HORMONAL SIGNALING AND PREADIPOCYTE DIFFERENTIATION

描述（由申请人提供）：肥胖个体中肥胖的增加是由于相邻细胞数量以及单个脂肪细胞大小的增加。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方法，以减少现代世界肥胖症的发病率。此外，肥胖的人比瘦的人更容易患上胰岛素抵抗，从而导致2型糖尿病。在这方面，重要的是要确定脂肪细胞调节体内胰岛素反应过程的机制。在过去的几年里，我们和其他人已经开始了详细和系统的奋进，以确定转录事件和相关的信号通路调节前脂肪细胞的生长和分化。我们也一直致力于定义的机制，调节胰岛素敏感性的脂肪细胞，以及那些控制生产的脂肪细胞因子参与整体能量平衡。我们的研究有助于证明C/EBP β通过启动导致脂肪形成的两个主要调节因子PPARgamma和C/EBP α表达的非常早期的事件在脂肪形成过程中起重要作用。该过程还涉及通过胰岛素和cAMP信号传导的效应物激活MEK/ERK信号传导途径。事实上，我们最近已经证明，在脂肪形成过程中，C/EBP β在ERK/GSK 3磷酸受体位点（Thr 188）的磷酸化是诱导C/EBP α和脂联素表达所必需的。提出的研究的目标是继续这一奋进，以了解调节成脂基因表达的分子机制，通过执行以下具体目标概述的调查：1。鉴定C/EBP β中调节前脂肪细胞增殖和分化的磷酸受体位点2.确定与C/EBP β相关的调节因子，以响应选择激酶位点的磷酸化。3.明确C/EB β相关蛋白在调节成脂基因表达中的功能。预计这些研究将大大有助于我们了解控制脂肪细胞形成和功能的分子机制，并最终导致对抗肥胖及其相关疾病的策略。

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.