Physiological and pathophysiological roles and signal transduction of adiponectin receptors

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Adiponectin is a hormone secreted by adipocytes that acts as an antidiabetic adipokine. Decreased adiponectin levels in obesity has been shown to play causal roles in the development of these diseases. A novel insulin sensitizer, IκB kinase β(IKKβ) inhibitor, ameliorated insulin resistance and at the same time up-regulated plasma levels of adiponectin potentially via cancellation of down-regulated PI3-kinase-Akt activation induced by inflammatory cytokines.We found that impaired multimerization and/or the consequent impaired secretion to be among the causes of a diabetic phenotype or hypoadiponectinemia in subjects having these mutations. Moreover, we found that HMW(high molecular weight) adiponectin, which could activate AMPK most potently, was down-regulated in obesity, and that PPARγ agonist up-regulated the reduced HMW adiponectin. Moreover, by using adiponectin knockout mice, we showed that PPARγ agonist up-ameliorated insulin resistance and diabetes via both adiponectin-dependent … More and independent pathways.Dr.Lodish's group reported that a small amount of globular adiponectin was detected in human plasma. We found that adiponectin cleavage appeared to be mediated by leukocyte elastase. However, almost all the adiponectin appears to exist as full-length adiponectin in plasma, thus the pathophysiological importance of adiponectin cleavage by leukocyte elastase in vivo remains to be determinedWe isolated cDNA encoding adiponectin receptors (AdipoR1 and R2) by expression cloning. Expression of AdipoR1/R2 or suppression of AdipoR1/R2 revealed that AdipoR1 and R2 serve as receptors for globular and full-length adiponectin, and mediate increased AMPK, PPAR ligands activities, the fatty-acid oxidation and glucose uptake by adiponectin. Obesity decreased expression levels of not only adiponectin but also AdipoR1/R2, thereby reducing adiponectin actions, which finally leads to insulin resistance. Thus our data suggest that not only agonism of AdipoR1/R2 but also strategies to increase AdipoR1/R2 may be a logical approach to provide a novel treatment modality for obesity-linked diseases.Finally, we showed osmotin, that is a ligand for the yeast homolog of AdipoR (PHO36), activated AMPK via AdipoR in C2C12 myocytes. This may facilitate efficient development of adiponectin receptor agonists. Moreover, we found that PPARα agonist up-regulated expressions of AdipoRs. These data suggest that dual activation of PPARγ and PPAR enhances the action of adiponectin by increasing both total and HMW adiponectin and adiponectin receptors, which can result in amelioration of obesity-induced insulin resistance. Less