The regulation and activation of STATs in adipocytes

描述(申请人提供)：脂肪细胞是高度专门化的细胞，在脊椎动物的能量平衡中起着重要作用。肥胖是脂肪细胞的主要疾病，也是非胰岛素依赖型糖尿病(NIDDM)、心血管疾病和高血压的主要危险因素。肥胖及其相关疾病导致控制脂肪细胞代谢基因表达的机制失调。通过鉴定转录因子来调节脂肪细胞的分化，并参与脂肪细胞基因表达的诱导和维持，在理解这些调控过程方面取得了重大进展。我们的研究主要集中在转录因子STAT家族上。STATs由一系列潜伏的转录因子组成，它们驻留在静息细胞的细胞质中。作为对各种刺激的反应，STATS被激活并转移到核内。与其他脂肪细胞转录因子不同，STATS可以被快速激活来调节基因表达，在脂肪细胞的转录调控中代表着一个相对未知的范例。我们发现STAT5蛋白(STAT5A和5B)的表达与脂质堆积和PPAR？在脂肪形成过程中的表达。已知STATs可以具有细胞特异性功能，我们假设这些转录因子在调节涉及脂肪代谢的基因中发挥关键作用，并可能调节赋予脂肪细胞胰岛素敏感性的基因。我们的初步研究清楚地表明，STAT 5A可以促进非前体细胞的脂肪生成。此外，我们还发现STAT5A与糖皮质激素受体(GR)相互作用，并且这两种转录因子在脂肪形成过程中受到调节。我们的初步研究还发现了脂肪细胞中一些潜在的STAT5靶基因。在特定目标中概述的研究重点是了解STAT5蛋白在脂肪细胞中的功能。我们预测，这些研究将有助于深入了解调节能量稳态的分子机制，并可能有助于理解肥胖和NIDDM背后的缺陷。

DESCRIPTION (provided by applicant): Adipocytes are highly specialized cells that play a major role in energy homeostasis in vertebrate organisms. Obesity is the primary disease of fat cells and a major risk factor for the development of non-insulin dependent diabetes mellitus (NIDDM), cardiovascular disease, and hypertension. Obesity and its related disorders result in dysregulation of the mechanisms that control the expression of metabolic genes in adipocytes. Significant advances towards an understanding of these regulatory processes have been made by the identification of transcription factors that regulate the differentiation of fat cells and are involved in the induction and maintenance of adipocyte gene expression. Our research has focused on the STAT family of transcription factors. STATs comprise a family of latent transcription factors that reside in the cytoplasm of resting cells. In response to a variety of stimuli, STATs become activated and translocate to the nucleus. Unlike other adipocyte transcription factors, STATs can be rapidly activated to regulate gene expression and represent a relatively unexplored paradigm in the transcriptional regulation of fat cells. We have shown that the expression of both STAT 5 proteins (STATs 5A, and 5B) strongly correlates with lipid accumulation and PPAR? expression during adipogenesis. It is known that STATs can have cell specific functions, and we hypothesize that these transcription factors play a key role in the regulation of genes involved in lipid metabolism and possibly in regulating genes that confer insulin sensitivity to the adipocyte. Our preliminary studies clearly demonstrate that STAT 5A can promote adipogenesis in non-precursor cells. In addition, we have shown that STAT 5A interacts with glucocorticoid receptor (GR) and the association of these two transcription factors is regulated during adipogenesis. Our preliminary studies have also identified some potential STAT 5 target genes in adipocytes. The studies outlined in the specific aims focus on understanding the function of STAT 5 proteins in adipocytes. We predict that these studies will lead to insights into the molecular mechanisms regulating energy homeostasis and may contribute to understanding the defects underlying obesity and NIDDM.