Adipose Tissue and Adipokines in Health and Disease (eBook)

Series Editor’s Introduction 7
Foreword 10
Preface 12
Contents 15
Contributors 17
I ADIPOSE TISSUE: STRUCTURE 20
The Adipose Organ 21
1. INTRODUCTION 21
2. GROSS ANATOMY 22
3. LIGHT AND ELECTRON MICROSCOPY 23
4. VASCULAR SUPPLY 23
5. NERVE SUPPLY 24
6. HISTOPHYSIOLOGY 25
7. DEVELOPMENT AND PLASTICITY 28
8. THE ADIPOSE ORGAN OF HUMANS 33
9. CONCLUSIONS 35
REFERENCES 35
Metabolism of White Adipose Tissue 38
1. INTRODUCTION 38
2. TAG SYNTHESIS AND STORAGE 39
3. LIPOLYSIS AND RELEASE OF FATTY ACIDS 43
4. CHOLESTEROL METABOLISM 47
5. CONCLUSIONS 48
REFERENCES 48
Leptin 51
1. ADIPOCYTE BIOLOGY AND LEPTIN 51
2. LEPTIN’S EFFECTS ON THE NEUROENDOCRINE AXIS 52
3. LEPTIN RECEPTORS AND SIGNAL TRANSDUCTION IN THE BRAIN 54
4. IMPLICATIONS OF LEPTIN SIGNAL TRANSDUCTION 57
5. LEPTIN ACTION IN PERIPHERAL TISSUES 58
6. CONCLUSIONS 59
REFERENCES 60
Adiponectin 63
1. INTRODUCTION 63
2. STRUCTURAL FEATURES OF ADIPONECTIN 64
3. PLEIOTROPIC BIOLOGICAL FUNCTIONS OF ADIPONECTIN 65
4. PUTATIVE ADIPONECTIN RECEPTORS 69
5. CLINICAL STUDIES ON ADIPONECTIN 70
6. ADIPONECTIN AS A POTENTIAL THERAPEUTIC TARGET 72
7. CONCLUSIONS 72
REFERENCES 73
II ADIPOKINES AS REGULATORS OF IMMUNITY AND INFLAMMATION 76
Vasoactive Factors and Inflammatory Mediators Produced in Adipose Tissue 77
1. INTRODUCTION 77
2. ADIPOSE TISSUE AS A DYNAMIC ENDOCRINE AND PARACRINE ORGAN 78
3. ADIPOKINES WITH VASOACTIVE OR INFLAMMATORY EFFECTS 80
4. OTHER ADIPOSE-DERIVED FACTORS 85
5. MOLECULAR LINKS UNDERLYING THE ADIPOSITY– INFLAMMATION – IMMUNITY CLUSTER 87
6. CONCLUSIONS 88
ACKNOWLEDGMENTS 89
REFERENCES 89
Regulation of the Immune Response by Leptin 92
1. INTRODUCTION 92
2. LEPTIN MODULATION OF INNATE IMMUNITY 93
3. LEPTIN MODULATION OF ADAPTIVE IMMUNE RESPONSE 96
4. MECHANISMS OF LEPTIN ACTION IN IMMUNE CELLS 98
5. LEPTIN AND PATHOPHYSIOLOGY OF THE IMMUNE SYSTEM 101
6. CONCLUSIONS 102
REFERENCES 102
Leptin in Autoimmune Diseases 104
1. INTRODUCTION 104
2. LEPTIN IN MULTIPLE SCLEROSIS 105
3. LEPTIN IN TYPE 1 AUTOIMMUNE DIABETES 106
4. LEPTIN IN RHEUMATOID ARTHRITIS 107
5. LEPTIN IN LIVER AND KIDNEY IMMUNE-MEDIATED DISORDERS 108
6. LEPTIN IN ENDOMETRIOSIS 109
7. LEPTIN AND THE HYGIENE/AFFLUENCE HYPOTHESIS IN AUTOIMMUNITY 110
8. CONCLUSIONS 112
ACKNOWLEDGMENTS 112
REFERENCES 112
Leptin and Gastrointestinal Inflammation 114
1. INTRODUCTION 114
2. LEPTIN AS PIVOTAL MEDIATOR OF INTESTINAL INFLAMMATION 116
3. DIRECT ROLE OF LEPTIN ON T-CELL ACTIVATION IN INTESTINAL INFLAMMATION 117
4. BIOLOGICAL SIGNIFICANCE OF LEPTIN PRODUCED AT THE SITE OF INFLAMMATION 118
5. INFLUENCE OF LEPTIN ON ANTIGEN PROCESSING AND PRESENTING CELLS 118
6. SPONTANEOUS INTESTINAL INFLAMMATION 119
7. INFECTIOUS COLITIS MODELS 119
8. HUMAN INFLAMMATORY BOWEL DISEASE 120
9. FUTURE PERSPECTIVE 120
10. CONCLUSIONS 121
ACKNOWLEDGMENTS 121
REFERENCES 122
Adiponectin and Inflammation 124
1. INTRODUCTION 124
2. DISCOVERY OF ADIPONECTIN AND ITS CLINICAL SIGNIFICANCE 125
