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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.
 Concentration: 2~20 μg/mL in the blood
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/ proinflammatory effects, as well as metabolic
effects.
 These proteins are called “adipocytokines” or
“adipokines”
 Examples: adiponectin, leptin, resistin.
Structure of adiponectin
 3 domains: Collagen-like domain,
globular domain, and a signal sequence.
Taken from Kadowaki
and Yamauchi, 2004
 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?
 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
 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?
 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
 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.
 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
 A study conducted by
Yamauchi et al.
(2001) showed that
adiponectin
stimulates glucose
utilization and fatty
acid oxidation by
activating AMPactivated protein
kinase.
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…
 3 methods have been studied.
 Upregulation of adiponectin
 Upregulation of adiponectin receptors
 Development of adiponectin receptor
agonists
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…
 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
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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
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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.