1. Sketch of Adiponectin Receptors Hongkui Yu Hongqiang Ye Jie Nie Xiangyu Sun These authors contributed equally to this work.

2. introduction Adipose tissue endocrine organ hypertention AS diabetes Metabolic syndrome infarction Heart failure Adiponectin

3. introduction Adipose tissue endocrine organ secretes adipokines –plasminogen activator inhibitor-1, –leptin, –resistin –TNF-alpha. – Adipose tissue endocrine organ

4. introduction Adipose tissue endocrine organ Adiponectin is one such adipokine that has recently attracted much attention.

5. Adiponectin

6. Reduced adiponectin levels are seen in patients with Adiponectin and disease cardiovascular diseases hypertension, metabolic syndrome

7. Adiponectin overexpression of adiponectin resulted in marked reduction of atherosclerotic lesion formation Adiponectin and AS

8. Adiponectin Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis.[J]. J Biol Chem.,2003,278(4):2461-2468. Adiponectin and AS reduction of atherosclerotic lesion formation overexpression of adiponectin

9. Adiponectin Adiponectin deficinet –Incresed myocardial infarct size –Myocardial apoptosis –TNF-alpha expression Administration of adiponectin –Diminish infarct size –Myocardial apoptosis –TNF-alpha expression Adiponectin and HF

10. Adiponectin Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2- dependent mechanisms. Adiponectin and HF Nature medicine. 2005.11(10):1096-1103

11. Adiponectin Adiponectin and Adiponectin Receptors[J]. Endocr. Rev.Endocrine Reviews,2005,26(3):439-451. Adiponectin and structure high molecular weight multimers (HMW) dodecamers and 18 mers Homomultimer trimers and hexamers full-length or globular fragment

12. Adiponectin Receptors

14. AdipoR1 and AdipoR2 integral membrane proteins; N internal, C external;not GPCR conserved from yeast to man Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome [J]. J. Clin. Invest.,2006,116(7):1784-1792. AdipoR and structure

15. C Adiponectin; N interacts with an adaptor protein, APPL (Adaptor protein containing Pleckstrin homology domain, Phosphotyrosine-binding domain and a Leucine zipper motif). AdipoR and structure

16. highly expressed in insulin-sensitive tissue mediateds lipid oxidation, glucose uptake GLUT4 translocation crosstalk adiponectin & insulin signalling pathways APPLied mechanics: Uncovering how adiponectin modulates insulin action[J]. Cell Metabolism,2006,4(1):5-6.

17. lanes: 1, brain; 2, heart; 3, kidney; 4, liver; 5, lung; 6, skeletal muscle; 7, spleen; 8, testis AdipoR1 and AdipoR2 Cloning of adiponectin receptors that mediate antidiabetic metabolic effects[J]. Nature,2003,423:762-769. AdipoR and distribution AdipoR1 –ubiquitously, – globular adiponectin AdipoR2 –abundantly in the live –full-length adiponectin

18. AdipoR1 and AdipoR2 Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome [J]. J. Clin. Invest.,2006,116(7):1784-1792. Brief summary

19. Biological function AdipoR1 or R2 over-expression AdipoR1-KO, AdipoR2-KO AdipoR1/R2-KO function and AdipoR

20. AdipoR1 over-expression Via AMPK Reduce gluconeogenesis –glucose-6-phosphatase –phosphoenolpyruvate carboxykinase 1 Reduce lipogenesis –sterol regulatory element-binding protein 1 (Srebf1) ↓ function and AdipoR

21. AdipoR1-KO normal and fertile impaired glucose tolerance insulin resistance gluconeogenic enzymes ↑ Lipogenesis ↑ –Srebf-1↑ function and AdipoR

22. AdipoR1/R2-KO abolished adiponectin binding –although T-cadherin express in liver tissue triglyceride content↑ inflammation and oxidative stress ↑ insulin resistance glucose intolerance. function and AdipoR

23. Cardiovascular disease vs AdipoR1/R2

24. Cardiovascular vs AdipoR1/R2 Adiponectin and receptors are expressed in adult ventricular cardiomyocyte AdipoR1 /2 non-diseased carotid artery areas –SMC and endothelial cell slightly induced atherosclerotic lesions – lipid-enriched macrophages lipid core Regulation and AdipoR

