Table of Contents
Preface xiii
1 Introduction 1
2 History, Definition, and Diagnosis of the Metabolic Syndrome 4
Historical Aspects of the Metabolic Syndrome 4
Definition and Diagnosis of the Metabolic Syndrome Suggested by Various Groups and Associations 5
3 Insulin Resistance in the Metabolic Syndrome 13
Is Insulin Resistance Responsible for the Metabolic Syndrome? 13
Exercise and Insulin Resistance 14
Anti-inflammatory Nature of Exercise 15
4 Is It Necessary to Redefine the Metabolic Syndrome? 22
Criteria 23
5 Is Insulin Resistance a Disorder of the Brain? 26
Parasympathetic and Sympathetic Tones and Insulin Resistance 26
Hypothalamo-pituitary-adrenal Pathway and Parasympathetic and Sympathetic System, and GLUT-4 and Hypothalamic Neuropeptide Y in Insulin Resistance, Obesity, and the Metabolic Syndrome 27
Interaction(s) among NPY, Leptin, GLUT-4, Melanocortin, and Insulin and Its Relevance to Obesity, Insulin Resistance, and the Metabolic Syndrome 29
Insulin and Brain 31
Insulin and Brain Monoamines 34
Obesity and Basal Energy Expenditure 39
6 Obesity 43
Definition of Obesity 44
Incidence and Prevalence of Obesity 44
Obesity Could Run in the Family 45
Growth of Fast Food Industry and Obesity 45
Why Is Obesity Harmful? 46
Genetics of Obesity 47
Gene Expression Profile in Obesity 49
Biochemical and Functional Differences between Adipose Cells of Different Regions 49
Intramyocellular Lipid Content and Insulin Resistance 51
Intramyocellular Lipid Droplets and Insulin Resistance 53
Intramyocellular Lipid Droplets, Insulin Resistance, Perilipins, and HSL 54
Perilipins in Humans 55
Factors Regulating the Expression and Action of Perilipin 56
Perilipins and Inflammation 59
Low-grade Systemic Inflammation Occurs in Obesity 59
What Causes Abdominal Obesity? 61
11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD-1) Enzyme and Obesity 61
Glucocorticoids and Perilipins 63
Glucocorticoids, TNF-α, and Inflammation 64
Perilipins, 11β-HSD-1, and Abdominal Obesity and the Metabolic Syndrome in High-Risk Groups Such as South Asians 65
7 Perinatal Nutrition and Obesity 74
Appetite Regulatory Centers Develop during the Perinatal Period 74
Ventromedial Hypothalamus Plays a Significant Role in the Development of Obesity, Type 2 Diabetes Mellitus, and the Metabolic Syndrome 76
Glucokinase in Hypothalamic Neurons and VMH Lesion in Goto-Kakizaki Rats and Their Relationship to Obesity, Type 2 Diabetes Mellitus, and the Metabolic Syndrome 77
Insulin and Insulin Receptors in the Brain and Their Role in the Pathobiology of Obesity, Type 2 Diabetes Mellitus, and the Metabolic Syndrome 78
NPY, Insulin, and Nitric Oxide in Obesity, Type 2 Diabetes Mellitus, and the Metabolic Syndrome 80
Insulin, Endothelial Nitric Oxide, and Metabolic Syndrome 81
Perinatal Programming of Adult Diseases 81
Fetal Nutrition Influences the Developing Neuroendocrine Hypothalamus 82
8 Essential Hypertension 86
Prevalence and Incidence of Hypertension 86
Free Radicals in the Pathobiology of Hypertension 88
Increase in Superoxide Anion Production in Hypertension: How and Why? 89
Mechanism(s) of Induction of Hypertension by Superoxide Anion 91
Role of NO in Hypertension 92
Salt, Cyclosporine, and Calcium Modulate O2−. and Endothelial NO Generation 94
L-Arginine, NO, and Asymmetrical Dimethylarginine in Hypertension and Pre-eclampsia 95
Antihypertensive Drugs Suppress Superoxide Anion and Enhance NO Generation 97
