Ch 9, Adipocytokines and the Pathogenesis of the Metabolism Syndrome

1. Ch 9, Adipocytokines and the Pathogenesis of the Metabolism Syndrome Geng-Ruei Chang 2006.10.26

2. Cardiovascular complication Metabolism syndrome Type 2 diabetes

3. Introduction • Adipose tissue is traditionally viewed as major site for steroid hormone metabolism, and a passive reservoir for energy storage to concert the disequilibrium of energy intake and expenditure imposed by physiological needs through removing or releasing lipid metabolites from and to the circulation with either loss or gain of body weight. • Adipose tissue is now recognised to be a multifunctional organ; in addition to the central role of lipid storage, it has a major endocrine function secreting several hormones.

4. Introduction • These adipose tissue-secreted proteins, i.e. leptin, adiponectin, resistin, pro-inflammatory cytokines, complement factors and so on, have been given the collective name ‘adipocytokines’ or ‘adipokines’. • However, since most are neither ‘cytokines’ nor ‘cytokine-like’, it is recommended that the term ‘adipokine’ be universally adopted to describe a protein that is secreted from (and synthesised by) adipocytes.

5. Adipokines classified by functional role. (Trayhurn and Wood, 2004)

6. Adipocytokines secreted by adipose tissue.

7. Inflammatory and acute-phase response proteins secreted from adipocytes. Others: Acrylation-stimulating protein (ASP) Plasminogen activator inhibitor-1 (PAI-1) Protein of the renin-angiotensin system (RAS) (Trayhurn and Wood, 2004)

8. Cytokine family Leptin

9. Leptin • In 1994, the obese (ob) gene was first identified in genetic obesity mouse (ob/ob mice) adipose tissue through a positional cloning approach by Zhang et al. • Leptin, a 167 amino acid peptide hormone that is the product of the ob gene, and released from adipose tissue into the blood as 16-kDa protein. • Leptin has a tertiary structure strikingly resembling the members of the long-chain cytokine family, such as IL-6, leukaemia inhibitorr factor (LIF) and GCSF.

10. Domain structure of alternatively sliced LEPR isoforms. The long isoform, LEPRb, has intracellular motifs necessary for JAK-STAT signaling. LEPRe lacks a transmembrane domain (TM) and intracellular domains and circulates as a soluble receptor.

11. Intracellular signaling by LRb.

12. Leptin signalling.

13. 瘦體素 接受體 Regulation ofleptin 下視丘 白色脂肪組織中的瘦體素 交感神經系統活性上升 胰島素 脂肪組織 產熱作用 食物攝取 ( Diabetolgia et al., 1997 )

14. Cross-talk between insulin and leptin signalling .

15. Regulation of AMPK and fatty acid oxidation by leptin in skeletal muscle.

16. Body weight regulation by leptin.

17. Causes of leptin resistance

18. Leptin in the immune response • Leptin-null humans and ob/ob mice manifest a complex syndrome that is characteristic of an adaptive response to starvation, including thymic atrophy, T cell hyporesponsiveness and macrophage mal-phagocytic activity. • Leptin treatment stabilizes thymic homeostasis, restores the number and responsiveness of circulation CD4 T cells and balances the cytokine production by T helper 1(TH1) and TH2 cells. • Leptin together with C-reactive protein, IL-1 and IL-6 can act as an acute-phase reactant to regulate inflammatory process.

19. Leptin in the cardiovascular system • Leptin signalling in vascular endothelia, stimulates the production of monocyte chemoattractant protein-1 (MCP-1) and reactive oxygen species, leading to increased monocyte infiltration and foam cell accumulation in the injured arterial wall, and induces the synthesis of endothelin-1, enhancing vasoconstriction. • Leptin signalling activation in platelets further promotes platelet aggregation around the atherosclerotic lesion. • High leptin levels to accelerate the development of atherothrombotic disease in obesity.

20. Cardiovascular actions of leptin

21. Interleukin 6 • IL-6 is traditionally denoted as a protein secreted by leucocytes, is now to be another adipose tissue-derived cytokine that has been strongly implicated in obesity and insulin-resistance. • IL-6 circulates in multiple glycosylated forms of 22-27 kDa and as much as 1/3 of the circulating IL-6 in the blood circulation originates from the adipose tissue.