3. ADIPOSE TISSUE AND INFLAMMATION 126
4. ADIPONECTIN AS A POTENT ANTI-INFLAMMATION ADIPOCYTOKINE 127
5. CONCLUSIONS 129
REFERENCES 129
III INTERACTIONS BETWEEN ADIPOCYTES AND IMMUNE CELLS 131
Macrophages, Adipocytes, and Obesity 132
1. INTRODUCTION 132
2. OBESITY ACTIVATES INTRACELLULAR PATHWAYS THAT REGULATE INFLAMMATORY RESPONSES 133
3. MACROPHAGE PHYSIOLOGY 135
4. MACROPHAGES CONTRIBUTE TO OBESITY-INDUCED ADIPOSE TISSUE INFLAMMATION 136
5. RECRUITMENT OF MONOCYTES TO ADIPOSE TISSUE IN OBESITY 138
6. CONCLUSIONS 139
REFERENCES 139
Interactions of Adipose and Lymphoid Tissues 143
1. INTRODUCTION 143
2. PARACRINE INTERACTIONS OF ADIPOSE TISSUE IN HUMAN DISEASES 150
3. CONCLUSIONS 156
ACKNOWLEDGMENTS 157
REFERENCES 157
Adipose Tissue and Mast Cells 161
1. INTRODUCTION 161
2. ADIPOSE TISSUE 162
3. ADIPOSE MAST CELLS 163
4. PARACRINE EFFECTS OF ADIPOSE TISSUE 164
5. CONCLUSIONS 166
REFERENCES 167
Bone Marrow Adipose Tissue 169
1. INTRODUCTION 169
2. PLASTICITY OF BM ADIPOSE TISSUE 170
3. MORPHOLOGICAL AND FUNCTIONAL CHARACTERIZATION OF BM ADIPOCYTES 172
4. BM FAT CELL PRODUCTS 172
5. BM ADIPOCYTES ORIGINATE FROM MESENCHYMAL STEM CELLS 175
6. ADIPOCYTES AND BONE-FORMING CELLS 179
7. BM ADIPOCYTES AND HEMATOPOIESIS 183
8. CONCLUSIONS 185
REFERENCES 186
IV WEIGHT GAIN AND WEIGHT LOSS 191
The Epidemiology of Obesity 192
1. INTRODUCTION 192
2. DEFINITION 193
3. WORLDWIDE EPIDEMIC 193
4. OBESITY EPIDEMIC IN THE UNITED STATES 193
5. GENDER AND OBESITY 196
6. ETHNICITY/RACE AND OBESITY 196
7. OBESITY AND SOCIOECONOMIC STATUS 197
8. CHILDHOOD OBESITY 199
9. ADIPOSE TISSUE DISTRIBUTION 200
10. CONCLUSIONS 203
REFERENCES 204
Developmental Perspectives on the Origins of Obesity 216
1. UNDERSTANDING OBESITY REQUIRES A DEVELOPMENTAL AND EVOLUTIONARY PERSPECTIVE 216
2. DEVELOPMENTAL PERSPECTIVE ON ENERGY BALANCE IN HUMAN EVOLUTION 218
3. DEVELOPMENTAL PATHWAYS TO OBESITY 220
4. CONCLUSIONS 225
REFERENCES 226
Genetics of Obesity 229
1. INTRODUCTION 229
2. SUPPORTIVE EVIDENCE FOR THE FAMINE HYPOTHESIS 230
3. SOME FUNDAMENTAL PROBLEMS WITH THE FAMINE HYPOTHESIS 232
4. CONCLUSIONS 242
ACKNOWLEDGMENTS 242
REFERENCES 242
Inherited and Acquired Lipodystrophies 245
1. INTRODUCTION 245
2. CONGENITAL GENERALIZED LIPODYSTROPHY FROM MUTATIONS IN BSCL2 AND AGPAT2 246
3. FPL CAUSED BY MUTATIONS IN LMNA, PPARG, OR AKT2 249
4. SYNDROMIC LIPODYSTROPHIES 252
5. ACQUIRED PARTIAL LIPODYSTROPHY 253
6. ACQUIRED GENERALIZED LIPODYSTROPHY 254
7. LIPODYSTROPHY IN HIV-INFECTED SUBJECTS 254
8. ADIPOSE TISSUE DISTRIBUTION IN HUMANS AND ADIPOCYTE DIFFERENTIATION 255
9. POSSIBLE MECHANISMS FOR LOSS OF ADIPOSE TISSUE IN LIPODYSTROPHIES 258
10. CONCLUSIONS 260
ACKNOWLEDGMENTS 260
REFERENCES 260
Mechanisms of Cachexia 263
1. INTRODUCTION 263
2. MALNUTRITION VS CACHEXIA 264
3. ANOREXIA AND CACHEXIA 264
4. ENERGY EXPENDITURE IN CACHEXIA 265
5. ADIPOSE TISSUE AND LIPID METABOLISM IN CACHEXIA 266
6. SKELETAL MUSCLE IN CACHEXIA 266
7. CYTOKINES AND MUSCLE PROTEIN DEGRADATION IN CACHEXIA 267
