Heart Disease

Dementia

Stroke

Metabolic Syndrome

Alzheimer Disease

Depression

Parkinson Disease

METABOLIC SYNDROME AND NEUROLOGICAL DISORDERSEdited byTahira Farooqui and Akhlaq A. Farooqui

METABOLIC SYNDROME ANDNEUROLOGICAL DISORDERS

METABOLIC SYNDROME ANDNEUROLOGICAL DISORDERS

Edited by

TAHIRA FAROOQUI AND AKHLAQ A. FAROOQUI

This edition first published 2013 C© 2013 by John Wiley & Sons, Inc.

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Library of Congress Cataloging-in-Publication Data

Metabolic syndrome and neurological disorders / Tahira Farooqui and Akhlaq A. Farooqui, editors.p. ; cm.

Includes bibliographical references and index.ISBN 978-1-118-39527-1 (cloth : alk. paper) – ISBN 978-1-118-39528-8 (Epub) – ISBN 978-1-118-39529-5 (Epdf) –

ISBN 978-1-118-39530-1 (Emobi) – ISBN 978-1-118-39531-8 (ebook)I. Farooqui, Tahira, editor of compilation. II. Farooqui, Akhlaq A., editor of compilation.[DNLM: 1. Metabolic Syndrome X–etiology. 2. Metabolic Syndrome X–metabolism. 3. Nervous System Diseases–etiology.

4. Nervous System Diseases–metabolism. WK 820]RC629616.3′99–dc23

2013029484

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Cover image: body image C© angelhellCover design by Nicole Teut

Set in 10/12pt Times by Aptara R© Inc., New Delhi, India

1 2013

Dedicated to our late parents

For their unconditional love, support and understanding.

“Every human being is the author of his own health or disease.”

Siddhartha Gautama Buddha

CONTENTS

Foreword xiMark P. Mattson

Preface xiiiTahira Farooqui and Akhlaq A. Farooqui

Acknowledgments xvTahira Farooqui and Akhlaq A. Farooqui

Contributors xvii

1 Insulin Resistance and Metabolic Failure Underlie Alzheimer Disease 1Suzanne M. de la Monte and Ming Tong

2 Insulin Receptor and the Pathophysiology of Alzheimer Disease 31Johanna Zemva and Markus Schubert

3 Contribution of Insulin Resistance in Pathogenesis of Alzheimer Disease 51Adnan Erol

4 Insulin–Leptin Signaling in the Brain 75Vicente Barrios, Emma Burgos-Ramos, and Jesus Argente

5 The Janus Face of Insulin in Brain 85Ana Duarte, Emanuel Candeias, Sonia C. Correia, Renato X. Santos, Cristina Carvalho,Susana Cardoso, Ana I. Placido, Maria S. Santos, Catarina R. Oliveira, and Paula I. Moreira

6 Modulation of Cognition by Insulin and Aging: Implications for Alzheimer Disease 115Maite Solas and Maria J. Ramırez

vii

viii CONTENTS

7 Contribution of Phospholipid, Sphingolipids, and Cholesterol-Derived Lipid Mediators inthe Pathogenesis of Metabolic Syndrome and Neurological Disorders 137Akhlaq A. Farooqui and Tahira Farooqui

8 Lipids, Cholesterol, and Oxidized Cholesterol in Alzheimer Amyloid Beta-MediatedNeurotoxicity 163Mun’delanji C. Vestergaard, Masamune Morita, Tsutomu Hamada, and Masahiro Takagi

9 Of Sound Mind and Body: Dietary Lifestyles, Promotion of Healthy Brain Aging, andPrevention of Dementia in Healthy Individuals 179Giulio Maria Pasinetti, Amanda Bilski, Lap Ho, Jun Wang, Mario Ferruzzi, Masahito Yamada,Kenjiro Ono, and Salvatore Mannino

10 Metabolic Syndrome as an Independent Risk Factor of Silent Brain Infarction 191Jae-Sung Lim and Hyung-Min Kwon

11 Neurochemical Linkage Among Metabolic Syndrome, Alzheimer Disease, and Depression 197Undurti N. Das

12 Alterations in the Endocannabinoid System as a Link Between Unbalanced EnergyHomeostasis, Neuroinflammation, and Neurological and Neuropsychiatric Disorders 219Tiziana Bisogno and Vincenzo Di Marzo

13 Metabolic Syndrome, Alzheimer Disease, Schizophrenia, and Depression: Role for Leptin,Melatonin, Kynurenine Pathways, and Neuropeptides 235George Anderson and Michael Maes

14 Binge Eating and Metabolic Syndrome 249Ignacio Jauregui-Lobera

15 Phytochemical Principles in the Traditional Indian System of Medicine Used for theManagement of Metabolic Syndrome 261Syed Ibrahim Rizvi and Neetu Mishra

16 Oxidative Stress and Obesity: Their Impact on Metabolic Syndrome 275Morihiro Matsuda and Iichiro Shimomura

17 The Relationship Among Obesity, Inflammation, and Insulin Resistance 283Jean-Philippe Bastard and Bruno Feve

18 Involvement of Adipocytokines in Pathogenesis of Insulin Resistance, Obesity,and Metabolic Syndrome 297Hardik Gandhi and Ramachandran Balaraman

