Adipokines

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Adipokines

  1. 1. ADIPOKINES Dr. Tulasi Raman P
  2. 2. DEFINITION  Adipocytes + Cytokines  Adipocytes: Fat cells  Cytokines: They are a category of signaling molecules that are used extensively in cellular communication. They may be proteins, peptides, or glycoproteins.
  3. 3. THE CONCEPT  Adipose tissue was traditionally considered to be a long-term energy storage organ.  But it is now appreciated that it has a key role in the integration of systemic metabolism.  This metabolic function is mediated, in part, by its ability to secrete numerous proteins.  Factors that are secreted by adipose tissue are collectively referred to as adipokines.
  4. 4. ADIPO-INSULAR AXIS
  5. 5. COMPLEX INTERACTION BETWEEN ADIPOKINES IN B-CELL SPECIFIC EFFECTS
  6. 6. THE CELLULAR EFFECTS OF ADIPOKINES ON INSULIN SIGNALING
  7. 7. MULTIPLICITY OF CELL-SIGNALLING RESPONSES TO ADIPOKINES AND THEIR CARDIAC EFFECTS
  8. 8. CO-EXPRESSION AND MECHANISMS OF ADIPOKINES IN OBESITY
  9. 9. HYPOTHETICAL LINK BETWEEN ADIPOKINES, INSULIN AND LONGEVITY
  10. 10. ADIPOKINES – MAJOR CATEGORIES 1. Factors directly affecting metabolism 2. Pro-inflammatory factors and acute phase reactants 3. Extracellular matrix components 4. Pro-mitogenic and pro-angiogenic factors
  11. 11. FACTORS DIRECTLY AFFECTING METABOLISM  Adiponectin Adipsin Apelin  Leptin Omentin Resistin  RBP4 Visfatin  Lipoprotein lipase  Insulin like growth factor 1 (IGF-1)  Adipocyte fatty acid binding protein (aP2)
  12. 12. PRO-INFLAMMATORY FACTORS AND ACUTE PHASE REACTANTS  TNFα, Adipsin  Apelin Resistin  Serum amyloid A3  IL-1β, 4, 6, 8, 10, 18  Alpha 1 acid glycoprotein  Macrophage migration inhibitory factor (MIF)  Macrophage chemoattractant protein (MCP1)
  13. 13. EXTRACELLULAR MATRIX COMPONENTS  Alpha 2 macroglobin  Collagen I, III, IV, VI  Fibronectin  Gelsolin  Lysyl Oxidase  MMP1, 7, 9, 10, 11, 14, 15
  14. 14. PRO-MITOGENIC AND PRO-ANGIOGENIC FACTORS  TGFβ VEGF  Adiponectin Tissue factor  Angiopoietin 1, 2 Nerve growth factor  Insulin like growth factor 1 (IGF-1)  Fibroblast growth factor (FGF)  Hepatic growth factor (HGF)  Stromal derived factor (SDF-1)
  15. 15. LEPTIN
  16. 16. LEPTIN  Secreted predominantly by WAT, Sc AT > Om AT.  ↑ In human obesity, correlates with BMI,  ↓ after fasting or weight loss General
  17. 17. LEPTIN  LR isoforms a–e  Stimulation of TNF- α and IL-6 expression  Suppression of resistin and retinol binding protein 4 expression  Stimulation of adiponectin expression Glucose Homeostasis
  18. 18. LEPTIN  Satiety signal.  Promotes increased energy expenditure  Stimulation of fatty acid oxidation in liver, pancreas and skeletal muscle  Modulation of hepatic gluconeogenesis  Modulation of pancreatic β-cell function Glucose Homeostasis
  19. 19. MODEL OF LEPTIN ACTION ON HYPOTHALAMUS AND IMMUNE RESPONSE REGULATION
  20. 20. LEPTIN  Proatherogenic  ↑ Vascular inflammation/EC dysfunction  ↑ VSMC migration and proliferation  Hypertrophy  ↓ Apoptosis  ↓ Cardiac output  ↑ MABP, HR  ↓ Lipotoxicity Cardiovascular pathophysiology
  21. 21. ADIPONECTIN
