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

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physiological role and molecular mechanism of adiponectin

Physiological Role and Molecular Mechanism of Adiponectin

Yumi Ando

Pomona College

Advanced Biochemistry

what is adiponectin
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
aside adipose tissue
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.
structure of adiponectin
Structure of adiponectin
  • 3 domains: Collagen-like domain, globular domain, and a signal sequence.

Taken from Kadowaki and Yamauchi, 2004

slide5
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

two forms two different functions
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
genetic factors
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.
why is it important to study adiponectin
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!!
correlation between adiponectin and insulin resistance
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.
slide11
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.
molecular mechanism of adiponectin
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.
adiponectin receptors
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.
possible therapeutic strategies
Possible therapeutic strategies…
  • 3 methods have been studied.
  • Upregulation of adiponectin
  • Upregulation of adiponectin receptors
  • Development of adiponectin receptor agonists
osmotin
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.
5 things to remember
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.
references
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.