HORMONAL SIGNALING AND PREADIPOCYTE DIFFERENTIATION

激素信号传导和前细胞分化

• 批准号: 7648049
• 负责人: STEPHEN ROBERT FARMER
• 金额: $ 31.7万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7648049
• 关键词: Adipocytes; CCAAT-Enhancer-Binding Protein-alpha; CCAAT-Enhancer-Binding Protein-beta; CRSP7 gene; Classification; Commit; Complex; Consensus; Cyclic AMP; Cyclin D1; Cyclin-Dependent Kinase 4; Differentiation and Growth; Disease; Event; Gene Expression; Goals; Hormonal; Incidence; Individual; Insulin; Insulin Resistance; Insulin Signaling Pathway; Investigation; Lead; MEKs; Mediator of activation protein; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Obesity; PPAR gamma; Peptidylprolyl Isomerase; Phosphorylation; Phosphotransferases; Play; Process; Production; Proteins; Role; Signal Pathway; Signal Transduction; Site; Therapeutic; adipokines; adiponectin; combat; energy balance; insulin sensitivity; lipid biosynthesis; programs; response

DESCRIPTION (provided by applicant): The increase in adiposity in obese individuals results from an increase in the number of adjpocytes as well as the size of individual fat cells. Consequently, understanding the mechanisms regulating preadipocyte proliferation and differentiation will provide valuable information that will aid in the search for safe and effective therapeutics to reduce the growing incidence of obesity in the modern world. Additionally, obese individuals are more likely than their lean counterparts to develop insulin resistance, which leads to type 2 diabetes. In this regard, it is important to define the mechanisms by which adipocytes regulate insulin responsive processes in the body. During the last several years, we and others have embarked on a detailed and systematic endeavor to define the transcriptional events and associated signaling pathways regulating preadipocyte growth and differentiation. We have also been committed to defining the mechanisms, which regulate insulin sensitivity in the adipocyte as well as those that control production of adipocytokines involved in overall energy balance. Our studies have contributed to the demonstration that C/EBPbeta plays an important role during adipogenesis by initiating a very early event leading to expression of the two master regulators of adipogenesis, PPARgamma and C/EBPalpha. This process also involves activation of the MEK/ERK signaling pathway by insulin and effectors of cAMP signaling. In fact, we have recently demonstrated that phosphorylation of C/EBPbeta at a consensus ERK/GSK3 phosphoacceptor site (Thr188) is required for the induction of C/EBPalpha and adiponectin expression during adipogenesis. The goal of the proposed studies is to continue with this endeavor to understand the molecular mechanisms regulating adipogenic gene expression by performing the investigations outlined in the following specific aims: 1. Identify the phosphoacceptor sites in C/EBPbeta regulating preadipocyte proliferation and differentiation. 2. Identify regulatory factors associating with C/EBPbeta in response to phosphorylation of select kinase sites. 3. Define the function of C/EBPbeta-associated proteins in regulating adipogenic gene expression. It is anticipated that these studies will contribute significantly to our understanding of the molecular mechanisms controlling adipocyte formation and function and ultimately lead to strategies to combat obesity and its associated disorders.

描述（由申请人提供）：肥胖个体的肥胖增加是由于邻接细胞数量增加以及单个脂肪细胞的大小而导致的。因此，了解调节前脂肪细胞增殖和分化的机制将提供有价值的信息，这将有助于寻找安全有效的治疗剂，以减少现代世界中肥胖的日益增长的发生。此外，肥胖个体比瘦肉的人更有可能产生胰岛素抵抗，从而导致2型糖尿病。在这方面，重要的是要定义脂肪细胞调节体内胰岛素反应过程的机制。在过去的几年中，我们和其他人开始了一项详细而系统的努力，以定义转录事件以及相关的信号通路，以调节前脂肪细胞的生长和分化。我们还致力于定义机制，这些机制调节脂肪细胞中的胰岛素敏感性以及控制与整体能量平衡有关的脂肪细胞的产生的机制。我们的研究有助于证明C/EBPBETA通过发起非常早期的事件在脂肪生成过程中起重要作用，从而导致表达脂肪形成的两个主要调节剂，Ppargamma和C/Ebpalpha。该过程还涉及通过胰岛素和cAMP信号传导的效应子激活MEK/ERK信号通路。实际上，我们最近证明，在共识ERK/GSK3磷酸acctector位点（THR188）磷酸化是诱导C/EBPALPHA和脂肪蛋白表达过程中所必需的。拟议的研究的目的是继续进行这项努力，以通过执行以下具体目的概述的研究来了解调节成脂基因表达的分子机制：1。确定调节preadipocyte的磷酸acceptor位点，从而调节phospbeta的位点，从而调节phospbeta的磷酸化基因表达。 2。确定与C/EBPBETA相关的调节因素，以响应某些激酶位点的磷酸化。 3。定义C/EBPBETA相关蛋白在调节成脂基因表达中的功能。可以预料，这些研究将对我们对控制脂肪细胞形成和功能的分子机制的理解产生重大贡献，并最终导致打击肥胖及其相关疾病的策略。