25. Cardiovascular vs AdipoR1/R2 Regulation and AdipoR AdipoR1 /2 mediate the effects of adiponectin in the subendothelial space and cardiomyocyte in a autocrine & paracrine way

26. Mechanism cardiac energy β-oxidation of fatty acids AMPK phosphorylate acetyl coenzyme A carboxylase (ACC) malonyl-CoA↓ Carnitine palmitoyltransferase-1 (CPT-1) Regulation and AdipoR Lehninger 4th, FIGURE 17–6

27. Mechanism Regulation and AdipoR Carnitine palmitoyltransferase-1 AMPKACC-Pi malonyl- CoA↓ CPT-1↑ AdipoR Lehninger 4th, FIGURE 17–6

28. Mechanism Regulation and AdipoR Adiponectin modulates carnitine palmitoyltransferase-1 through AMPK signaling cascade in rat cardiomyocytes[J]. Regulatory Peptides,2007,139(1-3):72-79. Phospho-AMPK Phospho-ACC

29. Adiponectin and AdipoRs as Therapeutic Targets Up-regulation of plasma adiponectin –PPAR gamma agonists have been shown to increase adiponectin levels Therapeutic and AdipoR

30. Adiponectin and AdipoRs as Therapeutic Targets Cardiomyocytes Up-regulation of adiponectin receptors Rosiglitazone elevate expression of adipone- ctin and adipoR1/2 cultured cardiomyocytes Therapeutic and AdipoR Cardiomyocytes

31. Adiponectin and AdipoRs as Therapeutic Targets Macrophages Up-regulation of adiponectin receptors LXR (liver X receptors) agonist ↑AdipoR1/2 PPAR alpha and PPAR gamma activators ↑AdipoR2 Therapeutic and AdipoR macrophages

32. Osmotin Adiponectin and AdipoRs as Therapeutic Targets development of AdipoRs agonists Therapeutic and AdipoR

33. Osmotin pathogenesis-related (PR)-5 family Plant defense protein in tobacco activate AMP kinase in C2C12myocytes. Stable remain active in contact with the digestive or respiratory systems. Therapeutic and AdipoR

34. Summary hypertention AS diabetes Metabolic syndrome Heart failure Adiponectin AdipoRs Osmotin

35. References [1] Yamauchi T, Kamon J, Waki H, et al. Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis.[J]. J Biol Chem.,2003,278(4):2461-2468. [2] Kadowaki T, Yamauchi T. Adiponectin and Adiponectin Receptors[J]. Endocr. Rev.Endocrine Reviews,2005,26(3):439-451. [3] Kadowaki T, Yamauchi T, Kubota N, et al. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome[J]. J. Clin. Invest.,2006,116(7):1784-1792. [4] Toshimasa Yamauchi, Junji Kamon, Yusuke Ito, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects[J]. Nature,2003,423:762-769. [5] Hug C, Wang J, Ahmad N S, et al. T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin[J]. PNAS,2004,101(28):10308-10313. [6] Yamauchi T, Nio Y, Maki T, et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions.[J]. Nat Med,2007,13:332 – 339.

36. [7] Atsushi Tsuchida, Toshimasa Yamauchi, Yusuke Ito, et al. Insulin/Foxo1 Pathway Regulates Expression Levels of Adiponectin Receptors and Adiponectin Sensitivity[J]. J. Biol. Chem.,2004,279(29):30817-30822. [8] Hosch S E, Olefsky J M, Kim J J. APPLied mechanics: Uncovering how adiponectin modulates insulin action[J]. Cell Metabolism,2006,4(1):5- 6. [9] Ding Gl, Qin Qh, He N E A. Adiponectin and its receptors are expressed in adult ventricular cardiomyocytes and upregulated by activation of peroxisome proliferator-activated receptor gamma[J]. J. molecular AND cellular cardiology,2007,43(1):73-84. [10] Li L, Wu L, Wang C, et al. Adiponectin modulates carnitine palmitoyltransferase-1 through AMPK signaling cascade in rat cardiomyocytes[J]. Regulatory Peptides,2007,139(1-3):72-79. [11] Chinetti G, Zawadski C, Fruchart J C, et al. Expression of adiponectin receptors in human macrophages and regulation by agonists of the nuclear receptors PPAR[alpha], PPAR[gamma], and LXR[J]. Biochemical and Biophysical Research Communications,2004,314(1):151- 158.