V vaccenic acid, 385 vagal nerve, ghrelin and, 108 valine, 482 valvulopathy, 205 vanadium, 509 vanadyl sulfate, 509 vascular cell adhesion molecule 1 (VCAM-1), 96 vascular dysfunction, 55 vascular endothelial growth factor (VEGF), 156, 157, 158, 159, 160, 161 vascular injury, 55

vascular smooth muscle cell (VSMC), 53, 54 vascular tone, 97, 99 vascular wall homeostasis, 96–97 vascular wall remodeling, 97–99 vascularization, 157, 158, 160, 161 vasculature, 93–100 vasoconstriction, 50, 52, 55, 95 vasodilation, 50, 52, 97 vasopressin, 55 vegans, 299, 300, 304, 306, 308, 309, 310 vegetable diets, 299–311 vs. non-vegetarian diets, 306 vegetable oils, 465 vegetables, 234 consumption of, 56 polyphenols from, 321–332 ventricular function, 270 ventromedial nucleus of the hypothalamus (VMH), 85, 86, 95 vertical banded gastroplasty, 531, 532 very-low-density lipoprotein (VLDL), 144, 460 viruses, monolaurin, and, 459 visceral fat, 143, 144, 240, 241, 242, 258, 363, 391, 409, 482, 488, 518 resistance training, and, 518 visceral obesity, 5, 43, 53, 141, 143, 144 visfatin, 145 vitamin C, 131, 160 vitamin D, 478 vitamin E, 53, 127, 130, 131–132, 148, 160, 206 vitamins, antioxidant, 127 vitexin, 326 vomiting, self-induced, 64

W waist circumference, 5, 10, 22, 43, 125, 126, 129, 141, 143, 147, 220, 252, 257, 291, 300, 301, 304, 306, 361, 406, 408, 427, 428, 446, 516 waist-to-hip ratio, 22, 43, 96, 125, 141, 304, 363 walking, 222 water content of foods, 234 weight cycling, 242 weight loss approaches to, 350, 423–424 chromium (III), and, 341–344 dietary supplements, and, 507–511 glucomannan, and, 433–440 glycemic load, and, 251–254 supplements, sale of, 434

3802_C042.fm Page 569 Monday, January 29, 2007 3:41 PM

Index

weight loss, benefits of, 14–15, 25, 146, 220 weight management, 316, 318, 321–332, 350, 366, 423 calcium, and, 477–488 Caralluma fimbriata, and, 443–448 childhood, 515–516 chitosan, and, 419 Citrus aurantium, and, 371–381 dietary supplements, and, 507–511 energy ratios, and, 317 HCA-SX, and, 364–365 medium-chain triglycerides, and, 451–460 nutritional/dietary approaches to, 233–236 physical activity, and, 219–229 tea, and, 401–409 Weight Watchers, 316 weight-to-height ratio, 4 Western Samoa, 3 wheat-based amylase inhibitor (WAI), 287, 288 whey, 481, 482 white adipose tissue (WAT), 49, 97, 105, 156–157, 180, 183, 185, 187, 206, 269, 328, 386, 387, 390, 391, 465, 467, 468–469, 470, 472, 482

569

white bean extract, 425–429 white kidney bean, 282, 283, 284, 285, 286, 288, 425 wine, 273, 327, 329, 331, 340 World Health Organization (WHO), 3, 16, 21, 23, 123, 140, 220, 247, 321, 331, 349, 413, 497, 515 standards of obesity, 4, 10, 21

X Xenadrine EFX™, 375, 378, 379 XENICAL®, 328, 380

Y yerba maté, 331, 375, 376 YGD, 331

Z Zhi shi, 371, 372 Zone, The, 316 zonisamide, 210 Zucker rat model, 166, 167–168

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