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Inserm Institut National de la Santé et de la Recherche Médicale

Inserm Institut National de la Santé et de la Recherche Médicale. Physiopathology of obesity and current theories on the association between an excess of fat mass and insulin resistance Prof. Dominique Langin. Contents. Slides. Fat stores, adipose tissue and complications of obesity 3-7

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Inserm Institut National de la Santé et de la Recherche Médicale

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  1. Inserm Institut National de la Santé et de la Recherche Médicale Physiopathology of obesity and current theories on the association between an excess of fat mass and insulin resistance Prof. Dominique Langin

  2. Contents Slides Fat stores, adipose tissue and complications of obesity 3-7 White and brown adipose tissues: Adipocyte differentiation 8-13 Metabolism and pathogenic action of fatty acids 14-23 Diversity of adipose tissue cell types and production of endocrine 24-22 and paracrine factors Summary 33 Abbreviations used 34-36

  3. Fat stores, adipose tissue and complications of obesity

  4. Fat mass, adipose tissue and energy stores Liver triglycerides = 450 kcal Muscle triglycerides =3000 kcal Liver glycogen = 400 kcal Muscle glycogen =2500 kcal Adipose tissue triglycerides = 120,000 kcal Data for a 70 kg lean subject. Subject with morbid obesity : x 8 TG

  5. Anatomical distribution of adipose tissue • Subcutaneous adipose tissue : • - abdominal • - femoral • Intraabdominal adipose tissue : • - visceral (mesenteric and omental) • - retroperitoneal (perirenal and perigonadic) • Other depots : • - intra and intermuscular • - perivascular • - epicardiac Different physiological and pathogenic roles of the fat depots

  6. Heterogeneous distribution of adipose tissue and risks of metabolic and cardiovascular complications The apple The pear Visceral vs. subcutaneous obesity Gender differences Differences in risk for complications Dyslipidemia, type 2 diabetes, hypertension, coronary heart disease, … Nature. 2006 444:881-7

  7. Medical Complications of Obesity Idiopathic intracranial hypertension Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome Stroke Cataracts Nonalcoholic fatty liver disease steatosis steatohepatitis cirrhosis Coronary heart disease Diabetes Dyslipidemia Hypertension Gall bladder disease Severe pancreatitis Gynecologic abnormalities abnormal menses infertility polycystic ovarian syndrome Cancer breast, uterus, cervix colon, esophagus, pancreas kidney, prostate Osteoarthritis Phlebitis venous stasis Skin Gout

  8. White and brown adipose tissues Adipocyte differentiation

  9. White adipose tissue For letter symbols, see slide 36

  10. WAT BAT For letter symbols, see slide 36

  11. Multilocular adipocyte Lipid storage and mobilization (++) Mitochondria (+++) Fatty acid oxidation (+++) Respiratory chain (+++) UCP1 (+++) PGC-1a(+++) Brown adipocyte Characteristics of brown and white adipocytes White adipocyte Unilocular adipocyte ( 200µm) Lipid storage and mobilization (+++) Mitochondria (+) Fatty acid oxidation (+) Respiratory chain (+) UCP1 (0) PGC-1a(+)

  12. SREBP1c / ADD1 RXRa PPARb PPARg C/EBPb/d C/EBPa Wnt signaling GATA 2 & 3 Transcriptional control of adipocyte differentiation proliferation differentiation fat cell-specific gene expression J. Lipid Res., 2002, 43, 835-860

  13. Thermogenesis Fat storage & mobilization Endocrine organ PGC-1a PRDM16 Biochem J. 2006 398:153-68 Genes Dev, 2000, 14, 1293-1307

  14. Metabolism and pathogenic action of fatty acids

  15. Overview of fatty acid metabolism Alternate fuel source for brain and other organs Liver NEFA TG Ketone bodies and CO2 Adipose tissue VLDL TG LPL Lipases NEFA Chylomicrons (lymphatic circulation) LPL TG FA Muscle, myocardium, kidney cortex, etc. Intestinal absorption CO2 Essays Biochem. 2006;42:89-103.

  16. IR Glucose VLDL CL LPL ASP CD36 FAT GLUT4 NH2 IRS GLUT4 PDE 3B PI3-K COOH Glucose 6-P PKB Pyruvate Fatty acids Acetyl-CoA Glycerol 3-P Fatty acids DGAT Fatty acid and glucose metabolism in white adipocytes 1- 2- 3- AR 2-AR NH2 AC Gs Gi COOH ATP cAMP 5' AMP PKA ALBP ATGL HSL HSL P Perilipins Fatty acids Triglycerides

  17. Lipolysis in human white adipocytes ATGL FFA glycerol Natriuretic peptide receptor A ? Aquaporin 7 Insulin receptor ALBP-FA GC MGL AMPK cGMP IRS triglycerides HSL HSL PKG PI3-K ? PDE-3B PKB Perilipin PKA cAMP b1/2-AR, Others ? Gs AC Gi a2-AR, HM74A, A1 receptor, EP3 receptor, Y1 receptor Pharmacol. Res. 2006 53:482-91

  18. Coordination of the regulation of fat deposition and fat mobilization in white adipose tissue Fed Fasting LPL Triglycerides Fatty acids + Gut Esterification + Triglycerides - + Catecholamines Glycerol 3-phophate ANP, BNP Lipases Glucose Fatty Acids + Glycerol To liver, muscle + Glut4 To liver Pancreas Insulin

