 |
Adipose tissue in health and disease / edited by Todd Leff and James G. Granneman. — Weinheim : Wiley-Blackwell, c2010. – (63.8515/A235) |
Contents
Contents
Preface
List of Contributors
Part One Adipose Tissue Development and Morphology
1 Transcriptional Control of Adipogenesis and Fat Cell Gene Expression
1.1 Introduction 3
1.2 Transcriptional Control of Adipogenesis 4
1.2.1 AP-1 Transcription Factors 4
1.2.2 Signal Transducers and Activators of Transcription 5
1.2.3 Kruppel-Like Factors 6
1.2.4 SREBPs 7
1.2.5 C/EBP 7
1.2.6 PPAR-y 8
1.3 Identification of Adipocyte Transcription Factor Target Genes 9
1.3.1 C/EBP Target Genes 9
1.3.2 SREBP-1 Target Genes 10
1.3.3 PPAR-y Target Genes 11
1.3.4 STAT-5 Target Genes 12
1.3.5 Summary 13
References 14
2 Cellular and Molecular Basis of Functional Differences among Fat Depots
2.1 Introduction 21
2.1.1 Fat Tissue Function 21
2.1.2 Diversity in Fat Distribution 23
2.1.3 Regional Differences in Fat Tissue Growth 24
2.1.4 Disease Associations 26
2.2 Physiology 27
2.2.1 Contribution of Inherent Cell Dynamic Mechanisms to Regional Differences
2.2.2 Preadipocyte Function 29
2.2.3 Preadipocyte Replication 29
2.2.4 Differences in Adipogenesis among Depots 30
2.2.5 Regional Variation in Susceptibility to Apoptosis 32
2.2.6 Differences in Preadipocyte Subpopulations among Fat Depots 32
2.2.7 Differences in Preadipocyte Gene Expression Profiles among Depots 33
2.3 Conclusions 35
References 36
3 Plasticity of the Adipose Organ 49
3.1 Introduction 49
3.2 Gross Anatomy Demonstrates that WAT and BAT are Mixed Together in the Adipose Organ 50
3.3 Light and Electron Microscopy show that White and Brown Adipocytes have a Well-Defined and Distinct Morphology 51
3.3.1 WAT 51
3.3.2 BAT 52
3.4 WAT and BAT have a Different Vascular and Nerve Supply 53
3.5 WAT and BAT have a Different Physiology 54
3.6 Phenotype of the Adipose Organ is Variable: Plasticity of the Adipose Organ
3.6.1 Transformation of the Phenotype: Cold and Warm Exposure and Acclimatization
3.6.2 Transformation of the Phenotype: Pregnancy and Lactation 58
3.6.3 Transformation of the Phenotype: Hypertrophy and Hyperplasia (Positive Energy Balance: Overweight and Obesity) 59
3.6.4 Transformation of the Phenotype: Hypoplasia (Negative Energy Balance: Caloric Restriction and Fasting) 60
3.7 Adipose Organ of Humans 61
References 63
4 Biology of Adipose Tissue Stem Cells 69
4.1 Introduction 69
4.2 In Situ Localization and Embryology 69
4.3 Isolation Methods 70
4.3.1 Yield， Proliferation Rate， Depot， and Aging Influences 70
4.4 Characterization 71
4.4.1 Immunophenotype 71
4.4.2 Immunogenicity 71
4.4.3 Proteomic and Transcriptomic Analysis 72
4.4.4 Cytokine Profile 72
4.4.5 Clonality 72
4.5 Differentiation and Potential Utility for Regenerative Medicine
4.5.1 Mesodermal Lineages 73
4.5.2 Endodermal and Ectodermal Lineages 73
4.6 Conclusions 74
References 74
Part Two Metabolic Functions of Adipose Tissue 81
5 Molecular Mechanisms of Adipocyte Lipolysis 83
5.1 Introduction 83