  22. 22. ADIPONECTIN  Improves energy homoeostasis, insulin sensitivity and glucose uptake.  Anti-inflammatory properties  Secreted exclusively by adipocytes.  mRNA and protein in Sc AT > Om AT.  2–3x greater secretion in females  ↓ In mouse models of obesity and insulin resistance  ↓ In human obesity and T2DM. General
  23. 23. ADIPONECTIN  AdipoR1, AdipoR2, T-cadherin  Suppression of TNF-α and IL-6 expression  Suppression of hepatic gluconeogenesis  Stimulation of fatty acid oxidation in liver and skeletal muscle  Stimulation of glucose uptake in skeletal muscle  Stimulation of insulin secretion  Modulation of food intake and energy expenditure Glucose Homeostasis
  24. 24. ADIPONECTIN - PROPERTIES
  25. 25. ADIPONECTIN  Anti-atherogenic  ↓ EC monocyte adhesion  ↑ Angiogenesis  ↓ Apoptosis  ↓ VSMC proliferation  ↓ Systolic BP  ↓ Pressure overload induced cardiac hypertrophy  ↓ ET-1 induced hypertrophy  ↓ Post-MI systolic dysfunction  ↓ Myocardial damage Cardiovascular pathophysiology
  26. 26. ADIPONECTIN  Adiponectin induces PGE2, IL-6, IL-8, MMP-1, and MMP-13 in synovial fibroblasts  Adiponectin induces NO, IL-6, MMP-3, MMP-9, MCP-1, and IL-8 in human chondrocytes  Adiponectin promotes inflammation through increased TNF-α, IL-6, IL-8, and RANTES secretion by primary lymphocytes and macrovascular endothelial cells Rheumatoid Arthritis
  27. 27. TUMOR NECROSIS FACTOR-Α
  28. 28. TUMOR NECROSIS FACTOR-Α  Reduces insulin secretion and insulin sensitivity.  Stimulates lipolysis.  Predominantly expressed by macrophages.  Also expressed by WAT, Sc AT > Om AT  Correlates with BMI, ↑ in human obesity:  Obese (2X) > lean.  ↓ Adipose differentiation General
  29. 29. INTERLEUKIN-6
  30. 30. INTERLEUKIN-6  Affects glucose and lipid metabolism.  Improves insulin sensitivity and glucose tolerance.  35% of the basal supply is derived from WAT.  ↑ In morbidly obese patients.  ↓ After weight loss General
  31. 31. RESISTIN
  32. 32. RESISTIN  Affects glucose metabolism and causes insulin resistance in rodents.  In humans, it acts more as a pro-inflammatory cytokine.  Stimulation of TNF-α and IL-6 expression  In rodents, secreted by WAT.  In humans, secreted in macrophages and WAT  ↑ In human obesity, metabolic syndrome, T2DM and CVD General
  33. 33. SYNTHESIS AND FUNCTION OF RESISTIN IN HUMANS AND RODENTS
  34. 34. RESISTIN  ↑ Adhesion molecules  ↑ Proatherogenic inflammatory markers  ↑ CAD  ↑ Aortic SMC proliferation  ↓ Bradykinin induced dilation of coronary arteries  ↑ Coronary EC proliferation  ↑ Cardiac injury Cardiovascular pathophysiology
  35. 35. PLASMINOGEN ACTIVATOR INHIBITOR-1 (PAI-1)
  36. 36. PAI-1  Potent inhibitor of fibrinolytic pathway  Expressed by Sc and Om AT.  Positive correlation with abdominal adiposity.  ↑ In human obesity, metabolic syndrome and T2DM General
  37. 37. INTERLEUKIN-8
  38. 38. INTERLEUKIN-8  Neutrophil chemotaxis and degranulation.  Pro-atherogenic  Predominantly macro-phages and monocytes.  Adipocytes: Om > Sc  ↑ In obesity, positively correlates with BMI and TNF a General
  39. 39. RETINOL BINDING PROTEIN 4 (RBP-4)
  40. 40. RBP-4  Implicated in insulin resistance as well as increased hepatic glucose output and impaired muscle insulin signaling.  Secreted by adipocytes, macrophages and liver.  ↑ In obesity and insulin resistance. General
  41. 41. TRANSFORMING GROWTH FACTOR B (TGF- B)
