Metabolic Syndrome Pathophysiology: The Role of Essential Fatty Acids

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