The regulation and activation of STATs in adipocytes

 描述(申请人提供)：脂肪细胞是高度专业化的细胞，在能量平衡中发挥重要作用。肥胖影响着美国30%的成年人口，是罹患2型糖尿病(T2D)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和基因表达的崩溃有关。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控，在理解代谢性疾病状态方面取得了重大进展。我们的研究集中在STATS(信号转导和转录激活因子)，这是一个转录因子家族，其活性在很大程度上受激素诱导的酪氨酸磷酸化控制。Stat5a促进前脂肪细胞中的脂肪沉积，但我们有证据表明，STAT5蛋白在成熟脂肪细胞中的作用是减少脂肪堆积和胰岛素敏感性。STATs可以具有细胞特有的功能，我们假设脂肪细胞中的STAT5蛋白通过调节脂肪细胞的葡萄糖和脂肪代谢以及脂肪因子的产生来促进全身的糖脂代谢和全身能量消耗。该提案上一个资金周期的研究将我们引向了新的方向。我们有数据表明，STAT5A可以物理上与组成丙酮酸脱氢酶复合体(PDC)的几种蛋白质结合。总之，我们的长期目标是使用体外和体内方法评估STAT5蛋白在成熟脂肪细胞中的功能，并确定STAT5A和PDC核关联的功能相关性。第一个目标是对脂联素表达细胞中两个STAT5基因特异缺失的新型转基因小鼠进行代谢分析，以评估脂肪细胞STAT5蛋白对糖脂代谢的贡献。第二个目标是确定STAT5A与PDC-E2结合所需的结构域/残基，以及STAT5/PDC相互作用对STAT5靶基因表达调控的影响。我们认为脂肪细胞STAT5蛋白在脂肪分解和调节涉及脂肪和葡萄糖代谢的基因中起重要作用。我们预测，脂肪细胞STAT5的缺失将在体内产生显著的代谢效应，包括脂肪细胞脂肪分解的改变和全身性胰岛素敏感性的改变。

 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.