The regulation and activation of STATs in adipocytes

脂肪细胞中STATs的调节和激活

• 批准号: 8432887
• 负责人: Jacqueline M Stephens
• 金额: $ 31.5万
• 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 2015-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8432887
• 关键词: 3T3-L1 Cells; Adipocytes; Adipose tissue; Adult; Affect; Cardiovascular Diseases; Cells; Circadian Rhythms; Data; Deposition; Development; Diabetes Mellitus; Disease; Ectopic Expression; Endocrine; Family; Fatty acid glycerol esters; Fatty-acid synthase; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Health; Homeostasis; Hormones; Hypertension; Insulin Resistance; Laboratories; Link; Lipids; Mediator of activation protein; Metabolic Diseases; Non-Insulin-Dependent Diabetes Mellitus; Nutritional status; Obesity; Play; Population; Process; Production; Prolactin; Property; Proteins; Publishing; Regulation; Risk Factors; Rodent; Rodent Model; Role; STAT protein; STAT5A gene; STAT5B gene; STAT5a Transcription Factor; STAT5b Transcription Factor; Somatotropin; Testing; Tyrosine Phosphorylation; United States; Vertebrates; adipocyte differentiation; adipokines; base; diabetic; hormone resistance; in vivo; insulin sensitivity; knock-down; lipid biosynthesis; lipid metabolism; research study; transcription factor

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.

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着重要作用。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。在美国，肥胖影响了30%的成年人，是非胰岛素依赖型糖尿病（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，对这些调节过程的理解取得了重大进展。众所周知，在脂肪细胞分化过程中，一些转录因子被诱导，在脂肪细胞基因表达的调控中发挥关键作用，并在肥胖和/或胰岛素抵抗的情况下发生改变。我们主要关注STATs（信号转导和转录激活因子），这是一类转录因子，其活性主要由激素诱导的酪氨酸磷酸化控制。我们的工作集中在两种STAT蛋白STAT5A和stat5b上，它们的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。虽然STAT5A促进脂肪前细胞的脂质沉积，但各种观察表明，STAT5A在成熟脂肪细胞中具有抗脂质生成作用。生长激素是一种有效的STAT 5蛋白诱导剂，众所周知，它具有溶脂、抗脂和致糖尿病的作用。已知STATs具有细胞特异性功能，我们假设STAT5蛋白在脂肪细胞脂质代谢和胰岛素抵抗相关基因的调控中发挥重要作用。我们的初步研究表明，白色脂肪组织中的STAT5酪氨酸磷酸化在肥胖的啮齿动物模型中发生了改变。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。在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。