Abdominal Obesity and the Endocannabinoid System - J. Despres, V. Di Marzo (Informa, 2009) WW

282 Pages·2009·4.4 MB·English

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about the book…

This internationally renowned author team provides a unique and thorough analysis and
distillation of the endocannabinoid system and its relationship to abdominal obesity, diabetes,
and cardiovascular disease. The endocannabinoid system (ECS) plays an important role in
cardiometabolic risk, as well as modulating energy balance, feeding behavior, hepatic
lipogenesis, and perhaps glucose homeostasis. Evidence suggests that the ECS is overactive
in human obesity and dyslipidemia.

Critical to the management of cardiometabolic risk, this new, timely book provides practical
overviews and management guidance on many important topics, including:
• abdominal obesity and the metabolic syndrome
• the endocannabinoid system and energy balance: functions and dysfunctions
• abdominal obesity, the EC system, and cardiometabolic risk

about the editors...

JEAN-PIERRE DESPRÉS is Professor at the Division of Kinesiology of the Department of Social
and Preventive Medicine at Université Laval, Québec, Canada. He received his Ph.D. in Exercise
Physiology from Université Laval and then pursued a post-doctoral training at the Department
of Medicine of the University of Toronto. Dr. Després is Director of Research at the Québec
Heart Institute in Québec City and holds the position of Scientific Director of the International
Chair on Cardiometabolic Risk, a multi-disciplinary academic organisation based at Université
Laval. Dr. Després has been the Editor for the International Journal of Obesity from 1992 to
2000, and he is currently a member of the editorial boards of several scientific journals He also
serves on the board of numerous organisation and has been the recipient of many awards.
Dr. Després has published more than 480 papers in peer-reviewed journals and has written
50 book chapters.

VINCENZO DI MARZO is Research Director at the Istituto di Chimica Biomolecolare, Pozzuoli
(Naples), Italy, and Adjunct Associate Professor at Department of Pharmacology and
Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA. Dr. Di Marzo
received his first degree in chemistry from the University of Naples “Federico II”, in Italy, and
his Ph.D. in biochemistry from the Imperial College of Science. Technology & Medicine,
London, UK. Among his many achievements, Dr. Di Marzo was the principal investigator of a
Human Frontier in Science Organization grant and past president of the International
Cannabinoid Research Society, and founded the Endocannabinoid Research Group, in which
several laboratories working on endocannabinoids in the Naples area converge. He has co-
authored over 340 articles in peer-reviewed scientific journals. In 2007 he received the
Mechoulam Award for “his outstanding contributions to cannabinoid research”.

Printed in the United States of America

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Abdominal Obesity and the Endocannabinoid System

From Basic Aspects to Clinical Management of Related Cardiometabolic Risk

Després

•

Di Marzo

From Basic Aspects to Clinical Management
of Related Cardiometabolic Risk

Abdominal Obesity
and the
Endocannabinoid System

Edited by Jean-Pierre Després and Vincenzo Di Marzo

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Abdominal Obesity
and the
Endocannabinoid System

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Edited by
Jean-Pierre Després
Université Laval
Quebec, Canada
Vincenzo Di Marzo
Consiglio Nazionale delle Ricerche
Pozzuoli, Napoli, Italy

From Basic Aspects to Clinical Management
of Related Cardiometabolic Risk

Abdominal Obesity
and the
Endocannabinoid System

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Printed in the United States of America on acid-free paper
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International Standard Book Number ISBN-13: 978-1-4200-6084-3
International Standard Book Number ISBN-10: 1-4200-6084-8

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Library of Congress Cataloging-in-Publication Data

Abdominal obesity and the endocannabinoid system : from basic aspects to clinical
management of related cardiometabolic risk / edited by Jean-Pierre Despres,Vincenzo Di Marzo.
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-1-4200-6084-3 (hardcover : alk. paper)
ISBN-10: 1-4200-6084-8 (hardcover : alk. paper)
1. Obesity–Molecular aspects.
2. Abdomen.
3. Cannabinoids.
I. Despr´es, Jean-Pierre.
II. Di Marzo, Vincenzo.
[DNLM: 1. Obesity–complications.
2. Abdominal Fat.
3. Cardiovascular
Diseases.
4. Endocannabinoids–physiology.
5. Metabolic Syndrome X. WD 210 A1355 2008]
RC628.A233 2008
362.196’398–dc22
2008042736

For Corporate Sales and Reprint Permissions call 212–520-2700 or write to: Sales
Department, 52 Vanderbilt Avenue, 16th floor, New York, NY 10017.