  19. PKA Adrenergic control of metabolism in brown fat cells 1, 2, 3 A C Plasma membrane Gs T HERMOGENESIS Mitochondrial biogenesis (PGC1) UCP1 transcription cAMP UCP1 activation Lipolysis (FA) b oxidation

  20. Lipolysis FA esterification FA esterification b oxidation Differences in the fate of fatty acids between brown and white fat cells White adipocyte Brown adipocyte Glycerol Glycerol FA FA Glycerol FA Glycerol Lipolysis Triglycerides Triglycerides FA FA FA FA FA FA Glycerol-3P Glycerol-3P Glucose, amino acids, lactate, pyruvate Glycerol, glucose

  21. Deleterious effects of an excess of nonesterified fatty acids SNS activity Triglycerides Myocardial performance Increased lipolysis Thrombosis Antilipolytic effect HDL-C NEFA VLDL secretion Insulin resistance LDL particle size Glucose utilisation Glucose production Glucose intolerance Hyperinsulinemia Hypertension

  22. Role of fatty acids in obesity complications Subcutaneous adipose tissue Visceral adipose tissue Vessels Thrombosis Heart Myocardial performance Portal and visceral FA Abdominal FA FA hepatic flux Skeletal muscle Liver Hepatic glucose production Non alcoholic steatohepatitis Glucose utlization Pancreas Increased synthesis of TG-rich VLDL Hyperinsulinemia Glucose intolerance Insulin resistance Hyperlipidemia Obesity complications

  23. Potential therapeutic strategies associated with fatty acid metabolism Inducers Ligands Gi Inhibitors PKA Nicotinic acid HM74a A C PGC1a Nuclear receptors cAMP Lipid utilization Fat mass? HSL ATGL Lipolysis A combination of PGC-1a inducers and nuclear receptor ligands may constitute a strategy to combat obesity Antilipolysis as a strategy to combat the metabolic syndrome Trends Endocrinol Metab 2006 ;17 :314-320. Trends Endocrinol Metab 2003;14 :439-441.

  24. Diversity of adipose tissue cell types and production of endocrine and paracrine factors

  25. Cell types in white adipose tissue -adipocytes (lipid-filled cells) 30% - preadipocytes and fibroblasts - matrix of collagen fibres - blood vessels (capillaries/endothelial cells) - immune cells (monocytes/macrophages, lymphocytes) Macrophages Lymphocytes Monocytes Preadipocytes Endothelial cells Adipocytes

  26. Adipose tissue development : beyond adipocyte differentiation Mature adipocytes Preadipocytes Endothelial cells Mature adipocytes ADIPOCYTE HYPERTROPHY & HYPERPLASIA ANGIOGENESIS INFLAMMATION Macrophages Preadipocytes

  27. Cellular origin of the peptides secreted by human adipose tissue Adipocytes  Adipokines Stromavascular fraction cells  cytokines & chemiokines Monocyte chemoattractant protein 1 (MCP1) Macrophage inflammatory protein (MIP) Tumor necrosis a (TNFa) Interleukins 1b, 6, 8, 10, …. Chemiokines Resistin Apelin … Leptin Adiponectin Serum amyloids Retinol binding protein 4 (RBP4) Apelin FIAF/PGAR

  28. Crosstalk between the cells ADIPOCYTE Leptin  HYPERTROPHIED ADIPOCYTE  NEFAs Cytokines  Hypertrophy of adipocytes & triglyceride overload Adiponectin NEFA others MCP-1 MIP-1a others TNF-a MCP-1 IL-1b others preadipocyte TNF-a others Macrophage TNF-a MIP-1a MCP-1 others Activation and infiltration of macrophages

  29. b oxidation FA, Other metabolites, Adipokines, … Glycerol Lipolysis FA FA Triglycerides FA FA esterification Glycerol-3P TNFa, Cytokines, Chemiokines, …

  30. Systemic and local roles of adipose tissue macrophages activation monocytes adhesion endothelial dysfunction insulin resistance Bone marrow transmigration PECAM-1, ICAM-1 PECAM-1, ICAM-1 leptin/adiponectin interplay MCP-1 proteases differentiation systemic effects: low-grade inflammatory state macrophages Adipocyte VEGF M-SCF MIF LPA…. retention local effects: angiogenesis, neovascularization adipose growth TNF-a, IL-6, IL-8 MCP-1, resistin, visfatin…… proinflammatory cytokines reactive oxygen species (ROS) Curr. Opin. Clin. Nutr. Metab. Care, 2005, 8: 347

  31. Adipose tissue infiltration by macrophages in obesity J. Clin. Invest. 2006;116:33-35 J. Intern. Med. 2007;262:422-430

  32. Role of adipokines and cytokines in obesity complications Subcutaneous adipose tissue Visceral adipose tissue macrophages IL-6 TNF-a Secretions : Leptin Adiponectin RBP4 TNF-a, IL-6… Skeletal muscle Liver utilisation glucose Other target tissues Vessels atherosclerosis, hypertension Non alcoholic CRP steatohepatitis PAI1 Glucose intolerance Insulin resistance Obesity complications

  33. To summarize : … Obesity Lipid mediators, Adipokines Fatty acids, Adipokines, Other peptides Fatty acids, Adipokines, Other peptides Insulin resistance Diabetes, cardiovascular disease,…

  34. Abbreviations Used: I

  35. Abbreviations Used: II

  36. Abbreviations Used: III Slides 8,9

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