The regulation and activation of STATs in adipocytes

 描述（由申请人提供）：脂肪细胞是高度特化的细胞，在能量稳态中起主要作用。肥胖影响美国>30%的成年人口，并且是2型糖尿病（T2 D）发展的主要风险因素。肥胖和胰岛素抵抗可能与脂肪细胞中细胞信号传导和基因表达的破坏有关。通过研究调节脂肪细胞发育的信号蛋白和转录因子的功能以及脂肪组织中基因表达的调节，已经在理解代谢疾病状态方面取得了重大进展。我们的研究主要集中在STAT（信号转导和转录激活因子），一个转录因子家族，其活性在很大程度上由酪氨酸诱导的酪氨酸磷酸化控制。STAT 5A促进前脂肪细胞中的脂质沉积，但我们有证据表明STAT 5蛋白在成熟脂肪细胞中的作用是减少脂质积累和胰岛素敏感性。STATs具有细胞特异性功能，我们推测脂肪细胞中的STAT 5蛋白通过调节脂肪细胞的糖脂代谢和脂肪因子的产生，促进全身糖脂代谢和全身能量消耗。这项建议的上一个供资周期的研究使我们走向了新的方向。我们有数据表明，STAT 5A可以物理地与几种蛋白质，包括丙酮酸脱氢酶复合物（PDC）。总的来说，我们的长期目标是使用体外和体内方法评估STAT 5蛋白在成熟脂肪细胞中的功能，并确定STAT 5A和PDC的核缔合的功能相关性。第一个目标是对一种新型转基因小鼠进行代谢分析，该小鼠在脂联素表达细胞中特异性缺失两种STAT 5基因，以评估脂肪细胞STAT 5蛋白对葡萄糖和脂质代谢的贡献。第二个目的是确定STAT 5A与PDC-E2结合所需的结构域/残基，以及STAT 5/PDC相互作用对STAT 5靶基因表达调节的影响。我们认为，脂肪细胞STAT 5蛋白在脂解和参与脂质和葡萄糖代谢的基因的调节中是重要的。我们预测，脂肪细胞STAT 5的缺失将在体内产生显著的代谢效应，包括脂肪细胞脂解的改变和胰岛素敏感性的全身变化。

 DESCRIPTION (provided by applicant): Adipocytes are highly specialized cells that play a major role in energy homeostasis. Obesity affects >30% of the adult population in the United States and is a major risk factor for the development of Type 2 Diabetes mellitus (T2D). Obesity and insulin resistance can be linked to a breakdown in the cellular signaling and gene expression in adipocytes. Significant advances towards understanding metabolic disease states have been made by studying the function of signaling proteins and transcription factors that regulate adipocyte development and the modulation of gene expression in adipose tissue. Our research has focused on STATs (Signal Transducers and Activators of Transcription), a family of transcription factors whose activity is largely controlled by hormone-induced tyrosine phosphorylation. STAT5A promotes lipid deposition in preadipocytes, yet we have evidence to suggest the role of STAT5 proteins in mature adipocytes is to reduce lipid accumulation and insulin sensitivity. STATs can have cell-specific functions, and we hypothesize that STAT5 proteins in adipocytes contribute to systemic glucose and lipid metabolism and whole body energy expenditure by regulating fat cell glucose and lipid metabolism and adipokine production. Studies from the last funding cycle of this proposal have led us in new directions. We have data to demonstrate that STAT5A can physically associate with several proteins that comprise the pyruvate dehydrogenase complex (PDC). Collectively, our long term objective is to assess the functions of STAT5 proteins in mature adipocytes using in vitro and in vivo approaches and determine the functional relevance of the nuclear association of STAT5A and PDC. The first aim will be to perform metabolic analyses on a novel transgenic mouse with both STAT5 genes deleted specifically in adiponectin-expressing cells to assess the contribution of adipocyte STAT5 proteins to glucose and lipid metabolism. The second aim will be to determine the domains/residues of STAT5A that are required for its association with PDC-E2, and the impact of the STAT5/PDC interaction on modulation of STAT5-target gene expression. We propose that adipocyte STAT5 proteins are important in lipolysis and in the regulation of genes involved in lipid and glucose metabolism. We predict that loss of adipocyte STAT5 will have prominent metabolic effects in vivo including alterations in adipocyte lipolysis and systemic changes in insulin sensitivity.