| Research Abstract |
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 metabolic diseases. We showed that inflammatory cytokines which are increased in obesity may play causal roles in these diseases (Nat. Cell Biol. 2003). In this study, we investigated the physiological and pathophysiological roles of adiponectin pathways.
Adiponectin secretion was up-regulated in PI3-kinase p85α regulatory subunit-deficient mice, which were characterized by increased insulin sensitivity. These observations suggest that "insulin-stimulated PI3-kinase-Akt activity in adipocytes" may play an important role in the regulation of adiponectin secretion (Diabetes 2004). 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 ind
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uced by inflammatory cytokines (BBRC 2004).
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 (JBC 2003). Moreover, we found that HMW (high molecular weight) adiponectin, which could activate AMPK most potently, was down-regulated in obesity. Moreover, we developed ELISA for specific measurement of HMW (CCA 2006), and showed that HMW/total adiponectin ratio was more tightly correlated with insulin resistance, and was more useful than total adiponectin in the diagnosis of metabolic syndrome (Diabetes Care, 2006). We found that adiponectin cleavage appeared to be mediated by leukocyte elastase (Endocrinology 2005).
We next generated adiponectin transgenic mice and crossed with apoE deficient mice. The en face Sudan IV-positive lesion areas of the arch and the descending aorta in adiponectin transgenic apoE deficient mice were significantly smaller than in nontransgenic apoE deficient littermates. Thus, overexpression of adiponectin resulted in marked reduction of atherosclerotic lesion formation (JBC 2003).
We isolated cDNA encoding adiponectin receptors (AdipoR1 and R2) by expression cloning (Nature 2003). Obesity decreased expression levels of not only adiponectin but also AdipoR1/R2, thereby reducing adiponectin actions, which finally leads to insulin resistance (JBC 2004). 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. Simultaneous disruption of both AdipoR1 and R2 abolished adiponectin binding and actions, resulting in increased tissue triglyceride content, inflammation and oxidative stress, and thus leading to insulin resistance and marked glucose intolerance. Moreover, we showed that AdipoR1 and R2 in the liver increased AMPK activation and PPAR-alpha signaling pathways, respectively (Nat. Med 2007). Furthermore, we also showed that adiponectin stimulated AMPK in the hypothalamus and increased food intake (Cell Metab. 2007).
Finally, we found that PPARα agonist up-regulated expressions of AdipoRs, whereas PPARγ agonist up-regulated the reduced HMW adiponectin (Diabetes 2005). Morevoer, we showed osmotin, that is a ligand for the yeast homolog of AdipoR (PHO36), activated AMPK via AdipoR in C2C12 myocytes (Mol. Cell. 2005). Less
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