5.2 Key Players in Adipocyte Lipolysis 83
5.2.1 Lipid Droplets and Droplet Scaffold Proteins 84
5.2.2 Lipases 86
5.3 Lipolytic Protein Trafficking 88
5.3.1 PLIN Subcellular Targeting 88
5.3.2 Interactions with CGI-58 88
5.3.3 Interactions with HSL 89
5.3.4 Interactions with ATGL 89
5.3.5 Disruption and Dispersion of Lipid Droplets Following PKA Activation 90
5.3.6 Additional Interactions 90
5.4 Working Model and Unresolved Issues 91
References 93
6 New Developments in the Lipolytic Processing of Triglyceride-Rich Lipoproteins 97
6.1 Introduction 97
6.2 LPL 98
6.3 Functional Domains of LPL 99
6.4 Regulation of LPL Activity by Angiopoietin-Like Proteins 100
6.5 Role of GPIHBP1 in the Lipolysis of Triglyceride-Rich Lipoproteins 101
6.6 Role of Apo-AV in Lipolysis 103
6.7 Newly Discovered Regulators of LPL Activity and their Physiological Significance 104
References 105
7 Intracellular Fatty Acid Transport， Activation， and Tramcking 109
7.1 Introduction 109
7.2 Fatty Acid-Binding Protein Family 109
7.2.1 Function and Regulation of FABP-4 110
7.2.2 Function and Regulation of FABP-5 112
7.3 Fatty Acid Activation and Channeling: Role of Long-Chain Acyl-CoA Synthetases and Fatty Acid Transport Proteins 113
7.4 Role of Acyl-CoA-Binding Protein in Acyl-CoA Metabolism 116
7.5 Regulation and Function of Distinct Fatty Acid and Acyl-CoA Pools / 17
7.6 Contribution of Fatty Acid and Acyl-CoA Metabolism to Metabolic Diseases 119
7.7 Conclusions 121
References 121
8 Aquaporins and Adipose Tissue: Lesson from Discovery to Physiopathology and to the Clinic of Aquaporin Adipose (AQP7) 129
8.1 Introduction 129
8.2 Characteristics of Adipocytes and Gycerol Metabolism in the Mammalian Body
8.3 Adipose Glycerol Channel: AQP7 132
8.3.1 AQP7: A Putative Adipose-Specific Glycerol Channel 132
8.3.2 Function and Regulation of AQP7 in Adipocytes 134
8.3.3 Human AQP7 Genetic Mutation 137
8.3.4 Adipose-Derived Glycerol and Gluconeogenesis through AQP7 - Lessons from AQP7-Deficient Mice and Cells 139
8.4 Hepatic Glycerol Channel: AQP9 141
8.4.1 AQP9: A Putative Hepatic-Specific Glycerol Channel 141
8.4.2 Gluconeogenesis through AQP9 - Lessons from AQP9-Deficient Mice 142
8.5 Coordination of Adipose Glycerol Channel， AQPT， and Hepatic Glycerol Channel， AQP9 143
8.6 Dysregulation of AQP7 and AQP9 in Obesity with Insulin Resistance 143
8.7 Conclusions 144
References 144
9 Signaling Pathways Controlling Lipolysis and Lipid Mobilization in Humans
9.1 Introduction 149
9.2 Role of Lipases in the Regulation of Hydrolysis of Fat Cell Triacylglycerols
9.2.1 Hormone-Sensitive Lipase 151
9.2.2 Adipose Tissue Triglyceride Lipase 151
9.3 Adrenergic Control of cAMP Production， Lipolysis and Lipid Mobilization 152
9.4 Control of cAMP Production by Adenylyl Cyclase Inhibitors - Inhibition of Lipolysis 157
9.5 Insulin: A Major Antilipolytic Agent Controlling cAMP Degradation 158
9.6 Natriuretic Peptides Control cGMP Production， Lipolysis， and Lipid Mobilization in Humans 159
9.6.1 Natriuretic Peptides 159