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Foreword

The worldwide development of an obesity epidemic with associated diabetes and cardiovas-
cular disease represents one of the major challenges of the 21st century. Both the biomedical
research investigator as well as the clinician are being challenged to advance our present under-
standing of the etiology and pathophysiology of obesity as well as to develop new therapeutic
approaches to control the epidemic. During the last several years major new insights have
been made in our understanding of the clinical importance of the adipocyte. The role of the
adipocyte has evolved from that of an uninteresting storage organ for lipids to that of a dynamic
endocrine organ which secretes hormones and cytokines which play a pivotal role in regulating
metabolism, inflammation, and cardiovascular disease. Of particular importance has been the
realization that there are marked differences in the metabolism of visceral and peripheral adi-
posity. Current evidence indicates that visceral obesity accompanied by ectopic fat in the liver
and muscle is associated with insulin resistance and an increased risk of the development of dia-
betes and vascular disease. The frequent combination of visceral obesity and insulin resistance
with increased triglycerides, low HDL, increased blood pressure and elevated blood glucose
has led to the codification of this multiplex risk factor as the insulin resistance syndrome or
metabolic syndrome. Although the academic community has struggled with the selection of the
most effective nosology to deal with this constellation of risk factors, the underlying evidence
that patients with the metabolic syndrome are at risk for the future development of diabetes
and cardiovascular events continues to accrue. The addition of risk factors associated with the
metabolic syndrome to the classical risk factors for cardiovascular disease has resulted in the
concept of global cardiometabolic risk. The ultimate clarification of whether the metabolic risk
factors associated with visceral adiposity and ectopic fat will predict cardiovascular events
beyond or independently from the classical risk factors awaits further clinical studies. An addi-
tional advancement in the clinical assessment of high risk patients will be the delineation of
individual risk factors as a continuum of severity rather than a dichotomized classification
system. For the practicing physician a clinical clue for the identification of the high risk obese
patient with insulin resistance and the metabolic syndrome from the low risk equally obese
individual is an increased waist circumference and elevated triglycerides.
A major breakthrough in our understanding of the pathophysiological basis of obesity
and the metabolic syndrome has been the elucidation of the role of the endocannabinoid system
in the regulation of caloric intake and metabolism. The identification of the CB1 receptor and
the metabolic effects of regulation of the endocannabinoid pathways in the brain as well as
peripheral organs have provided major new insights into lipid and glucose metabolism as well
as obesity. Although a definitive understanding of the endocannabinoid system is being actively
pursued in laboratories around the world, the ability to modulate a potentially dysfunctional
endocannabinoid system in obesity and the metabolic syndrome has arrived. Clinical experience
with CB1 antagonists, in conjunction with aggressive lifestyle changes, is currently underway
and the evaluation of side effects as well as the selection of the appropriate patient for treatment
will be ascertained.
The chapters in this book provide an up to date unique compendium of basic research
and clinical information from investigators with expertise in both obesity and the endocannabi-
noid system. A comprehensive analysis of the topics presented in the individual chapters will
provide the reader with an exceptional in-depth knowledge of this exciting and explosive area
of medicine
Bryan Brewer, Jr.
Cardiovascular Research Institute
Washington Hospital Center
Washington, D.C., U.S.A.

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Preface

Why a book on abdominal obesity and the endocannabinoid system? This work summarizes
about 20 years of exciting developments and conceptual advances in our understanding of
the form of overweight/obesity carrying the highest risk for chronic disease: visceral obesity.
Indeed, we now better understand that many complications of obesity are more related to the
distribution of body fat than to excess total fat per se. On the other hand, studies conducted
over the last decade have documented the importance of the endocannabinoid system in the
control of regional fat deposition and in the regulation of carbohydrate and lipid metabolism.
Thus, it is only recently that we have begun to recognize the interplay between a dysfunc-
tional endocannabinoid system and visceral obesity and its complications. These notions have
tremendously important clinical implications on how to target the endocannabinoid system in
order to reduce abdominal obesity. Unfortunately, the pharmaceutical industry and regulatory
agencies have used the old “overall obesity” paradigm to evaluate “anti-obesity” drugs under
development, including the antagonists of endocannabinoid action. This traditional view of
obesity, assessed in the old fashioned way on the basis of indices of relative weight such as the
body mass index, have led to a very difficult and uncertain path for drug developers and for
physicians and their patients who are still expecting a “miracle drug”.
This book is currently the most comprehensive effort at describing the endocannabinoid
system as a whole and its role in the regulation of body fat distribution and of abdominal
obesity-related metabolic complications that increase the risk of type 2 diabetes and cardiovas-
cular disease. Whether pharmaceutical companies and regulatory bodies will agree on better
experimental designs and more carefully selected patient populations for the evaluation of drugs
targeting the endocannabinoid system is, at this stage, unclear. We hope that this comprehensive
effort will help shed light on these issues.
Jean-Pierre Despr´es
Vincenzo Di Marzo

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Contents

Foreword
Bryan Brewer, Jr. . . . . iii
Preface . . . . iv
Contributors . . . . ix

