Functional Genomic Analysis of Adipocytes and Adiposity

前脂肪细胞的增殖和随后这些细胞分化为成熟脂肪细胞是肥胖的重要方面。我们已经发现，丰富的MKP-1，一个负调节MAPK，在脂肪细胞分化过程中增加。MKP-1在前脂肪细胞中的异位表达增加，而成熟脂肪细胞中内源性MKP-1的缺失抑制了分化，表明MKP-1通过下调MAPK活性在脂肪细胞分化中起重要作用。转录因子KLF15在脂肪细胞分化过程中上调。我们已经发现KLF15通过诱导PPARg（脂肪形成的主要调节剂）在脂肪细胞分化中也起重要作用。此外，发现KLF15有助于调节肝脏中的致瘤基因。我们已经建立了一个缺乏PDK1基因的细胞系。通过使用这些细胞，我们已经证明了PDK1在脂肪细胞中胰岛素作用中的重要作用。通过使用Cre-LoxP系统，我们已经产生了在肝脏中特异性缺乏PKCl的小鼠。这些小鼠表现出SREBP1c丰度的降低和全身胰岛素敏感性的增加。这些结果表明，PKCl有助于调节肝脏中的脂肪生成和维持胰岛素敏感性。我们发现转录因子STAT3在肝脏葡萄糖代谢的调节中起着至关重要的作用，并可能作为胰岛素抵抗和代谢综合征的治疗靶点。我们还表明，胰岛素血浆浓度的增加通过以IL-6依赖性方式激活脑中的胰岛素受体来刺激肝脏中STAT3的酪氨酸磷酸化。因此，这些结果表明，肝脏中的IL-6-STAT3信号传导有助于大脑中的胰岛素作用，导致肝脏葡萄糖产生的抑制。

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.