Adiponectin was discovered independently by several laboratories, hence its various
names: Acrp30 (adipocyte complement-related protein of 30kDa), apM1 (adipose
most abundant gene transcript 1), adipoQ and GBP28 (gelatin-binding protein of
28kDa) . Adiponectin is composed of an N terminal sequence, hypervariable
domain, 15 collagenous repeats and a C terminal domain. A trimeric form of
adiponectin is secreted by adipocytes and gives rise to higher order complexes, i.e.
dimers of trimers (hexamers, low molecular weight, LMW) and six trimers (18-mers,
high molecular weight, HMW) through noncovalent bonding. HMW adiponectin is thought to be the bioactive form in plasma. In contrast, trimeric and hexameric
adiponectin is predominant in the cerebrospinal fluid. Adiponectin also undergoes
posttranslational modifications including glycosylation . Although there is
structural similarity between the globular (head) of adiponectin and TNF- , these
adipokines do not appear to be functionally related.
In contrast to other polypeptide hormones, adiponectin circulates at very high
concentrations ( g/ml), raising the possibility that a smaller cleaved product mediates
its action on various tissues. Total and HMW adiponectin are more abundant
in females, partly due to suppression of adiponectin by androgens in males.
Adiponectin is inversely related to adiposity, in contrast to leptin and most
adipokines. Thus, adiponectin is markedly reduced in obesity and rises with prolonged
fasting and severe weight reduction. Adiponectin, particularly HMW, is
increased by thiazolidinediones (TZDs) and mediates the insulin sensitizing effect of
this class of antidiabetic drugs. A role for adiponectin in glucose homeostasis
is further exemplified by hepatic insulin resistance in rodents and humans lacking
adiponectin. In contrast, adiponectin treatment enhances insulin sensitivity,
primarily by suppressing glucose production. Adiponectin produced in
bacteria has been shown to decrease glucose, stimulate fatty acid oxidation and
reduce body weight and fat; however, these are likely to be pharmacological effects
since bacterially derived adiponectin is incapable of forming high order complexes. Administration of full length or globular adiponectin via systemic or intracerebroventricular
injection induces thermogenesis, fatty acid oxidation and weight
loss in mice. These actions are abrogated in agouti mice (Ay/a), indicating a crucial
role for melanocortin signaling in the central action of adiponectin.
Hypoadiponectinemia is related to insulin resistance, inflammation, dyslipidemia
and cardiovascular risk among various populations. Lack of adiponectin promotes
atherosclerosis in rodents. Adiponectin reverses this by inhibiting monocyte
190 Ahima · Osei adhesion, macrophage transformation, proliferation and migration of smooth muscle
cells in blood vessels. Studies have implicated activation of AMPK and inhibition of
nuclear factor B (NF- B) and vascular adhesion molecules as putative mechanisms
underlying the effects of adiponectin on the vascular system. Adiponectin also
exerts a protective action in myocardial remodeling in response to acute ischemiareperfusion. Adiponectin-deficient mice had increased myocardial apoptosis
and infarct size than wild-type. Importantly, adiponectin treatment diminished
infarct size, apoptosis and TNF- production in both knockout and wild-type mice.
These actions appear to be mediated through activation of AMPK, induction of
cyclooxygenase-2-dependent synthesis of prostaglandin E2.
Adiponectin receptors (AdipoR1 and AdipoR2) contain seven transmembrane
domains, but are structurally and functionally distinct from G-protein-coupled receptors. AdipoR1 is abundant in muscle and binds with high affinity to globular
adiponectin and low affinity to the full-length protein, whereas AdipoR2 is enriched in
liver and has intermediate affinity for globular and full-length adiponectin. Both
receptors mediate the phosphorylation and activation of AMPK. Although studies
have failed to demonstrate a blood-brain transport of adiponectin, both AdipoR1
and AdipoR2 are distributed widely in the brain. Injection of adiponectin into
the 4th ventricle depolarized AdipoR1 and AdipoR2-positive neurons in the area
postrema, suggesting a potential mechanism for its central adiponectin action.
In a recent study, adenovirus-mediated expression of AdipoR1 and AdipoR2 activated
AMPK and peroxisome proliferator-activated receptor (PPAR)- in the liver of
lepr null mice, reduced gluconeogenesis and increased fatty acid oxidation.
Targeted disruption of AdipoR1 prevented adiponectin-induced AMPK activation,
whereas disruption of AdipoR2 decreased PPAR- activity. Disruption of both
AdipoR1 and AdipoR2 abolished adiponectin binding and induced steatosis, inflammation,
oxidative stress, insulin resistance and glucose intolerance. Together, these
results support a role of AdipoR1 and AdipoR2 as major mediators of adiponectin
action on glucose and lipid metabolism.
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