Transforming Growth Factor-β, NO, and Hypertension 97
9 Dietary Factors and Hypertension 105
Carbohydrate-rich and High-fat Diet and Hypertension 105
Fructose-induced Hypertension and Insulin Resistance and Its Modulation by Dietary Salt 106
Energy-dense Diet, Salt, and Hypertension 106
Diet-induced Hypertension, Renin-Angiotensin-Aldosterone System, and Nitric Oxide 107
High-sugar and High-fat-induced Hypertension and Reactive Oxygen Species and Nitric Oxide 108
High-fructose and Salt-induced Hypertension and Insulin Resistance 109
High-fat and High-carbohydrate-induced Hypertension and Sympathetic Nervous Activity 111
10 Is Hypertension a Disorder of the Brain? 113
NO Synthase (NOS) Activity in the Brain, Kidney, and Endothelium and Its Relationship to Hypertension 114
Reduced Hypothalamic NOS Produces Hypertension without Altering Hypothalamic Blood Flow 115
Hypothalamic NO Regulates Sympathetic Outflow 116
Steroid-induced Hypertension and Hypothalamus 117
Exercise Enhances Hypothalamic NOS Activity 119
Both Hypertension and Type 2 Diabetes Mellitus and Hence the Metabolic Syndrome Are Disorders of the Brain 119
11 Type 2 Diabetes Mellitus 122
Type 1 Diabetes Mellitus 122
Pathobiology of Type 1 Diabetes 123
Type 2 Diabetes Mellitus 125
Diagnostic Criteria for DM 126
Impaired Glucose Tolerance and Impaired Fasting Glucose 127
Definition of Gestational Diabetes Mellitus 127
Diagnostic Criteria for GDM 127
12 Pathophysiology of Type 2 Diabetes Mellitus with Particular Reference to Hypothalamus 130
Type 2 Diabetes Mellitus as a Disorder of the Brain 130
Liver Communicates with the Brain through the Vagus 131
Liver and Pancreatic β Cells Communicate with Each Other through the Vagus 132
The Gut-brain-liver Axis Is Activated by Long-chain Fatty Acids (LCFAs or LCPUFAs) 132
BDNF and Obesity 136
BDNF and Type 2 Diabetes Mellitus in Humans 137
Insulin, Melanocortin, and BDNF 138
Ghrelin, Leptin, and BDNF 138
Low-grade Systemic Inflammation Occurs in Obesity and Type 2 Diabetes Mellitus 140
BDNF and Inflammation 141
13 Insulin and Insulin Receptors in the Brain and Their Role in the Pathogenesis of Obesity and Type 2 Diabetes Mellitus 146
Insulin and Insulin Receptors in the Brain 146
Glucose Transporters and Glucokinase in Hypothalamus 147
Neuron-specific Disruption of the Insulin Receptor Gene (NIRKO) 147
Insulin and Hypothalamic Neuropeptides 148
Leptin Receptors on Pancreatic β Cells 148
Glucagon-like Peptide, Insulin, and the Metabolic Syndrome 149
14 Insulin, Endothelial Nitric Oxide, and the Metabolic Syndrome 156
Insulin Resistance and Nitric Oxide 156
Ghrelin Improves Endothelial Function in the Metabolic Syndrome 159
Cross-talk between Insulin and Renin-Angiotensin-Aldosterone System 159
Pro-inflammatory Cytokines Produce Insulin Resistance 161
15 Obesity, Type 2 Diabetes Mellitus, the Metabolic Syndrome, and the Gut Microbiota 167
Gut Flora, Diet, Obesity, and Inflammation 167
Germ-free Mice Are Resistant to Obesity 168
Enteroendocrine Cell Expression of Gpr41 and Obesity 169
Low-grade Systemic Inflammation, Diet, and Obesity 171
Gastric Bypass Surgery for Obesity and the Metabolic Syndrome 171
Diet, Gut, Liver, Adipose Tissue, and Hypothalamus in Obesity and the Metabolic Syndrome 173
16 Is It Possible That the Metabolic Syndrome Originates in the Perinatal Period? 177
Perinatal Programming of Appetite Regulatory Centers and Hypothalamic Centers 177