22. Intracellular IL-6 signalling.

23. Interleukin 6 • An increase in IL-6 gene transcription rate, is associated with impaired energy expenditure, insulin action, and development of type 2 diabetes. • Peripgeral administration of IL-6 induces hyperlipidaemia, hyperglycaemia and other markers of insulin resistance. • Lack of IL-6 may induce mature-onset obesity and disturbed carbohydrate and lipid metabolism in IL-6 null mice.

24. Interleukin 6 • IL-6 reduces gene expression and activity of insulin signalling molecules and induces expression of SOCS-3 with consequently impaired insulin and leptin signalling. • Increased IL-6 release from visceral adipose tissue in abdominal obesity may constantly stimulate acute-phase protein production from the liver. • Very high interstitial concentrations of IL-6 have been demonstrated in human subcutaneous adipose tissue, where adiponectin is highly expressed, and IL-6 at similar concentrations in vitro reduces adiponectin gene expression.

25. Tumour necrosis factor alpha (TNF-α) TNF-αis initially identified as an endotoxin-indeced factor identical to cachectin that causes necrosis of tumours and plays a role in the metabolic disturbances and chronic inflammation. TNF-αis synthesized as a 26-kDa transmembrane monomer, and proteolytic cleavage of the membrane-bound precursors prodeces biologically active trimer protein that exerts it effects via type ⅠandⅡ TNF-αreceptors. TNF-αis expressed both in adipocyte and stromovascular cells, which enables TNF-α to regulate locally both adipogenesis and adipose tissue function.

26. TNF-α • Treatment with neutralizing soluble TNF-α receptors has been found beneficial in improving insulin sensitivity in obese rodents. • Targeted gene deletion of either TNF-α or TNF-α receptors significantly improves insulin sensitivity and circulating NEFAs in obese rodents.

27. TNF-α • TNF-αreduces expression levels of the genes encoding transcription factors and components essential for adipogenesis and lipogenesis, and alters the balance of adipocytokines such as adiponectin and IL-6. • In the liver, TNF-αproduces a gene expression that may lead to reduced glucose utilization and fatty acid oxidation while increasing synthesis of cholesterol and fatty acids; it also impairs insulin action.

28. Mechanisms of TNF-α-induced insulin resistance

29. The relationship between TNF-α and type 2 diabetes

30. Adiponectin • Adiponectin, also termed adipose most abundant gene transcript 1(apM1), adipocyte complement related protein of 30 kDa (Acrp30) , AdipoQ, or gelatine binding protein 28 kDa (GBP28). • Adiponectin is composed of an N-terminal signal sequence, a variable domain, a collagen-like domain and C-terminal globular domain, which structurally, adiponectin belongs to the collagen superfamily sharing homologies with collagens (type Ⅷ and Ⅹ), complement factors (C1 q)and TNFa.

31. Structure of adiponectin receptors. AdipoR1 and AdipoR2 (66.7% amino acid identity with AdipoR1) are predicted to contain 7 transmembrane domains but are structurally and topologically distinct from GPCRs.

32. The role of adiponectin (Saltiel, 2001 )

33. Adiponectin for insulin resistance, the metabolic syndrome, and atherosclerosis.

34. TZDs ameliorate diabetes by adiponectin-dependent and -independent pathways.

35. Adiponectin in the cardiovascular system • Human subjects harbouring adiponectin gene mutations associated with reduced plasma adiponectin levels seem to have a higher risk to develop hypertension and coronary heart disease. • Adiponectin reduces monocyte adhesion by inhibiting endothelial expression of cell adhesion molecules and release of reactive oxygen species. • Adiponectin increases endothelial production of nitric oxide and inhibits GF-induced vascular smooth muscle cell proliferation.

36. Adiponectin signal transduction.

37. Resistin • Resistin is a 12.5-kDa cysteine-rich peptide that as a novel factor secreted by adipocytes with an impact on insulin sensitivity was proposed as a new mechanism to explain the pathogenic sequence of adipocyte-obesity-insulin resistance. • Resistin inhibits the release of dopamine and norepinephrine while having no effect on serotonin release, • Similar to Leptin, to regulate appetite by acting on the hypothalamic satiety centre.

