Metabolic Syndrome Pathophysiology

Undurti N. Das, M.D. is the Chairman and Research Director of UND Life Sciences, USA and Ramalingaswami Fellow of the Department of Biotechnology, India. Dr Das is also the Editor-in-Chief of the journal Lipids in Health and Disease. He has published more than 400 international publications and has been awarded four USA patents.

• Preface xiii1 Introduction 12 History, Definition, and Diagnosis of the Metabolic Syndrome 4Historical Aspects of the Metabolic Syndrome 4Definition and Diagnosis of the Metabolic Syndrome Suggested by Various Groups and Associations 53 Insulin Resistance in the Metabolic Syndrome 13Is Insulin Resistance Responsible for the Metabolic Syndrome? 13Exercise and Insulin Resistance 14Anti-inflammatory Nature of Exercise 154 Is It Necessary to Redefine the Metabolic Syndrome? 22 Criteria 235 Is Insulin Resistance a Disorder of the Brain? 26Parasympathetic and Sympathetic Tones and Insulin Resistance 26Hypothalamo-pituitary-adrenal Pathway and Parasympathetic and Sympathetic System, and GLUT-4 and Hypothalamic Neuropeptide Y in Insulin Resistance, Obesity, and the Metabolic Syndrome 27Interaction(s) among NPY, Leptin, GLUT-4, Melanocortin, and Insulin and Its Relevance to Obesity, Insulin Resistance, and the Metabolic Syndrome 29Insulin and Brain 31Insulin and Brain Monoamines 34Obesity and Basal Energy Expenditure 396 Obesity 43Definition of Obesity 44Incidence and Prevalence of Obesity 44Obesity Could Run in the Family 45Growth of Fast Food Industry and Obesity 45Why Is Obesity Harmful? 46Genetics of Obesity 47Gene Expression Profile in Obesity 49Biochemical and Functional Differences between Adipose Cells of Different Regions 49Intramyocellular Lipid Content and Insulin Resistance 51Intramyocellular Lipid Droplets and Insulin Resistance 53Intramyocellular Lipid Droplets, Insulin Resistance, Perilipins, and HSL 54Perilipins in Humans 55Factors Regulating the Expression and Action of Perilipin 56Perilipins and Inflammation 59Low-grade Systemic Inflammation Occurs in Obesity 59What Causes Abdominal Obesity? 6111β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD-1) Enzyme and Obesity 61Glucocorticoids and Perilipins 63              Glucocorticoids, TNF-α, and Inflammation 64Perilipins, 11β-HSD-1, and Abdominal Obesity and the Metabolic Syndrome in High-Risk Groups Such as South Asians 657 Perinatal Nutrition and Obesity 74Appetite Regulatory Centers Develop during the Perinatal Period 74Ventromedial Hypothalamus Plays a Significant Role in the Development of Obesity, Type 2 Diabetes Mellitus, and the Metabolic Syndrome 76Glucokinase in Hypothalamic Neurons and VMH Lesion in Goto-Kakizaki Rats and Their Relationship to Obesity, Type 2 Diabetes Mellitus, and the Metabolic Syndrome 77Insulin and Insulin Receptors in the Brain and Their Role in the Pathobiology of Obesity, Type 2 Diabetes Mellitus, and the Metabolic Syndrome 78NPY, Insulin, and Nitric Oxide in Obesity, Type 2 Diabetes Mellitus, and the Metabolic Syndrome 80Insulin, Endothelial Nitric Oxide, and Metabolic Syndrome 81Perinatal Programming of Adult Diseases 81Fetal Nutrition Influences the Developing Neuroendocrine Hypothalamus 828 Essential Hypertension 86Prevalence and Incidence of Hypertension 86Free Radicals in the Pathobiology of Hypertension 88Increase in Superoxide Anion Production in Hypertension: How and Why? 