Adiponectin - Pomona College
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Transcript Adiponectin - Pomona College
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
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 adiponectinindependent 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.