1. Physiological Role and Molecular Mechanism of Adiponectin Yumi Ando Pomona College Advanced Biochemistry

2. What is Adiponectin??  A signaling molecule that is secreted from white and brown adipose tissue.  Composed of 247 amino acids.  Accounts for 0.05 % of total serum protein.  Concentration: 2~20 μg/mL in the blood

3. Aside: Adipose Tissue  Adipose tissue stores & releases energy in the form of TAG and free fatty acids, respectively.  HOWEVER, it is also gaining recognition as an endocrine organ that secretes proteins w/ pro- inflammatory effects, as well as metabolic effects.  These proteins are called “adipocytokines” or “adipokines”  Examples: adiponectin, leptin, resistin.

4. Structure of adiponectin  3 domains: Collagen-like domain, globular domain, and a signal sequence. Taken from Kadowaki and Yamauchi, 2004

5.  Form homomultimers  3 main oligomeric forms: LMW, MMW, and HMW  Oligomerization of adiponectin depends on disulphide bonds formed by Cys39 Taken from Kadowaki and Yamauchi, 2005

6. Two forms, two different functions?  Adiponectin can exist as a full-length protein or as a globular form by undergoing proteolytic cleavage, which leaves only the globular head domain intact.  The globular form of adiponectin appears to stimulate β oxidation in muscle, while the full-length form appears to decrease glucose output by the liver

7. Genetic Factors  The gene for adiponectin is located on chromosome 3q27.  This region of the chromosome has also been linked to type 2 diabetes.  A SNP located 276 base pairs downstream of the start site of the adiponectin gene was associated with increased insulin resistance and risk of developing type 2 diabetes.

9. Why is it important to study adiponectin?  Evidence strongly suggests that adiponectin plays a role in the pathophysiology of type 2 diabetes and other metabolic syndrome diseases!!

10. Correlation between adiponectin and insulin resistance  Obesity and type 2 diabetes are associated with decreased adiponectin levels  Reduced plasma adiponectin is also seen in people with conditions such as cardiovascular disease and hypertension, diseases that are often associated with insulin resistance.

11.  In a study conducted by Hotta et al., (2001), plasma adiponectin levels dropped in parallel to the observation of decreased insulin sensitivity in rhesus monkeys.  Monkeys w/ decreased insulin sensitivity developed type 2 diabetes.

13. Molecular Mechanism of Adiponectin  A study conducted by Yamauchi et al. (2001) showed that adiponectin stimulates glucose utilization and fatty acid oxidation by activating AMP- activated protein kinase.

15. Adiponectin Receptors  There are two known ones: AdipoR1 and AdipoR2.  They are integral membrane proteins that have seven transmembrane domains where the N terminus is located within the cell, and the C terminus is external.  AdipoR1 is a receptor that mainly binds globular adiponectin, while AdipoR2 binds to full-length adiponectin  AdipoR1 is abundant in skeletal muscle. On the other hand, AdipoR2 is most expressed in the liver.

18. Possible therapeutic strategies…  3 methods have been studied.  Upregulation of adiponectin  Upregulation of adiponectin receptors  Development of adiponectin receptor agonists

19. Osmotin  potential agonist for adiponectin!!  It is a plant protein that is implicated in the plant defense system. Causes apoptosis in yeast.  adiponectin and osmotin were able to induce phosphorylation of AMP kinase in C2C12 myocytes.

21. 5 things to remember…  adiponectin is a potent insulin sensitizing molecule.  The two forms (globular and full-length) bind to different receptors and have different effects.  Decreased levels of adiponectin induced by genetic mutations, obesity, and high fat diets lead to insulin resistance and pathological conditions such as type 2 diabetes.  Adiponectin activates signaling cascades that eventually increase glucose uptake by muslce, increase fatty acid oxidation by muscle and liver, and decrease gluconeogenesis in the liver.  In the future, Osmotin could be used as a novel therapeutic method for hypoadiponectinemia.

22. References  Cnop M. et al. (2003) Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia. 46: 459–469.  Fasshauer M., Paschke R., and Stumvoll, M. (2004) Adiponectin, obesity, and cardiovascular disease. Biochimie. 86: 779-784.  Lihn A.S., Pedersen S.B., and Richelsen B. (2004) Adiponectin: action, regulation, and association to insulin sensitivity. Obesity Reviews. 6: 13-21.  Fruebis J. et al. (2001) Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci USA. 98: 2005-2010.  Hara K., et al. (2002) Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population. Diabetes. 51:536–540.  Hotta K., et al. (2001) Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes. 50:1126–1133  Kadowaki T., and Yamauchi T. (2005) Adiponectin and Adiponectin Receptors. Endocrine Reviews. 26(3): 439-451.  Kadowaki T. et al.(2006) Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. Journal of Clinical Investigation. 116(7): 1784-1792.  Kubota N., et al. (2006) Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin-dependent and adiponectin- independent pathways. J. Biol. Chem. 281(13): 8748-8755.  Narasimhan M.L. et al. (2005) Osmotin is a homolog of mammalian adiponectin and controls apoptosis in yeast through a homolog of mammalian adiponectin receptors. Molecular Cell. 17(2): 171-180.  Qi Y. et al. (2004) Adiponectin acts in the brain to decrease body weight. Nature Medicine. 10: 524-529.  Shapiro L. and Scherer, P.E. (1998) The crystal structure of complement-1q family protein suggests an evolutionary link to tumor necrosis factor. Current Biology. 8: 335-338.  Yamauchi T., et al. (2001) The fat-derived horomone adiponectin reverses insulin resistance associated ith both lipoatrophy and obesity. Nature. 7(8): 941-946.  Yamauchi T., et al. (2002) Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nature. 8(11): 1288-1295.  Yamauchi et al. (2003) Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature. 423:762-769.