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Inserm Institut National de la Santé et de la Recherche Médicale Physiopathology of obesity and current theories on the association between an excess of.

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Presentation on theme: "Inserm Institut National de la Santé et de la Recherche Médicale Physiopathology of obesity and current theories on the association between an excess of."— Presentation transcript:

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 Fat stores, adipose tissue and complications of obesity3-7 White and brown adipose tissues: Adipocyte differentiation8-13 Metabolism and pathogenic action of fatty acids14-23 Diversity of adipose tissue cell types and production of endocrine24-22 and paracrine factors Summary33 Abbreviations used34-36 Slides

3 Fat stores, adipose tissue and complications of obesity

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

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

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

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

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

12 proliferation fat cell-specific gene expression differentiation Transcriptional control of adipocyte differentiation Wnt signaling GATA 2 & 3 SREBP1c / ADD1 C/EBP  /  PPAR  C/EBP  RXR  PPAR  J. Lipid Res., 2002, 43, 835-860

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

14 Metabolism and pathogenic action of fatty acids

15 Alternate fuel source for brain and other organs Liver Ketone bodies and CO 2 VLDL Adipose tissue TG LPL Lipases Chylomicrons (lymphatic circulation) Intestinal absorption Muscle, myocardium, kidney cortex, etc. LPL TG CO 2 FA TG NEFA Overview of fatty acid metabolism Essays Biochem. 2006;42:89-103.

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

17 cAMP  2 -AR, HM74A, A1 receptor, EP3 receptor, Y1 receptor PKA Perilipin PDE-3B FFA  1/2 -AR, Others ? triglycerides PKG Natriuretic peptide receptor A cGMP ALBP-FA GC AC Gs Gi HSL IRS PI3-K PKB Insulin receptor HSL ? ATGL glycerol AMPK MGL Aquaporin 7 ? Lipolysis in human white adipocytes Pharmacol. Res. 2006 53:482-91

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

19  1,  2,  3 cAMPPKA ACAC Gs Plasma membrane Mitochondrial biogenesis (PGC1) UCP1 transcription Lipolysis (FA) UCP1 activation  oxidation THERMOGENESISTHERMOGENESIS Adrenergic control of metabolism in brown fat cells

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

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

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

23 A combination of PGC-1  inducers and nuclear receptor ligands may constitute a strategy to combat obesity PGC1  Lipid utilization Fat mass? Nuclear receptors Ligands Inducers Potential therapeutic strategies associated with fatty acid metabolism HM74a cAMP ACAC Gi HSL PKA Lipolysis ATGL Nicotinic acid Inhibitors Antilipolysis as a strategy to combat the metabolic syndrome Trends Endocrinol Metab 2003;14 :439-441.Trends Endocrinol Metab 2006 ;17 :314-320.

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

25 Macrophages Adipocytes Preadipocytes Endothelial cells Monocytes Lymphocytes 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)

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

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

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

29 FA, Other metabolites, Adipokines, … TNF , Cytokines, Chemiokines, … FA Glycerol-3P FA Glycerol FA  oxidation Lipolysis FA esterification Triglycerides

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

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 IL-6 TNF-  Liver utilisation glucose Skeletal muscle macrophages Other target tissues Vessels atherosclerosis, hypertension Secretions : Leptin Adiponectin RBP4 TNF- , IL-6… Non alcoholicCRP steatohepatitisPAI1 Visceral adipose tissue Subcutaneous adipose tissue Obesity complications Glucose intolerance Insulin resistance

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

34 ACAdenylyl cyclase ADD1/SREBP1=SREBP1c (see below) ALBPAdipocyte lipid binding protein AMPKAMP-activated protein kinase ANPAtrial natriuretic peptide AR (α, etc)Adrenoreceptors ASPAcylation stimulating protein ATGLAdipose triglyceride lipase BNPBrain natriuretic peptide C/EBP (α etc)CCAAT enhancer binding protein CBP/p300CREB- (cAMP response element binding protein) binding transcriptional adaptor protein CD36/FATGene for long-chain FA transport in the plasma membrane CLCholesterol CRPC-reactive protein DGATDiacylglycerol acyltransferase FIAFFasting-induced adipose factor GATA 2 &3Transcription factors binding to the GATA sequence Gi, GsGuanine binding proteins (i = inhibiting, s = stimulating) HDLHigh-density lipoprotein HM74AThe nicotinic acid receptor GPR109A HSLHormone-sensitive lipase Abbreviations Used: I

35 Abbreviations Used: II ICAMIntercellular adhesion molecule ILInterleukin IRInsulin receptor IRSInsulin receptor substrate LPALysophosphatidic acid LPLLipoprotein lipase MCP1Monocyte chemotactic protein 1 MGLMonoglyceride lipase MIPMacrophage migration inhibitory factor M-SCFMembrane-bound stem cell factor NEFANon-esterified fatty acids P13-KPhosphatidylinositide 3-kinase PAI1Plasminogen activator inhibitor-1 PCAFp300/CBP-associated factor PDE 3BPhosphodiesterase 3B PECAMPlatelet/endothelial cell adhesion molecule 1 PGAR= FIAF PGC (1, α, etc)Peroxisome-proliferator-activated receptor-gamma co-activator PKAProtein kinase A PKBProtein kinase B PKGProtein kinase G

36 Abbreviations Used: III PPAR (α etc)Peroxisome proliferator-activated receptors RBP4Retinol binding protein 4 RXR (α etc)Retinoid X receptor SNSSympathetic nervous system SRC1Steroid receptor coactivator-1 SREBP1cSterol Regulatory Element Binding Protein 1c TGTriglyceride TNFTumour necrosis factor UCP-1Uncoupling protein 1 VEGFVascular endothelial growth factor VLDLVery low density lipoprotein WntWingless-type MMTV* integration site family member (signaling pathway) *Mouse mammary tumour virus Slides 8,9 CCytosol DDroplet (Lipid droplet) FFibroblast LLipid MMitochondrion NNucleus

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