1. Abdominal Obesity, Metabolic Syndrome, and Risk of Cardiovascular Disease
1
Jean-Pierre Despr´es and Vincenzo Di Marzo

2. Abdominal Obesity in Type 2 Diabetes
11
Isabelle Lemieux and Jean-Pierre Despr´es

3. Obesity and Hypertension
19
Paul Poirier and Caroline Rh´eaume

4. Visceral Adiposity, Liver Fat, and Atherogenic Dyslipidemia
27
Marja-Riitta Taskinen, Martin Adiels, and Jan Bor´en

5. Visceral Adiposity and Inflammation
33
Ulf Smith

6. Abdominal Obesity and Alterations in Haemostasis—Thrombosis
37
Ir`ene Juhan-Vague and Marie-Christine Alessi

7. Physiological and Metabolic Characteristics of Visceral Adipocytes
49
Alain Veilleux and Andr´e Tchernof

8. The Endocrine Function of Adipose Tissue: Implications of Visceral Obesity for Patients
With Cardiometabolic Risk
55
Max Lafontan

9. Free Fatty Acid Metabolism in Visceral Obesity
69
Asem Ali and Michael D. Jensen

10. Animal Models of Visceral Obesity
75
Derek M. Huffman and Nir Barzilai

11. Insulin Sensitivity and Visceral Adiposity: Effects of Rimonabant
81
Joyce M. Richey, Morvarid Kabir, Orison O. Woolcott, Stella P. Kim, Lisa N. Harrison,
Darko Stefanovski, Isabel Hsu, Dan Zheng, Maya Lottati, Cathryn Kolka, Viorica Ionut, Karyn
Catalano, Jenny D. Chiu, and Richard N. Bergman

12. Physical Activity in the Management of Visceral Obesity and Related
Cardiometabolic Risk
89
Peter M. Janiszewski and Robert Ross

13. Can We Change the Lifestyle of High-Risk Patients? Lessons from the Prevention
of Diabetes Trials
105
Jaakko Tuomilehto and Jaana Lindstr¨om

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vi
Contents

14. Can We Change the Body Fat Distribution Phenotype? Lessons from PPAR� Agonists
111
Zubin Punthakee and Hertzel C. Gerstein

15. Is There an Optimal Diet for the Management of Abdominal Obesity and Related
Cardiometabolic Risk
117
Benoˆıt Lamarche and Caroline Richard

16. The EC System and Central Control of Energy Balance—The Hypothalamus
123
Vincenzo Di Marzo

17. The EC System and Central Control of Energy Balance: The Nucleus Accumbens
129
Tim C. Kirkham

18. The EC System and the HPA Axis
137
Daniela Cota

19. The EC System and Gut–Brain Interactions Relevant to Satiety
141
Richard Jones, Galina Burdyga, David G. Thompson, and Graham J. Dockray

20. The Endogenous Cannabinoid System in the Gastrointestinal Tract
147
Angelo A. Izzo

21. The EC System in the Adipose Tissue and Endocrine Pancreas
153
Isabel Matias

22. The EC System in the Immune System and the Inflammatory Response
163
Tracy A. Sherwood and Thomas W. Klein

23. The Endocannabinoid System in the Liver
173
Ariane Mallat and Sophie Lotersztajn

24. The Endocannabinoid System and Cardiovascular Disease
179
P´al Pacher and George Kunos

25. The Endocannabinoid System, Energy Expenditure, and Thermogenesis
185
Luigi Bellocchio, Cristina Cervino, Valentina Vicennati, Renato Pasquali, and Uberto Pagotto

26. Effects of Dietary Fatty Acids on Endocannabinoid Signaling in the Brain and
Peripheral Organs
191
Alvin Berger and Vincenzo Di Marzo

27. Endocannabinoid Overactivity and Abdominal Obesity
203
Vincenzo Di Marzo and Jean-Pierre Despr´es

28. CB1 Antagonism in the Management of Abdominal Obesity
209
Luc F. Van Gaal

29. Abdominal Obesity and the Endocannabinoid System CB1 Blockade, Insulin Resistance,
and Type 2 Diabetes
219
Andr´e J. Scheen

30. Abdominal Obesity As a Therapeutic Target to Manage the Atherogenic Dyslipidemia and
Related Metabolic Abnormalities
227
Jean-Pierre Despr´es

31. CB1 Blockade and Hypertension
237
Luis M. Ruilope

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Contents
vii

32. Future Developments 1: CB1 Blockade for Weight Gain Subsequent
to Smoking Cessation
247
Jaimee L. Heffner and Robert M. Anthenelli

33. Future Developments 2: Cannabinoid CB1 Receptor Blockade in Weight Gain Subsequent
to Psychiatric Disorder Treatment
253
Ester Fride, Shimon Rabichev, and Nikolai Gobshtis

Index . . . . 261