1. ADIPOKINES
Dr. Tulasi Raman P

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. 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. ADIPO-INSULAR AXIS

5. COMPLEX INTERACTION BETWEEN ADIPOKINES IN
B-CELL SPECIFIC EFFECTS

6. THE CELLULAR EFFECTS OF ADIPOKINES ON
INSULIN SIGNALING

7. MULTIPLICITY OF CELL-SIGNALLING RESPONSES TO
ADIPOKINES AND THEIR CARDIAC EFFECTS

8. CO-EXPRESSION AND MECHANISMS OF
ADIPOKINES IN OBESITY

9. HYPOTHETICAL LINK BETWEEN
ADIPOKINES, INSULIN AND LONGEVITY

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. 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. 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. EXTRACELLULAR MATRIX COMPONENTS
 Alpha 2 macroglobin
 Collagen I, III, IV, VI
 Fibronectin
 Gelsolin
 Lysyl Oxidase
 MMP1, 7, 9, 10, 11, 14, 15

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. LEPTIN

16. LEPTIN
 Secreted predominantly by WAT, Sc AT > Om AT.
 ↑ In human obesity, correlates with BMI,
 ↓ after fasting or weight loss
General

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. 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. MODEL OF LEPTIN ACTION ON HYPOTHALAMUS AND
IMMUNE RESPONSE REGULATION

20. LEPTIN
 Proatherogenic
 ↑ Vascular inflammation/EC dysfunction
 ↑ VSMC migration and proliferation
 Hypertrophy
 ↓ Apoptosis
 ↓ Cardiac output
 ↑ MABP, HR
 ↓ Lipotoxicity
Cardiovascular pathophysiology

21. ADIPONECTIN

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. 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. ADIPONECTIN - PROPERTIES

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. 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. TUMOR NECROSIS FACTOR-Α

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. INTERLEUKIN-6

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. RESISTIN

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. SYNTHESIS AND FUNCTION OF RESISTIN IN
HUMANS AND RODENTS

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. PLASMINOGEN ACTIVATOR INHIBITOR-1
(PAI-1)

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. INTERLEUKIN-8

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. RETINOL BINDING PROTEIN 4 (RBP-4)

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. TRANSFORMING GROWTH FACTOR B (TGF-
B)

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. MONOCYTE CHEMOTACTIC PROTEIN-1 (MCP-
1)

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. REGULATED ON ACTIVATION, NORMAL T CELL
EXPRESSED AND SECRETED PROTEIN

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. VISFATIN

48. VISFATIN
NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE
(NAMPRTASE OR NAMPT)
PRE-B-CELL COLONY-ENHANCING FACTOR
1 (PBEF1)

49. VISFATIN
 Pro-inflammatory and insulin mimicking
 Secreted by adipocytes
 ↑ In obesity
 Stimulation of TNF- α and IL-6 expression
General

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. CHEMERIN

52. CHEMERIN
 Affects adipogenesis, inflammation as well as
glucose metabolism
 Secreted by WAT
 ↑ In obesity
General

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. CHEMERIN
 ↑ EC angiogenesis and cell survival pathways
 Associated with arterial stiffness
 ↑ ET-1- and PE-induced contractility
 ↓ Vascular inflammation
Cardiovascular pathophysiology

55. VASPIN

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. NESFATIN

58. NESFATIN
 Acts centrally to reduce appetite.
 Secreted in brain tissue, B cells and adipose tissue.
 ↓ In obesity, T2DM and PCOS
General

59. OMENTIN

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. OMENTIN
 ↑ Endothelium-dependent vasodilation
 ↓ Vascular inflammation
 ↓ EC migration and angiogenesis
Cardiovascular pathophysiology

62. APELIN

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. 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. THANK YOU