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Adipocytes and CVD – Part II

Adipocytes and CVD – Part II. Ms. Leonardo Roever. 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.

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Adipocytes and CVD – Part II

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  1. Adipocytes and CVD – Part II Ms. Leonardo Roever

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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.

  8. 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

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

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

  11. 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

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

  13. 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

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

  15. 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

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

  17. Lean, but not obese, fat is enriched for Tregs Normal mice Foxp3 Obese mice Lepob/+ Lepob/ob Expansion of Tregs in the fat improves insulin resistance! Feuerer M et al. Nat Med 2009

  18. Obesity + inflammatory infiltration of fat tissue Lean Obese Inflammatory Macrophages (M1) Resident (M2) Macrophages ↓Tregs Regulatory T cells (CD4+) Modified from Lumeng CN, Nat Med 2009

  19. CD8+ T cells recruit macrophages into fat tissue1 Normal chow High fat CD8 T cells 1Epididymal fat tissue of mice Nishimura S et al. Nat Med 2009

  20. CD8+ T cells recruit macrophages into fat tissue1 Insulin tolerance CD8 Ab depletion DIO: Diet-induce obesity CD8+ T cell interact with adipocytes, recruit monocytes and induce macrophage differentitaion and activation Nishimura S et al. Nat Med 2009

  21. Obesity + inflammatory infiltration of fat tissue Lean Obese Inflammatory Macrophages (M1) Resident (M2) Macrophages CCL2? ↓Tregs Regulatory T cells (CD4+) Effector T cells (CD8+) Modified from Lumeng CN, Nat Med 2009

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