89Mechanism(s) of Induction of Hypertension by Superoxide Anion 91Role of NO in Hypertension 92Salt, Cyclosporine, and Calcium Modulate O2−. and Endothelial NO Generation 94L-Arginine, NO, and Asymmetrical Dimethylarginine in Hypertension and Pre-eclampsia 95Antihypertensive Drugs Suppress Superoxide Anion and Enhance NO Generation 97Transforming Growth Factor-β, NO, and Hypertension 979 Dietary Factors and Hypertension 105Carbohydrate-rich and High-fat Diet and Hypertension 105Fructose-induced Hypertension and Insulin Resistance and Its Modulation by Dietary Salt 106Energy-dense Diet, Salt, and Hypertension 106Diet-induced Hypertension, Renin-Angiotensin-Aldosterone System, and Nitric Oxide 107High-sugar and High-fat-induced Hypertension and Reactive Oxygen Species and Nitric Oxide 108High-fructose and Salt-induced Hypertension and Insulin Resistance 109High-fat and High-carbohydrate-induced Hypertension and Sympathetic Nervous Activity 11110 Is Hypertension a Disorder of the Brain? 113NO Synthase (NOS) Activity in the Brain, Kidney, and Endothelium and Its Relationship to Hypertension 114Reduced Hypothalamic NOS Produces Hypertension without Altering Hypothalamic Blood Flow 115Hypothalamic NO Regulates Sympathetic Outflow 116Steroid-induced Hypertension and Hypothalamus 117Exercise Enhances Hypothalamic NOS Activity 119Both Hypertension and Type 2 Diabetes Mellitus and Hence the Metabolic Syndrome Are Disorders of the Brain 11911 Type 2 Diabetes Mellitus 122Type 1 Diabetes Mellitus 122Pathobiology of Type 1 Diabetes 123Type 2 Diabetes Mellitus 125Diagnostic Criteria for DM 126Impaired Glucose Tolerance and Impaired Fasting Glucose 127Definition of Gestational Diabetes Mellitus 127Diagnostic Criteria for GDM 12712 Pathophysiology of Type 2 Diabetes Mellitus with Particular Reference to Hypothalamus 130Type 2 Diabetes Mellitus as a Disorder of the Brain 130Liver Communicates with the Brain through the Vagus 131Liver and Pancreatic β Cells Communicate with Each Other through the Vagus 132The Gut-brain-liver Axis Is Activated by Long-chain Fatty Acids (LCFAs or LCPUFAs) 132BDNF and Obesity 136BDNF and Type 2 Diabetes Mellitus in Humans 137Insulin, Melanocortin, and BDNF 138Ghrelin, Leptin, and BDNF 138Low-grade Systemic Inflammation Occurs in Obesity and Type 2 Diabetes Mellitus 140BDNF and Inflammation 14113 Insulin and Insulin Receptors in the Brain and Their Role in the Pathogenesis of Obesity and Type 2 Diabetes Mellitus 146Insulin and Insulin Receptors in the Brain 146Glucose Transporters and Glucokinase in Hypothalamus 147Neuron-specific Disruption of the Insulin Receptor Gene (NIRKO) 147Insulin and Hypothalamic Neuropeptides 148Leptin Receptors on Pancreatic β Cells 148Glucagon-like Peptide, Insulin, and the Metabolic Syndrome 14914 Insulin, Endothelial Nitric Oxide, and the Metabolic Syndrome 156Insulin Resistance and Nitric Oxide 156Ghrelin Improves Endothelial Function in the Metabolic Syndrome 159Cross-talk between Insulin and Renin-Angiotensin-Aldosterone System 159Pro-inflammatory Cytokines Produce Insulin Resistance 16115 Obesity, Type 2 Diabetes Mellitus, the Metabolic Syndrome, and the Gut Microbiota 167Gut Flora, Diet, Obesity, and Inflammation 167Germ-free Mice Are Resistant to Obesity 168Enteroendocrine Cell Expression of Gpr41 and Obesity 169Low-grade Systemic Inflammation, Diet, and Obesity 171Gastric Bypass Surgery for Obesity and the Metabolic Syndrome 171Diet, Gut, Liver, Adipose Tissue, and Hypothalamus in Obesity and the Metabolic Syndrome 17316 Is It Possible That the Metabolic Syndrome Originates in the Perinatal Period? 