9.6.2 Lipolytic Effect of Natriuretic Peptides 160
9.6.3 Induction of Lipid Mobilization by Administration of Pharmacological Doses of ANP 162
9.6.4 Contribution of ANP to the Physiological Control of Lipid Mobilization in Humans 162
9.7 Other Lipolytic Pathways 163
9.7.1 Growth Hormone 163
9.7.2 IL-6 164
9.7.3 TNF-α 165
9.7.4 Other Lipolytic Peptides 166
9.8 Future Trends and Pharmacological Prospects 167
References 168
Part Three Endocrine Functions of Adipose Tissue 181
10 Leptin Secretion and Action 183
10.1 Introduction 183
10.2 Leptin Synthesis 184
10.2.1 Gender and Body Fat Distribution Determine Serum Leptin 184
10.2.2 Caloric Intake， Insulin， and Glucose Influence Serum Leptin 185
10.2.3 Transcriptional Regulation of Leptin Synthesis in Adipocytes 186
10.3 Leptin Receptors 187
10.4 Leptin Action in the Central Nervous System 187
10.5 Leptin Resistance in Obesity 189
10.6 Metabolic Complications of Hyperleptinemia in Obesity 190
10.6.1 Leptin and Obesity-Related Hypertension 190
10.6.2 Other Possible Pathologic Effects of Leptin 191
10.7 Leptin Therapy in Humans 192
10.7.1 Leptin， Weight Loss， and Human Obesity 192
10.7.2 Congenital Leptin Deficiency 192
10.7.3 Lipodystrophic Leptin Deficiency 193
10.7.4 Hypothalamic Amenorrhea 193
10.8 Conclusions 194
References 194
11 Adiponectin 201
11.1 Introduction 201
11.2 Adiponectin Structure and Post-Translational Modifications 202
11.3 Significance and Bioactivity of Adiponectin Multimers 204
11.4 Adiponectin and Liver 205
11.5 Adiponectin and Skeletal Muscle 206
11.6 Adiponectin and the Vasculature 206
11.7 Adiponectin and the Brain 207
11.8 Adiponectin Expression and Secretion 208
11.9 Adiponectin Secretion 209
11.10 Ectopic Adiponectin Expression 211
11.11 Regulation of Expression and Secretion 212
11.11.1 Oxidative stress 212
11.11.2 Activators of PPARy - TZDs and Fish Oils 213
11.11.3 Weight Loss 213
11.11.4 Other Agents 214
11.12 Adiponectin Clearance 214
11.13 Adiponectin Receptors and Downstream Effectors 215
11.14 Adiponectin Signaling 216
11.15 Conclusions 217
References 218
12 Preadipocyte factor-1 and Adipose Tissue-Specific Secretory Factor/Resistin - Two Secreted Factors from Adipose Tissue: Role in Adipogenesis and Insulin Resistance 231
12.1 Introduction 231
12.2 Pref-1 Structure 232
12.3 Pref-1 Inhibition of Adipocyte Differentiation 233
12.4 Mechanism for Pref-1 Function 234
12.5 In Vivo Effect of Pref-1 on Adipogenesis and Glucose/Insulin Homeostasis
12.6 ADSF/Resistin: Identification and Structure 236
12.7 ADSF/Resistin Expression and Function 237
12.8 Conclusions 239
References 240
13 Adipose Tissue and Blood Pressure Regulation 245
13.1 Introduction 245
13.2 Adipose Tissue Changes with Obesity:. Relation to Blood Pressure Control
13.2.1 Adipocyte RAS in Obesity-Related Hypertension 247
13.2.2 Leptin in Obesity-Related Hypertension 249
13.2.3 Adiponectin in Obesity-Related Hypertension 250
13.2.4 Insulin and Obesity-Related Hypertension 251