38. Resistin • Serum resistin levels are increased in mice with genetic (ob/ob mice or db/db mice) or diet-induced obesity, which is associated with impaired glucose metabolism and insulin resistance. • Resistin suppresses insulin-stimulated glucose uptake in vitro, and this effect is prevented by anti-resistin antibodies. • These data suggest that resistin induces insulin resistance and that hyperresistinemia contributes to impaired insulin sensitivity.

39. The role of resistin.

40. Resistin acts on skeletal muscle to cause insulin resistance

41. Acylation Stimulating Protein (ASP) • ASP is a small basic protein synthesized from complement factor C3, which was isolated from the human plasma and which has been shown to be the most potent stimulant yet discovered of triglyceride synthesis. • ASP is not an active immune modular and binds to a G-protein-coupled receptor in adipocytes to stimulate glucose uptake and diacylglycerol acyltransferase activity and to inhibit hormone sensitive lipase. • The involvement of ASP in metabolic syndrome has been showing the correlations of ASP or ASP precursors with body fat mass and levels of circulating hormones, carbohydrates and lipids.

42. ASP • ASP and ASP precursors are increased in obese and diabetic subjects and decreased in individuals with anorexia nervosa and lipodystrophies; they correlate with plasma insulin, glycosylated haemoglobin, triglycerides, fatty acids and disease, i.e. hypertension and cardiovascular disease. • Gene ablation of C3 and ASP in mice has found to increase fatty acid oxidation in the liver and skeletal mucle. • The mechanisms whereby ASP deficiency and/or ASP resistance induce metabolism and vascular disorders remain to be determined.

43. Macrophage and monocyte chemoattractant protein-1 (MCP-1) • MCP-1 is a chemokine that recruits monocytes to sites of inflammation and, in adipose tissue is primarily expressed. • MCP-1 are increased in rodent obesity, which is associated with increased infiltration of macrophage in the adipose tissue and increased release of pro-inflammatory cytokines such as IL-6 and TNF- α. • MCP-1 may potentially induce insulin resistance by impairing insulin-stimulated insulin receptor tyrosine phosphorylation and insulin-stimulated glucose uptake by the adipose cells, and also impair adipogenesis.

44. Plasminogen activator inhibitor-1 (PAI-1) • PAI-1 is a member of the serine protease inhibitor family that inhibits the fibrinolysis system with reduced intravascular thrombolysis by inactivating urokinase-type and tissue-type plasminogen activator. • Adipose tissue gene expression and plasma concentrations of PAI-1 are elevated in obesity and insulin resistance and correlated with visceral fat accumulation and levels of insulin and triglycerides.

45. PAI-1 • Targeted deletion of PAI-1 in mice reduces diet-induced weight gain and enhances energy expenditure, accompanied by improved glucose tolerance and insulin sensitivity. • Therefore, increased PAI-1 production in obesity may thus play an important role in the metabolic syndrome, type 2 DM, and atherosclerotic cardiovascular disease.

46. PAI-1 in the obesity and diabetes.

47. Factors contributing to increased PAI-1 production in obesity.

48. Proteins of the renin-angiotensin system (RAS) • Cardiovascular risk factors are associated with activation of the tissue RAS that mediates vascular tone, aldosterone secretion and sodium and water re-absorption. • New findings have been reported concerning the metabolic syndrome in relation to the renin-angiotensin system, ie, that treatment with inhibitors of the angiotensin-converting enzyme (ACE) not only decreases blood pressure levels but prevents the development of diabetes mellitus. • Adipiose tissue expresses angiotensinogen and enzymes required for angiotensin synthesis, including angiotensin-converting enzyme, chymase, cathepsins D and G and tonin, and is a major source of the vasoactive peptides in obesity.

49. Renin-angiotensin system

50. RAS • Increasing adipose tissue expression of angiotensinogen by glucocorticoids activates the RAS with increased plasma levels of angiotensinogen, angiotensin Ⅱ and aldosterone, together with increased blood pressure. • Angiotensin has been found to stimulate hapatic gluconeogenesis and glycogenolysis and to inhibit insulin-stimulated glucose uptake. • Increased RAS activity disturbs the balance of adipocytokine secretion, i. e. leptin, pAI-1….. • Inhibition of the RAS significantly reduces the risk of cardiovascular death and the progression of atherosclerosis, and improves metabolic disorders.