Insulin and Insulin Receptors in the Brain 178
17 Essential Fatty Acids: Biochemistry and Physiology 181
Metabolism of EFAs 181
Dietary Sources of EFAs 183
Modulators of Metabolism of EFAs 183
PUFAs and SREBPs 184
Cholesterol, Saturated Fats, and Trans-fats Interfere with the Activity of ∆6 and ∆5 Desaturases 185
Actions of EFAs and Their Metabolites 188
Brief Description of Formation of Lipoxins, Resolvins, Neuroprotectin D1 (Protectins), and Maresins 193
Nitrolipids 194
18 Role of EFAs/PUFAs in Brain Growth and Development and Pathophysiology of the Metabolic Syndrome 201
PUFAs in Brain Growth and Development 201
RAR-RXR Nuclear Receptors, PUFAs, and Neuronal Growth 202
Interaction among TNF-α, AA/EPA/DHA, and Insulin and Their Role in Neuronal Growth and Synapse Formation 202
PUFAs and Catenin, wnt, and Hedgehog Signaling Pathway in Brain Growth and Development 203
β-Catenin-Wnt Signaling and PUFAs 205
Modulation of the Secretion and Function of NMDA, γ –Aminobutyric Acid (GABA), Serotonin, and Dopamine by PUFAs 205
Leptin Regulates NPY/AgRP and POMC/CART Neurons and Programs Hypothalamic “Body Weight/Appetite/Satiety Set Point” 209
PUFAs Regulate Leptin, NPY/AgRP, and POMC/CART Neurons and Participate in Programming Hypothalamic “Body Weight/ Appetite/Satiety Set Point” 212
PUFAs, Insulin, and Acetylcholine Not Only Interact among Themselves but Are Also Neuroprotective in Nature 215
PUFAs and Insulin Resistance 215
Maternal Diet Influences δ∆6 and δ∆5 Desaturases and Leptin Levels 216
Interaction(s) among Hypothalamic Neuropeptides, Gut, Adipose Tissue, Insulin, Cytokines, and Free Radicals and Its Relevance to the Pathophysiology of the Metabolic Syndrome 217
Hypothalamic Gene Expression Profile in the RYGB Animal Model 218
Increased Phospholipase A2 Expression after RYGB Surgery and Its Relevance to Suppression of Low-grade Systemic Inflammation in the Obese and Formation of Anti-inflammatory Lipids 219
Expression of Gene for eNOS in RYGB 220
RYGB-induced Weight Loss Is Due to Changes in the Levels of Hypothalamic Neuropeptides and Monoamines 220
What Are the Diagnostic and Prognostic Implications of This Knowledge? 221
Therapeutic Implications 223
PUFAs and Endocannabinoids 224
PUFAs and Type 2 Diabetes Mellitus 224
Hypothalamic PUFAs Regulate Insulin Secretion and Glucose Homeostasis by Influencing ATP-sensitive K+ Channels 225
Vagus as the Communicator between Gut, Liver, and Hypothalamus 227
19 EFAs/PUFAs and Their Metabolites in Insulin Resistance 240
GLUT-4 in Insulin Resistance 240
Tumor Necrosis Factor Induces Insulin Resistance 242
Caloric Restriction Influences Insulin Signaling Pathway, Antioxidants, daf genes, PTEN, Sirtuins (Silent Mating Type Information Regulation 2 Homologue), and Longevity and Their Relationship to Insulin Resistance 242
PUFAs Can Reduce Insulin Resistance 244
PUFAs, GLUT-4, TNF-α, Anti-oxidants, daf Genes, SIRT1, and PPARs 245
Clinical Implications of the Interactions among PUFAs, daf Genes, PPARs, and Sirtuins 246
20 EFAs/PUFAs and Atherosclerosis 252
Atherosclerosis Is a Systemic Inflammatory Condition 252
Cross-talk among Platelets, Leukocytes, and Endothelial Cells 253
Leukocytes and Atherosclerosis 254
EFAs Modulate Uncoupling Protein-1 Expression 255
Interaction(s) among ω-3 and ω-6 Fatty Acids and Trans-fats and Saturated Fats 255
Atheroprotective Actions of ω-3 and ω-6 Fatty Acids: How and Why? 259
Index 265
