Elucidation of molecular mechanism of exocytosis in adipocytes

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By exocytosis, adipocytes release adiponectin and increase of surface expression of glucose transporter-4 (GLUT4) molecules. We have developed assays for evaluating GLUT4 translocation in 3T3 adipocytes and cardiac muscle cells and found that H_2O_2, an oxidative stress, induced GLUT4 translocation via AMP-dependent protein kinase (AMPK) pathway in cardiac muscle cells. The small GTPase Ral have been demonstrated to play an important role in the regulation of GLUT4 translocation in adipocytes. We have demonstarated that Ral regulates the granule secretion via its effector, the exocyst tethering factor complex, by enhancing the calcium-ion sensitivity of the exocytosis in our established granule secretion assay using permeabilized platelets. We then identified Ral GAPs, the inhibitory regulators for Ral, for the first time. We have generated mice lacking Ral GAPs. We are investigating their adipose tissue structures and their serum glucose levels in response to insulin. On the other hand, we have established a gene trap method for identification of adipocyte differentiation factors using retrovirus insertion-mediated random mutagenesis. With the method, we have identified several molecules including TG-interacting factor and enkepharin. Hypoadiponectinemia is a risk of atherosclerotic diseases. We have found that serum adiponectin levels are associated with higher motality in chronic heart failure patients.