19 Obesity, Inflammation, and Vascular Disease: Novel Insight in the Role of Adipose Tissue 311Paolo Calabro, Enrica Golia, Valeria Maddaloni, Giuseppe Limongelli, Brunella Ziello, Fabio Fimiani,Ilaria Jane Romano, Mario Crisci, Maria Giovanna Russo, Edward T.H. Yeh, and Raffaele Calabro

CONTENTS ix

20 Is Diabetes a Risk Factor for Parkinson Disease? 327Akhlaq A. Farooqui and Tahira Farooqui

21 Role of Iron in the Pathogenesis of Diabetes and Metabolic Syndrome 335Lu Cai

22 Contributions of AMP Kinase to the Pathogenesis of Type 2 Diabetes andNeurodegenerative Diseases 363Mohamed Kodiha, Hicham Mahboubi, and Ursula Stochaj

23 A� Deposition, Insulin Signaling, and Tau Phosphorylation in Animal Models ofAlzheimer Disease and Diabetes 383Naoyuki Sato and Ryuichi Morishita

24 In Vivo Evidence of the Convergence of Type 2 Diabetes and Alzheimer Disease 395Sun Ah Park

25 Metabolic Syndrome and its Impact on Cardiovascular Disease 409John A. Larry

26 Contribution of Inflammation, Adiponectin, and Obesity in Cardiovascular Diseases 423Harald Mangge and Gunter Almer

27 Brain and Cardiovascular Diseases: Molecular Aspects 439Ewa Szczepanska-Sadowska

28 Molecular Aspects of Dietary–Exercise Regimen for the Prevention of Metabolic Syndrome 461Wataru Aoi

29 Ghrelin, Lipid Metabolism, and Metabolic Syndrome 475Pablo B. Martınez de Morentin, Sulay Tovar, Ruben Nogueiras, Miguel Lopez, and Carlos Dieguez

30 Leptin and Cognitive Function 485Jenni Harvey

31 Fructose, Sugar Consumption, and Metabolic Diseases 501Virgile Lecoultre and Luc Tappy

32 Inflammation-Mediated Cognitive and Emotional Alterations in Experimental Modelsof Metabolic Syndrome 515Nathalie Castanon and Sophie Laye

33 Summary and Perspective 529Tahira Farooqui and Akhlaq A. Farooqui

Index 539

Color plate section is located between pages 196 and 197.

FOREWORD

Metabolic syndrome (MetS) is a pathologic state thatmost often results from a chronic positive energy bal-ance due to an excessive energy intake (particularlyrefined sugars and saturated and trans fats) and asedentary lifestyle. The defining clinical features ofMetS are insulin resistance, central obesity, dyslipi-demia, and hypertension. It was established severaldecades ago that MetS is prodromal to diabetes andthat individuals with MetS have a high risk of myocar-dial infarction and stroke. However, within the pastten years it has become clear that MetS adverselyaffects brain structure and function and is a risk factorfor Alzheimer disease (AD) and stroke. In MetabolicSyndrome and Neurological Disorders Tahira andAkhlaq Farooqui have drawn upon the knowledgeof experts in the fields of neuroscience, neurology,endocrinology, cardiovascular disease, obesity, anddiabetes to compile a timely review of the impactof MetS on the brain and its vulnerability to neuro-logical disorders. This is a critically important areaof research for four major reasons: (1) there is anongoing epidemic of overweight, obesity, and MetSin modern societies; (2) due to advances in the earlydiagnosis and treatment of cancers and cardiovascu-lar disease, large numbers of individuals are reach-ing their seventh, eighth, and ninth decades of life,the “danger zones” for AD and stroke; (3) there areno effective drugs to counteract the neuronal damage

that occurs in AD and stroke; and (4) AD patients andstroke patients often require a decade or more of con-stant care, and therefore place a greater personal andeconomic burden on society than many other majordiseases. Although less profound, emerging evidencealso suggests that, in addition to AD and stroke, theMetS may predispose to a broader range of neurolog-ical disorders including Parkinson disease, depres-sion, and possibly schizophrenia.

Because of its adverse effects on essentially allorgan systems including the brain, an understandingof the molecular and cellular alterations that cause theMetS, and the mechanisms by which the MetS pro-motes dysfunction and degeneration of brain cells,will be required to develop novel approaches forpreventing and treating MS and associated diseases.As detailed in Metabolic Syndrome and Neurolog-ical Disorders, alterations resulting from a chronicpositive energy balance that are involved in the gen-esis of the MetS include oxidative stress and inflam-mation and associated dysregulation of lipid (sph-ingolipids, cholesterol, and others) metabolism. Asa result, signaling pathways that normally protectbrain cells and promote their optimal functionality areimpaired, including pathways activated by the hor-mones insulin, leptin, adiponectin, and brain-derivedneurotrophic factor (BDNF). In addition, oxidativestress, inflammation, and abnormal lipid metabolism

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xii FOREWORD

can increase the production and/or reduce the removalof the neurotoxic amyloid beta-peptide, which likelycontributes to the dysfunction and degeneration ofneurons in AD. With regards to the pathogenesis ofstroke, hypertension, dyslipidemia, and local oxida-tive stress and inflammation in cerebral blood vesselsresult in a narrowing and weakening of the vessels.