177Perinatal Programming of Appetite Regulatory Centers and Hypothalamic Centers 177Insulin and Insulin Receptors in the Brain 17817 Essential Fatty Acids: Biochemistry and Physiology 181Metabolism of EFAs 181Dietary Sources of EFAs 183Modulators of Metabolism of EFAs 183PUFAs and SREBPs 184Cholesterol, Saturated Fats, and Trans-fats Interfere with the Activity of ∆6 and ∆5 Desaturases 185Actions of EFAs and Their Metabolites 188Brief Description of Formation of Lipoxins, Resolvins, Neuroprotectin D1 (Protectins), and Maresins 193Nitrolipids 19418 Role of EFAs/PUFAs in Brain Growth and Development and Pathophysiology of the Metabolic Syndrome 201PUFAs in Brain Growth and Development 201RAR-RXR Nuclear Receptors, PUFAs, and Neuronal Growth 202Interaction among TNF-α, AA/EPA/DHA, and Insulin and Their Role in Neuronal Growth and Synapse Formation 202PUFAs and Catenin, wnt, and Hedgehog Signaling Pathway in Brain Growth and Development 203β-Catenin-Wnt Signaling and PUFAs 205Modulation of the Secretion and Function of NMDA, γ –Aminobutyric Acid (GABA), Serotonin, and Dopamine by PUFAs 205Leptin Regulates NPY/AgRP and POMC/CART Neurons and Programs Hypothalamic “Body Weight/Appetite/Satiety Set Point” 209PUFAs Regulate Leptin, NPY/AgRP, and POMC/CART Neurons and Participate in Programming Hypothalamic “Body Weight/ Appetite/Satiety Set Point” 212PUFAs, Insulin, and Acetylcholine Not Only Interact among Themselves but Are Also Neuroprotective in Nature 215PUFAs and Insulin Resistance 215Maternal Diet Influences δ∆6 and δ∆5 Desaturases and Leptin Levels 216Interaction(s) among Hypothalamic Neuropeptides, Gut, Adipose Tissue, Insulin, Cytokines, and Free Radicals and Its Relevance to the Pathophysiology of the Metabolic Syndrome 217Hypothalamic Gene Expression Profile in the RYGB Animal Model 218Increased 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 219Expression of Gene for eNOS in RYGB 220RYGB-induced Weight Loss Is Due to Changes in the Levels of Hypothalamic Neuropeptides and Monoamines 220What Are the Diagnostic and Prognostic Implications of This Knowledge? 221Therapeutic Implications 223PUFAs and Endocannabinoids 224PUFAs and Type 2 Diabetes Mellitus 224Hypothalamic PUFAs Regulate Insulin Secretion and Glucose Homeostasis by Influencing ATP-sensitive K+ Channels 225Vagus as the Communicator between Gut, Liver, and Hypothalamus 22719 EFAs/PUFAs and Their Metabolites in Insulin Resistance 240GLUT-4 in Insulin Resistance 240Tumor Necrosis Factor Induces Insulin Resistance 242Caloric 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 242PUFAs Can Reduce Insulin Resistance 244PUFAs, GLUT-4, TNF-α, Anti-oxidants, daf Genes, SIRT1, and PPARs 245Clinical Implications of the Interactions among PUFAs, daf Genes, PPARs, and Sirtuins 24620 EFAs/PUFAs and Atherosclerosis 252Atherosclerosis Is a Systemic Inflammatory Condition 252Cross-talk among Platelets, Leukocytes, and Endothelial Cells 253Leukocytes and Atherosclerosis 254EFAs Modulate Uncoupling Protein-1 Expression 255Interaction(s) among ω-3 and ω-6 Fatty Acids and Trans-fats and Saturated Fats 255Atheroprotective Actions of ω-3 and ω-6 Fatty Acids: How and Why? 259Index 265