13.2.5 Plasminogen Activator Inhibitor-1 and Obesity-Related Hypertension 252
13.2.6 Free Fatty Acids and Obesity-Related Hypertension 252
13.2.7 Resistin and Obesity-Related Hypertension 253
13.2.8 11β-HSD-1 and Obesity-Related Hypertension 254
13.3 Regional Adipose Deposition and Blood Pressure Regulation 254
13.3.1 Changes in Visceral Adipose Tissue in Obesity-Related Hypertension 255
13.3.2 Potential Role for Perivascular Adipose Tissue in Obesity-Related Hypertension 255
13.4 Conclusions 256
References 257
14 Adipokines， Inflammation， and Obesity 265
14.1 Introduction 265
14.2 Contribution of Adipose Tissue in Systemic Inflammation during Obesity 266
14.3 Adipose Tissue Depots and Adipokine Production 268
14.4 Adipokines and Adipose Tissue Cell Types 269
14.5 Adipokines， Macrophages， and the Biology of Adipocytes 270
14.5.1 Chemoattraction 271
14.5.2 Paracrine Cross-Talk in the Adipose Tissue via Adipokines 272
14.6 Adipokines and Complications of Obesity 274
14.7 Adipokines and Weight Loss 275
14.8 Conclusions 276
References 276
Part Four Adipose Tissue and Disease 283
15 Depot-Specific Biology of Adipose Tissues: Links to Fat Distribution and Metabolic Risk 285
15.1 Introduction 285
15.2 Adipose Depots: Definitions 286
15.3 Physiological and Anatomical Differences among Depots may Drive Functional Heterogeneity 286
15.3.1 Depot Differences in Cellular Composition 286
15.3.2 Definition of Visceral Fat Depots 287
15.4 Heterogeneity in Adipocyte Function among Adipose Depots 288
15.4.1 Lipolysis 288
15.4.2 Triglyceride Deposition 289
15.4.3 Glucose Uptake and Insulin Action 290
15.5 Regional Differences in Adipose Tissue Gene Expression and Protein Production: Relationship to the Metabolic Syndrome 291
15.6 Search for Novel Adipokines with Depot-Specific Expression that Link Regional Adiposity to Metabolic Risk 291
15.7 Importance of Adipose Tissue Macrophages and other Immunocytes in Regional Adipose Tissue Dysfunction 293
15.8 Gene Expression Profiles are Providing New Insights on Regional Adipose Growth and Function 295
15.9 Depot Differences in Cell Proliferation and Differentiation Capacity 296
15.10 Conclusions and Future Directions 297
References 298
16 Viral Induction of Obesity and Adipogenesis 307
16.1 Introduction 307
16.2 Viruses 313
16.2.1 Canine Distemper Virus 313
16.2.2 Rous-Associated Virus-7 314
16.2.3 Borna Disease Virus 314
16.2.4 Adenoviruses 315
16.3 Chlamydia pneumoniae 320
16.4 Gut Microbiota 320
16.5 Gut Parasites 321
16.6 Scrapie Agents 322
16.7 Interaction of Pathogens and Adipose Tissue 323
16.8 Adipogenic Pathogens and Humans 324
16.9 Conclusions 324
References 325
17 Adipose Tissue Cachexia 333
17.1 Introduction 333
17.2 Changes in Adipose Tissue in Cachexia 333
17.3 Energy Expenditure in Cancer Patients 335
17.4 Factors Governing Adipose Tissue Mass 336
17.5 Mechanism of Loss of Adipose Tissue in Cachexia 337
17.6 Requirements of Tumor-Bearing Animals for Lipids 338
17.7 Fat-Mobilizing Substances in Cancer Cachexia 338
17.8 Conclusion 340
