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，也是工业世界中最常见的代谢紊乱。肥胖影响美国>30%的成年人口，并且是非胰岛素依赖性糖尿病（NIDDM）、心血管疾病和高血压发展的主要危险因素。最近的研究表明，肥胖及其相关疾病可能与控制脂肪细胞中多种基因表达的调节机制的崩溃有关。通过研究调节脂肪细胞分化和参与脂肪细胞基因表达调节的转录因子的功能，已经取得了对这些调节过程的理解的重大进展。众所周知，几种转录因子在脂肪细胞分化过程中被诱导，在脂肪细胞基因表达的调节中起关键作用，并且在肥胖和/或胰岛素抵抗的条件下被改变。我们关注的是STAT（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。我们的努力集中在两个STAT蛋白，STAT 5A和STAT 5 B，其表达在脂肪形成过程中被诱导。我们实验室和其他几个实验室的研究已经证明了STAT 5A的成脂能力。尽管STAT 5A促进前脂肪细胞中的脂质沉积，但有多种观察结果表明STAT 5A在成熟脂肪细胞中具有抗脂肪生成作用。生长激素是STAT 5蛋白的有效诱导剂，已知其具有脂解、抗脂肪生成和致糖尿病的作用。STATs具有细胞特异性功能，我们推测STAT 5蛋白在脂肪细胞中参与脂质代谢和胰岛素抵抗的基因调控中发挥重要作用。我们的初步研究表明，在肥胖的啮齿动物模型中，白色脂肪组织中的STAT 5酪氨酸磷酸化发生了改变。此外，我们有证据表明STAT 5蛋白可能通过调节几种脂肪因子的表达来影响脂肪细胞的内分泌特性。具体目标中概述的研究重点是了解STAT 5蛋白在成熟脂肪细胞中的功能，以及这些转录因子如何影响脂肪生成，胰岛素敏感性和脂肪细胞内分泌因子的产生。公共卫生相关性：通过研究参与控制脂肪细胞基因表达的转录因子的功能，对肥胖和糖尿病的认识取得了重大进展。我们的研究重点是了解STAT 5蛋白在脂肪细胞中的功能，以及这些转录因子如何影响脂肪细胞中的脂肪生成、胰岛素敏感性和内分泌因子的产生。

DESCRIPTION (provided by applicant): Adipocytes are highly specialized cells that play a major role in energy homeostasis in vertebrates. Obesity is the primary disease of fat cells and the most common metabolic disorder in the industrial world. Obesity affects >30% of the adult population in the United States and is a major risk factor for the development of non-insulin dependent diabetes mellitus (NIDDM), cardiovascular disease, and hypertension. Recent studies suggest that obesity and its related disorders may be linked to a breakdown in the regulatory mechanisms which control the expression of a variety of genes in adipocytes. Significant advances towards an understanding of these regulatory processes have been made by studying the function of transcription factors which regulate the differentiation of fat cells and are involved in the modulation of adipocyte gene expression. It is well recognized that several transcription factors are induced during adipocyte differentiation, play a critical role in the regulation of adipocyte gene expression, and are altered in conditions of obesity and/or insulin resistance. We have focused on STATs (Signal Transducers and Activators of Transcription), a family of transcription factors whose activity is largely controlled by hormone induced tyrosine phosphorylation. Our efforts have focused on two STAT proteins, STAT5A and STAT 5B, whose expression is induced during adipogenesis. Studies from our laboratory and several others have demonstrated the adipogenic capabilities of STAT 5A. Although STAT5A promotes lipid deposition in preadipocytes, there is a variety of observations to indicate that STAT 5A has anti-lipogenic actions in mature adipocytes. Growth hormone, a potent inducer of STAT 5 proteins is well known to have effects that are lipolytic, anti-lipogenic and diabetogenic. It is known that STATs can have cell specific functions, and we hypothesize that STAT5 proteins play a vital role in the regulation of genes involved in lipid metabolism and insulin resistance in adipocytes. Our preliminary studies demonstrate that STAT5 tyrosine phosphorylation in white adipose tissue is altered in rodent models of obesity. In addition, we have evidence to suggest that STAT 5 proteins may affect the endocrine properties of adipocytes by regulating the expression of several adipokines. The studies outlined in the specific aims focus on understanding the function of STAT 5 proteins in mature adipocytes and how these transcription factors affect lipogenesis, insulin sensitivity, and the production of endocrine factors from fat cells. PUBLIC HEALTH RELEVANCE: Significant advances towards understanding obesity and diabetes have been made by studying the function of transcription factors which are involved in controlling adipocyte gene expression. Our studies focus on understanding the function of STAT 5 proteins in fat cells and how these transcription factors affect lipogenesis, insulin sensitivity, and the production of endocrine factors in adipocytes.