Physiological Role and Molecular Mechanism of Adiponectin

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Physiological Role and Molecular Mechanism of
Adiponectin

• Yumi Ando
• Pomona College
• Advanced Biochemistry

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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 220 µg/mL in the blood

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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.

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Structure of adiponectin

• 3 domains Collagen-like domain, globular domain,
  and a signal sequence.

Taken from Kadowaki and Yamauchi, 2004
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• 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
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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 ß oxidation in muscle, while the
  full-length form appears to decrease glucose
  output by the liver

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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.

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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!!

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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.

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• 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.

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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.

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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.

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Possible therapeutic strategies

• 3 methods have been studied.
• Upregulation of adiponectin
• Upregulation of adiponectin receptors
• Development of adiponectin receptor agonists

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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.
  

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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.

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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 459469.
• Fasshauer M., Paschke R., and Stumvoll, M. (2004)
  Adiponectin, obesity, and cardiovascular disease.
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• Lihn A.S., Pedersen S.B., and Richelsen B. (2004)
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  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
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• 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
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• 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. 5011261133
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• Narasimhan M.L. et al. (2005) Osmotin is a
  homolog of mammalian adiponectin and controls
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• Qi Y. et al. (2004) Adiponectin acts in the brain
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• Shapiro L. and Scherer, P.E. (1998) The crystal
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• Yamauchi T., et al. (2001) The fat-derived
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• Yamauchi T., et al. (2002) Adiponectin stimulates
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• Yamauchi et al. (2003) Cloning of adiponectin
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