The regulation and activation of STATs in adipocytes

脂肪细胞中STATs的调节和激活

• 批准号: 9135631
• 负责人: Jacqueline M Stephens
• 金额: $ 18.5万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2016-06-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9135631
• 关键词: Acetyl Coenzyme A; Acetylation; Adipocytes; Adipose tissue; Adult; Affect; Animal Model; Binding; Binding Sites; Cell Nucleus; Cell physiology; Cells; Chromatin; DNA Binding; Data; Deposition; Development; Diabetes Mellitus; Disease; Dose; Energy Metabolism; Family; Fatty acid glycerol esters; Fatty-acid synthase; Funding; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Health; Histones; Homeostasis; Hormones; Human; In Vitro; Insulin; Insulin Resistance; Link; Lipids; Lipolysis; Metabolic; Metabolic Diseases; Metabolic Pathway; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Translocation; Obesity; Phenotype; Play; Population; Production; Proteins; Pyruvate Dehydrogenase Complex; Regulation; Research; Risk Factors; Role; STAT protein; STAT1 gene; STAT5B gene; Signal Transduction; Signaling Protein; Site; Small Interfering RNA; Stat5 protein; Testing; Time; Transgenic Mice; Tyrosine Phosphorylation; United States; adipocyte differentiation; adiponectin; energy balance; glucose metabolism; glucose tolerance; in vivo; insulin sensitivity; insulin tolerance; lipid metabolism; novel; protein function; pyruvate dehydrogenase complex E2; pyruvate dehydrogenase kinase 4; research study; response; transcription factor

 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.

 描述（由申请人提供）：脂肪细胞是高度特化的细胞，在能量稳态中发挥重要作用。肥胖影响美国超过 30% 的成年人口，是发生 2 型糖尿病 (T2D) 的主要危险因素。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和脂肪组织基因表达调节的信号蛋白和转录因子的功能，在理解代谢疾病状态方面取得了重大进展。我们的研究重点是 STAT（转录信号转导和激活因子），这是一个转录因子家族，其活性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质沉积，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质积累和胰岛素敏感性。 STATs 可以具有细胞特异性功能，我们假设脂肪细胞中的 STAT5 蛋白通过调节脂肪细胞葡萄糖和脂质代谢以及脂肪因子的产生，有助于全身葡萄糖和脂质代谢以及全身能量消耗。该提案上一个资助周期的研究为我们指明了新的方向。我们有数据证明 STAT5A 可以与构成丙酮酸脱氢酶复合物 (PDC) 的多种蛋白质发生物理关联。总的来说，我们的长期目标是使用体外和体内方法评估成熟脂肪细胞中 STAT5 蛋白的功能，并确定 STAT5A 和 PDC 核关联的功能相关性。第一个目标是对一种新型转基因小鼠进行代谢分析，该转基因小鼠在脂联素表达细胞中特异性删除了两个 STAT5 基因，以评估脂肪细胞 STAT5 蛋白对葡萄糖和脂质代谢的贡献。第二个目标是确定 STAT5A 与 PDC-E2 关联所需的结构域/残基，以及 STAT5/PDC 相互作用对 STAT5 靶基因表达调节的影响。我们认为脂肪细胞 STAT5 蛋白在脂肪分解以及脂质和葡萄糖代谢相关基因的调节中很重要。我们预测脂肪细胞 STAT5 的缺失将在体内产生显着的代谢影响，包括脂肪细胞脂肪分解的改变和胰岛素敏感性的全身变化。