8. PROTEOLYSIS-INDUCING FACTOR 268
9. LEPTIN AND GHRELIN IN CACHEXIA 268
10. NEUROPEPTIDES IN CACHEXIA 269
11. CONCLUSIONS 271
REFERENCES 271
Effect of Weight Loss on Disease 273
1. INTRODUCTION 273
2. METHODS OF INDUCING WEIGHT LOSS IN THE OBESE PATIENT 274
3. SPECIFIC DISEASES AFFECTED BY SUBSTANTIAL WEIGHT LOSS 276
4. CONCLUSIONS 284
REFERENCES 285
V ADIPOSE TISSUE AND DISEASE 287
Adipose Tissue and Insulin Resistance 288
1. INTRODUCTION 288
2. OBESITY AS AN INFLAMMATORY CONDITION 289
3. ROLE OF LEPTIN RESISTANCE IN OBESITY AND INSULIN RESISTANCE 289
4. ROLE OF TNF- 290
IN LINKING OBESITY TO INSULIN RESISTANCE 290
5. ROLE OF ADIPONECTIN IN INSULIN RESISTANCE 291
6. ROLE OF RESISTIN IN INSULIN RESISTANCE 291
7. ROLE OF IL-6 IN INSULIN RESISTANCE 292
8. OTHER POSSIBLE MEDIATORS OF INSULIN RESISTANCE 293
9. CONCLUSIONS 293
REFERENCES 295
Adipokines in Non-Alcoholic Fatty Liver Disease 298
1. INTRODUCTION 298
2. PATHOGENESIS OF NASH 299
3. ADIPOSE TISSUE, ADIPOKINES, AND NAFLD 299
4. ADIPOKINES IN THE EXPERIMENTAL MODELS OF NAFLD 300
5. ADIPOKINES IN PATIENTS WITH NAFLD 301
6. ROLE OF ADIPOKINES IN PROMOTING HEPATIC STEATOSIS, IR, OXIDATIVE STRESS, AND HEPATIC FIBROSIS IN NAFLD 303
7. CONCLUSIONS 309
REFERENCES 310
Adiposity and Cancer 313
1. INTRODUCTION 313
2. ASSESSMENT OF OVERWEIGHT AND OBESITY IN EPIDEMIOLOGICAL STUDIES OF DISEASE 314
3. MECHANISMS RELATING ADIPOSITY TO CANCER RISK 315
4. EPIDEMIOLOGICAL STUDIES OF OBESITY AND CANCER 316
5. ADIPOSITY AND INDIVIDUAL CANCER SITES 318
6. OVERWEIGHT, OBESITY, AND CANCER MORTALITY 325
7. POPULATION ATTRIBUTABLE FRACTION 326
8. CONCLUSIONS 326
ACKNOWLEDGMENT 327
REFERENCES 327
Obesity and the Heart 332
1. INTRODUCTION 332
2. OBESITY AND MORTALITY 332
3. STRUCTURAL AND METABOLIC CHANGES IN OBESITY AND IMPACT ON CVD RISK 333
4. CARDIOVASCULAR RISK FACTORS OF OBESITY 337
5. METABOLIC SYNDROME 337
6. CONCLUSIONS 340
REFERENCES 341
Obesity and Asthma 345
1. INTRODUCTION 345
2. DEFINITION AND EPIDEMIOLOGY OF ASTHMA 346
3. DEFINITION OF OBESITY 346
4. ASSOCIATION BETWEEN OBESITY AND ASTHMA 346
5. CAUSAL HYPOTHESES 348
6. CONCLUSIONS 352
REFERENCES 352
Adiposity and Kidney Disease 354
1. INTRODUCTION 354
2. EFFECT OF ADIPOSE TISSUE ON PROGRESSION OF KIDNEY DISEASE 355
3. MANAGEMENT 358
4. EFFECTS OF KIDNEY DISEASE ON ASSOCIATIONS OF ADIPOSITY WITH CARDIOVASCULAR RISK FACTORS AND CARDIOVASCULAR DISEASE 358
5. CONCLUSIONS 360
REFERENCES 360
Obesity and Joint Disease 362
1. INTRODUCTION 362
2. OBESITY AND JOINT STRUCTURE 363
3. ASSOCIATION BETWEEN OBESITY AND OA AT DIFFERENT JOINTS 366
4. ROLE OF OBESITY IN THE ONSET AND PROGRESSION OF OA 368
5. ASSOCIATION BETWEEN OA AND BODY FAT DISTRIBUTION 369
6. MECHANISMS FOR OBESITY IN THE PATHOGENESIS OF OA 369
7. ROLE OF WEIGHT LOSS IN PREVENTION AND MANAGEMENT OF OA 371
8. CONCLUSIONS 372
REFERENCES 372
APPENDICES 375
Appendix I 376
ABBREVIATIONS 376
Appendix II 382
USEFUL READING MATERIAL 382
BOOKS 382
JOURNALS 383
USEFUL WEB SITES 383