  42. 42. TGF-B  Varied role in proliferation, differentiation, apoptosis and development.  Multifunctional, produced by variety of cells.  Inhibitor of differentiation  ↑ ob/ob and db/db mice.  ↑ Preadipocyte cell proliferation, as with TNF a General
  43. 43. MONOCYTE CHEMOTACTIC PROTEIN-1 (MCP- 1)
  44. 44. MCP-1  Increases insulin resistance, macrophage infiltration in adipose tissue and hepatic steatosis.  Secreted by WAT  ↑ ob/ob and db/db mice.  ↑ In obesity, T2DM and CVD General
  45. 45. REGULATED ON ACTIVATION, NORMAL T CELL EXPRESSED AND SECRETED PROTEIN
  46. 46. RANTES  Pro-inflammatory.  Secreted by T cells, monocytes and to a lesser degree in WAT  No correlation of serum levels with obesity although ↑ gene expression in adipose tissue General
  47. 47. VISFATIN
  48. 48. VISFATIN NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE (NAMPRTASE OR NAMPT) PRE-B-CELL COLONY-ENHANCING FACTOR 1 (PBEF1)
  49. 49. VISFATIN  Pro-inflammatory and insulin mimicking  Secreted by adipocytes  ↑ In obesity  Stimulation of TNF- α and IL-6 expression General
  50. 50. VISFATIN  Proatherogenic effect  Induction of MCP-1 expression and production of proinflammatory factor that affects to plaque stabilization.  Antiatherogenic effect  Visfatin improves endothelial function by increased eNOS expression Atherosclerosis
  51. 51. CHEMERIN
  52. 52. CHEMERIN  Affects adipogenesis, inflammation as well as glucose metabolism  Secreted by WAT  ↑ In obesity General
  53. 53. CHEMERIN  CMKLR1  Suppression of TNF-α and IL-6 expression  Stimulation of adiponectin expression  Enhancement of insulin-stimulated glucose uptake and IRS-1 phosphorylation in 3T3-L1 adipocytes Glucose Homeostasis
  54. 54. CHEMERIN  ↑ EC angiogenesis and cell survival pathways  Associated with arterial stiffness  ↑ ET-1- and PE-induced contractility  ↓ Vascular inflammation Cardiovascular pathophysiology
  55. 55. VASPIN
  56. 56. VASPIN  Improves insulin sensitivity  Secreted by WAT Om > Sc.  ↑ In obesity, insulin resistance and T2DM  Suppression of leptin, resistin, and TNF-α expression  Stimulation of adiponectin expression General
  57. 57. NESFATIN
  58. 58. NESFATIN  Acts centrally to reduce appetite.  Secreted in brain tissue, B cells and adipose tissue.  ↓ In obesity, T2DM and PCOS General
  59. 59. OMENTIN
  60. 60. OMENTIN  Increases insulin sensitivity  Secreted by omental adipose tissue  ↓ In obesity  Enhancement of insulin-stimulated glucose transport and Akt phosphorylation in human adipocytes General Glucose Homeostasis
  61. 61. OMENTIN  ↑ Endothelium-dependent vasodilation  ↓ Vascular inflammation  ↓ EC migration and angiogenesis Cardiovascular pathophysiology
  62. 62. APELIN
  63. 63. APELIN  Improves insulin sensitivity mainly acting in skeletal muscle and adipocytes in mice.  Produced in a wide range of tissue.  ↑ In obesity, impaired glucose tolerance and T2DM.  ↓ After weight loss following diet or bariatric surgery General
  64. 64. APELIN  Anti-atherogenic  ↓ BP  ↑ HR and cardiac contractility  Regulates cardiomyocyte specification and cardiac development  ↓ Heart failure  ↓ Ischaemic cardiomyopathy  ↑ Cardioprotection  Maintain cardiac function in pressure overload and aging Cardiovascular pathophysiology
  65. 65. THANK YOU

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