References 342
18 Obesity and Diabetes: Lipotoxicity 347
18.1 Introduction 347
18.2 White Adipose Tissue at the Center of Lipid Homeostasis and Delivery 348
18.3 Insulin Resistance in Adipocytes Disrupts the Balance between Lipid Storage and Secretion 348
18.4 Scenarios that may Result in Ectopic Fat Deposition 348
18.4.1 Altered Plasticity of the Adipose Tissue: A Shift in Expansion Towards Hypertrophy 349
18.4.2 Impaired Fat Deposition Capacity in Adipose Tissue 350
18.4.3 Inappropriate Balance of Substrate Uptake and Oxidative Capacity in Peripheral Tissue 353
18.5 Mechanisms Contributing to the Lipotoxicity in the Peripheral Organs 355
18.5.1 Lipotoxicity in Skeletal Muscle 355
18.5.2 Molecular Mechanisms for the Generation of Muscle Lipotoxicity 356
18.6 Impaired Oxidation as a Trigger for Lipotoxicity 360
18.6.1 Adipocytokine's Proinflammatory Activity Contributes to Lipotoxicty in Skeletal Muscle 361
18.6.2 Lipotoxicity and Insulin Resistance Affecting Liver Metabolism 362
18.7 Pancreatic β-Cell as a Target for Lipotoxicity 363
18.8 New Analytical and Computational Methods to Identify Lipotoxicity-Related Metabolic Networks 363
18.9 Lessons from Lipotoxicity - Potential Antilipotoxic
Therapeutic Strategies 365
References 365
19 Obesity and Cancer 369
19.1 Introduction 369
19.2 Epidemiology 369
19.2.1 Excess Body Weight and Cancer Risk 369
19.2.2 Excess Body Weight and Cancer Mortality 370
19.3 Biological Mechanisms 371
19.3.1 Candidate Mechanisms 371
19.3.2 Insulin and IGFs 372
19.3.3 Sex Steroids 376
19.3.4 Adipokines 378
19.4 Other Biological Candidates 380
19.4.1 Obesity-Related Inflammatory Markers 380
19.4.2 Nuclear Factor-xB System 381
19.4.3 Oxidative Stresses 381
19.5 Mechanical Mechanisms 381
19.6 New Research Areas 382
References 382
2O Overview of Acquired and Genetic Lipodystrophies 385
20.1 Introduction 385
20.2 Congenital Lipodystrophies 386
20.2.1 Congenital Generalized Lipodystrophy (Berardinelli-Seip Syndrome) 386
20.2.2 Familial Partial Lipodystrophy 390
20.3 Acquired Lipodystrophies with a Possible Genetic Component 393
20.3.1 Acquired Generalized Lipodystrophy 393
20.3.2 Acquired Partial Lipodystrophy (Barraquer-Simons Syndrome) 393
20.3.3 HIV-Related Lipodystrophy 394
20.4 Lipodystrophy Associated with other Syndromes 395
20.4.1 Mandibuloacral Dysplasia 395
20.4.2 SHORT Syndrome 396
20.4.3 Neonatal Progeroid Syndrome 396
20.4.4 Hutchinson-Gilford Progeria Syndrome 396
20.4.5 Werner Syndrome 397
2O.5 Conclusions 397
References 398
21 Mouse Models of Lipodystrophy 403
21.1 Introduction 403
21.2 Physiological Mechanisms of Lipodystrophy in Mouse Models 403
21.3 Lipodystrophic Models with Impaired Adipogenesis 407
21.3.1 A-ZIP/F1 Transgenic Mouse 408
21.3.2 aP2- SREBP-lc Transgenic Mouse 408
21.3.3 Mouse Models with Altered PPAR-y Levels 409
21.3.4 C/EBPct-Deficient Mouse 410
21.3.5 Zmpste24-Deficient Mice 410
21.4 Lipodystrophic Models with Impaired Triacylglycerol Biosynthesis 411
21.4.1 GPAT1-Deficient Mouse 411
