Functional Genomic Analysis of Adipocytes and Adiposity

前体脂肪细胞的增殖和随后向成熟脂肪细胞的分化是肥胖症的重要方面。我们发现，在脂肪细胞分化过程中，MAPK的负调控因子MKP-1的丰度增加。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发挥重要作用。转录因子KLF15在脂肪细胞分化过程中上调。我们发现KLF15还通过PPARg的诱导在脂肪细胞分化中发挥重要作用，PPARg是脂肪形成的主要调节因子。此外，KLF15被发现有助于调节肝脏中的糖异生基因。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在脂肪细胞的胰岛素作用中扮演着重要的角色。随着Cre-loxP系统的使用，我们产生了肝脏中特异性缺乏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参与了肝脏脂肪生成的调节和胰岛素敏感性的维持。我们发现转录因子STAT3在肝脏葡萄糖代谢的调节中起着关键作用，可能成为胰岛素抵抗和代谢综合征的治疗靶点。我们还表明，血浆胰岛素浓度的增加通过激活大脑中的胰岛素受体，以IL-6依赖的方式刺激肝脏中STAT3的酪氨酸磷酸化。这些结果表明，肝脏中的IL-6-STAT3信号参与了大脑中胰岛素的作用，从而抑制了肝脏葡萄糖的产生。

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.