The good news for those with motivation isthat the MetS can be effectively prevented andtreated by adherence to prescriptions for exerciseand dietary energy restriction. Exercise and energyrestriction (particularly intermittent fasting) can pre-vent or reverse MetS by enhancing insulin sensitiv-ity, increasing utilization of fats, stimulating antioxi-dant and anti-inflammatory pathways, and enhancingparasympathetic tone, which decreases blood pres-sure. Recent findings from animal research, and epi-demiological and clinical studies, suggest that ADand stroke may also be prevented or delayed by reg-ular exercise and moderation in energy intake dur-ing adult life. In addition to protecting the brainby reversing all of the peripheral manifestations ofthe MetS, exercise and energy restriction have beenshown to have direct effects on brain cells that opti-mize brain function and may forestall AD and stroke.These include increased production of neurotrophicfactors, improved cellular bioenergetics, and reducedoxidative stress.

For those unwilling or unable to exercise regularlyand restrict their calorie intake so as to maintain a

normal body weight Metabolic Syndrome and Neuro-logical Disorders reviews potential dietary and druginterventions that are being developed and tested inclinical studies. As with research toward understand-ing disease mechanisms, translational research forMetS and neurodegenerative disorders is acceleratedby the use of animal models. Studies of animal modelsof AD and stroke have demonstrated beneficial effectsof insulin, leptin, incretin peptides such as glucagon-like peptide 1 analogs, and PPAR-� agonists thatare insulin-sensitizing agents such as metformin androsiglitazone. Many of these drugs are now in clinicaltrials in patients with mild cognitive impairment orearly AD. Targeting lipid metabolism is also beingpursued via studies of dietary supplementation withomega-3 fatty acids or the use of cholesterol-loweringdrugs. Other approaches that might prove beneficialfor protecting the brain in subjects with MetS includedrugs that suppress appetite, such as cannabinoidreceptor antagonists. This book will provide a valu-able resource to guide future research projects to dis-entangle the complex cellular and molecular under-pinnings of MetS-related neuropathologies, and tothereby inform the development of novel therapeuticinterventions for neurological disorders.

MARK P. MATTSON

National Institute on AgingIntramural Research Program

Baltimore, MD

PREFACE

At the end of 2011, the United Nations declaredfor the first time in the history of human-ity that non-communicable diseases had outpacedinfectious diseases as the main global threat tohuman health. Among non-communicable diseases,metabolic syndrome (MetS), cardiovascular diseases,and Alzheimer disease (AD) are of paramount impor-tance. MetS is a condition characterized by clusteringof insulin resistance, hyperinsulinemia, hypertension,dyslipidemia, impaired glucose disposal, type 2 dia-betes, abnormal blood fat levels, fatty liver disease,and abdominal obesity. Changes in human dietaryhabits in recent decades have led to the consumptionof hypercaloric diets that are rich in saturated fatsand simple sugars (sucrose, glucose, and fructose).The MetS is a highly prevalent pathological conditionthat affects a considerate number of adult humans.Approximately one-fourth of European, American,and Canadian adults suffer from MetS. Clusteringof insulin resistance, hyperinsulinemia, hyperten-sion, dyslipidemia, impaired glucose disposal, type2 diabetes, and abdominal obesity reflects over-nutrition, sedentary lifestyles, physical inactivity, andresultant excess adiposity. At the molecular level,MetS is accompanied not only by dysregulation inthe expression of adipocytokines and chemokines,but also by increase in levels of lipids and lipidmediators (free fatty acids, di- and triacylglycerols,

and ceramide). These changes modulate immuneresponse and inflammation that lead to alterationsin the hypothalamic body-weight/appetite/satiety setpoint, resulting in the initiation and developmentof MetS.

MetS is a risk factor for neurological disorderssuch as stroke, depression, and AD. The molecu-lar mechanism underlying the relationship betweenMetS and neurological disorders is not fully under-stood. However, major mechanisms through whichMetS may influence stroke, AD, and depressioninclude insulin resistance, impairment in insulinreceptor, and insulin growth factor signaling, glu-cose toxicity, elevated levels of phospholipid-,sphingolipid-, and cholesterol-derived lipid media-tors, generation of advanced glycation endproducts,activation of receptor for advanced glycation end-products, cerebrovascular injury, and vascular inflam-mation that may represent a pathological bridgebetween MetS and neurological disorders such asstroke, AD, and depression.

Information on molecular links between MetS andneurological disorders is scattered throughout the lit-erature mainly in the form of original papers andsome reviews. Although, many books are publishedon biochemistry of MetS and neurological disordersseparately, at present there are no books on the rela-tionship between MetS and neurological disorders.

xiii