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，在脊椎动物生物体的能量稳态中起主要作用。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中代谢基因表达的机制失调。通过鉴定调节脂肪细胞分化并参与脂肪细胞基因表达的诱导和维持的转录因子，对这些调控过程的理解取得了重大进展。我们的研究集中在STAT家族的转录因子。STAT包含存在于静息细胞的细胞质中的潜伏转录因子家族。在对各种刺激的反应中，STAT被激活并移位到细胞核。与其他脂肪细胞转录因子不同，STAT可以被快速激活以调节基因表达，并代表了脂肪细胞转录调节中相对未开发的范例。我们已经表明，这两个STAT 5蛋白（STAT 5A和5B）的表达与脂质积累和过氧化物酶体增殖物激活受体？在脂肪形成过程中表达。已知STAT可以具有细胞特异性功能，并且我们假设这些转录因子在参与脂质代谢的基因的调节中起关键作用，并且可能在调节赋予脂肪细胞胰岛素敏感性的基因中起关键作用。我们的初步研究清楚地表明，STAT 5A可以促进非前体细胞中的脂肪形成。此外，我们已经表明，STAT 5A与糖皮质激素受体（GR）相互作用，这两个转录因子的关联在脂肪形成过程中受到调节。我们的初步研究还确定了脂肪细胞中一些潜在的STAT 5靶基因。具体目标中概述的研究重点是了解STAT 5蛋白在脂肪细胞中的功能。我们预测，这些研究将导致对调节能量稳态的分子机制的深入了解，并可能有助于理解肥胖和NIDDM的潜在缺陷。

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.