Adipose Tissue and Insulin Resistance (p. 281-282)

Stephen E. Borst

21 Abstract

Adiposity, especially visceral adiposity, is an important risk factor for the development of insulin resistance and type 2 diabetes. In addition to its role in storing energy, adipose tissue also secretes into the circulation a number of hormones and other factors that can alter the response to insulin in distant tissues, such as liver and muscle. Many of these factors are cytokines, which have been associated with the immune system.

Fat-derived hormones that can enhance insulin signaling include leptin, adiponectin, and possibly visfatin. Those impairing insulin signaling include tumor necrosis factor- , resistin, and several of the interleukins. Obesity has also been identified as a low-grade inflammatory state. Several possible mechanisms are discussed whereby rapid growth of adipose tissue might trigger a local inflammatory response. It is suggested that this inflammatory response and associated release of cytokines may constitute the link between obesity and insulin resistance.

Key Words: Tumor necrosis factor, resistin, adiponectin, interleukins, free fatty acids, subcutaneous fat, visceral fat, insulin signaling.

INTRODUCTION

Obesity and type 2 diabetes are the most common metabolic diseases in Western society, together affecting as much as half of the adult population (1). Not only is the prevalence of these conditions high, but it also continues to increase. Insulin resistance a prediabetic condition, characterized by a failure of target organs to respond normally to insulin. Insulin resistance includes a central component (incomplete suppression of hepatic glucose output) and a peripheral component (impaired insulin-mediated glucose uptake in skeletal muscle and adipose tissue) (2). When increased insulin secretion is no longer sufficient to prevent hyperglycemia, the subject progresses from insulin resistance to type 2 diabetes. Insulin resistance is associated with other conditions such as central obesity, hypertension, and dyslipidemia, all risk factors for cardiovascular disease. The constellation of these metabolic abnormalities has been termed metabolic syndrome.

Obesity is a well-recognized risk factor for the development of insulin resistance and metabolic syndrome. In addition to the total amount of fat, distribution of adipose tissue also important, with most studies concluding that visceral fat contributes considerably more to insulin resistance than does subcutaneous fat (3). However, one report, by Misra al., documented a robust correlation between posterior abdominal subcutaneous fat and insulin resistance (4). Underscoring the importance of visceral fat is the report by Klein et al. that liposuction, resulting in a substantial reduction of subcutaneous fat, did not enhance insulin responsiveness in insulin-resistant subjects (5). In rats, we (6) and others (7) have found that surgical removal of visceral fat reverses insulin resistance.

Traditionally, adipose tissue has been regarded largely as a depot for stored fat. More recently, it has become clear that adipose tissue plays an active role in energy metabolism and is the source of hormones, cytokines, and metabolites that play an important role in whole-body metabolism (8). The role of these substances may be either autocrine or endocrine. Adipose tissue, especially visceral fat, is the source of a number of substances that might play a role in the development of insulin resistance. Among the latter are tumor necrosis factor (TNF)- , adiponectin, interleukin (IL)-6, resistin, and free fatty acids. The difference in the metabolic effects of visceral versus subcutaneous fat may be attributed both to differences in the hormones secreted by the two types of fat and to the fact that hormones secreted by visceral fat reach the liver in high concentration. The latter is due to the fact that visceral fat drains into the portal circulation, whereas subcutaneous fat drains into the systemic circulation (8). This review will focus on the regulation of insulin responsiveness by adipokines and on evidence supporting the hypothesis that these hormones play a role in the pathophysiology of insulin resistance.