21.4.2 AGPAT6-Deficient Mouse 412
21.4.3 DGAT1-Deficient Mouse 412
21.4.4 Lipin-l-Deficient Mouse 412
21.5 Lipodystrophic Models with Enhanced Energy Expenditure 414
21.5.1 Leptin Transgenic Mouse 414
21.5.2 PPAR-8 Transgenic Mouse 415
21.5.3 FOXC2 Transgenic Mouse 415
21.6 Mouse Models with Acquired or Conditional Lipodystrophy 416
21.6.1 aP2-DTATransgenic Mouse 416
21.6.2 FAT-ATTAC Transgenic Mouse 416
21.6.3 RSK2 Deficient Mouse 417
21.6.4 Drug-Induced Lipoatrophy 417
21.6.5 Diet-Induced Lipoatrophy 417
21.7 Conclusions 418
References 419
22 Caloric Restriction， Longevity， and Adiposity 423
22.1 Introduction 423
22.2 Physiological Changes with Aging 424
22.3 Aging and Caloric Restriction 424
22.4 Energy Restriction may Alter the "Rate of Living" 425
22.5 CR and Oxidative Stress 426
22.6 CR and Cardiovascular Disease 427
22.7 CR and Insulin Resistance/Type 2 Diabetes Mellitus 427
22.8 What is Known from Humans? 427
22.8.1 Centenarians from Okinawa 427
22.8.2 Vallejo Study 428
22.8.3 Unexpected CR in Biosphere 2 428
22.8.4 Randomized Controlled Trials of Prolonged CR in Humans 429
22.9 Could CR Increase Longevity in Humans? 431
22.9.1 How Much CR? 432
22.9.2 How Long is CR Required? 432
22.10 CR Mimetics 433
22.11 Conclusions 434
References 434
23 Peroxisome Proliferator-Activated Receptor-y: A Key Regulator of Adipose Tissue Formation， Remodeling， and Metabolism 441
23.1 Introduction 441
23.2 Molecular Biology of PPAR-y 442
23.2.1 PPAR-y Structure and DNA Binding 442
23.2.2 Transcriptional Regulation by PPAR-y 444
23.3 PPAR-y is a Master Regulator of Adipose Tissue Development 447
23.3.1 Role of PPAR-7 in Adipogenesis - Cell Culture Studies 447
23.3.2 PPAR-y is Required for Adipose Tissue Development In Vivo 448
23.4 Metabolic Functions of PPAR-~ 449
23.5 White versus Brown Fat-Specific Functions of PPAR-y 450
23.6 PPAR-y Function in Adipose Tissue Maintenance and Remodeling 452
23.7 Conclusions 454
References 454
24 Early-Life Programming of Adipogenesis and Adiposity 459
24.1 Introduction 459
24.2 Theories for the Developmental Origins of Obesity 460
24.3 Evidence for the Developmental Origins of Obesity 460
24.3.1 Data from Humans 461
24.3.2 Data from Animal Models 461
24.4 Adipogenesis 462
24.4.1 Adipogenesis In Vitro 462
24.4.2 Control of Adipogenesis 463
24.4.3 Developmental Alterations to Adipogenesis 464
24.5 Potential Mechanisms? 465
24.5.1 Glucocorticoids 465
24.5.2 Leptin 465
24.5.3 Epigenetic Alterations 467
24.6 Future Perspectives 467
24.6.1 Optimizing Early Life Nutrition? 467
24.6.2 Interventions? 467
References 468
25 Evolutionary Aspects of Obesity and Adipose Tissue Function 473
25.1 Introduction 473
25.2 Thrifty Genotype and Phenotype Hypotheses 474
25.3 Ethological Approach 476
25.3.1 Ontogeny 477
25.3.2 Fitness Value 478
25.3.3 Evolutionary History 480
25.4 Significance of Agriculture 482
25.5 Significance of Colonizing 483
25.6 Significance of Social Inequality 485
25.7 New Obesogenic Environment 486
References 487
Index 491
