| Budget Amount *help |
¥38,600,000 (Direct Cost: ¥38,600,000)
Fiscal Year 2007: ¥7,300,000 (Direct Cost: ¥7,300,000)
Fiscal Year 2006: ¥7,300,000 (Direct Cost: ¥7,300,000)
Fiscal Year 2005: ¥8,000,000 (Direct Cost: ¥8,000,000)
Fiscal Year 2004: ¥8,000,000 (Direct Cost: ¥8,000,000)
Fiscal Year 2003: ¥8,000,000 (Direct Cost: ¥8,000,000)
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| Research Abstract |
Proliferation of preadipocytes and subsequent differentiation of these cells into mature adipocytes are important aspects of adiposity. We have found that the abundance of MKP-1, a negative regulator of MAPK, was increased during adipocyte differentiation. Ectopic expression of MKP-1 in preadipocytes increased, and depletion of endogenous MKP-1 in mature adipocytes inhibits the differentiation, indicating that MKP-1 plays an essential role in adipocyte differentiation through down-regulation of MAPK activity. The transcription factor KLF15 is upregulated during adipocyte differentiation. We have found that KLF15 also plays an important role in adipocyte differentiation through the induction of PPARg, a master regulator for adipogenesis. Moreover KLF15 was found to contribute to the regulation of gluconeogenic genes in the liver. We have establishes a cell line that lacks the PDK1 gene. With the use of these cells, we have demonstrated an essential role of PDK1 in insulin action in adipocytes. With the use of the Cre-LoxP system, we have generated mice lacking PKCl specifically in the liver. These mice manifested the decrease in the abundance of SREBP1c and the increase in the whole body insulin sensitivity. These results indicate that PKCl contribute to the regulation of lipogenesis in the liver and the maintenance of insulin sensitivity. We have found that transcription factor STAT3 plays a crucial role in the regulation of hepatic glucose metabolism and may serve as a therapeutic target of insulin resistance and metabolic syndrome. We also have shown that an increase in the plasma concentration of insulin stimulates tyrosine phosphorylation of STAT3 in the liver via the activation of the insulin receptor in the brain in a IL-6 dependent manner. These results thus indicate that IL-6-STAT3 signaling in the liver contributes to insulin action in the brain leading to the suppression of hepatic glucose production.
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