Role of LRP130 in brown adipocyte determination

描述（由申请人提供）： 肥胖症在美国是一种日益增长的流行病，容易患2型糖尿病和心血管疾病。脂肪组织是全身能量平衡的中心调节器，强调其在肥胖中的重要性。存在两种主要类型的脂肪组织，白色和棕色，并且每个贮库由其必需的脂肪细胞组成。白色脂肪细胞以甘油三酯的形式储存能量，而棕色脂肪细胞则以热量的形式（产热作用）消耗其燃料储存。棕色脂肪的产热能力被认为是抗肥胖的。在肥胖症的治疗中，理性疗法的一个梦想是配制化合物，将棕色脂肪的产热特性赋予其对应的白色脂肪细胞。实现这一目标的核心是对棕色脂肪细胞生物学的基本理解。PGC-1家族的辅激活因子调节棕色脂肪细胞的决定，然而，这种特异性的分子基础是未知的。我们最近发现，LRP 130指定PGC-1？LRP 130在肝脏发育中的作用，并已开始探索LRP 130在棕色脂肪发育中的作用。实验数据表明LRP 130在棕色脂肪测定中起关键作用。LRP 130调节几种PGC-1依赖的棕色脂肪标志物，包括解偶联蛋白1（Ucp 1），这对产热很重要，是棕色脂肪细胞决定的标志。本申请的目的是评估LRP 130在棕色脂肪细胞确定中的作用，并确定其潜在的转录机制。我们假设LRP 130调节PGC-1靶点的一个子集，这对棕色脂肪细胞的确定很重要。三个具体的目标将测试假设如下：目的（1）评估棕色脂肪细胞的测定和线粒体功能的脂肪细胞缺乏LRP 130。目的（2）评价异位表达LRP 130的脂肪细胞中棕色脂肪细胞的确定。目的（3）鉴定Ucp 1启动子对LRP 130的调控区域。该项目的完成将推进目前对棕色脂肪细胞决定机制的理解，并可能为寻找新的诊断和治疗干预提供信息。

DESCRIPTION (provided by applicant): Obesity is a growing epidemic in the United States, and predisposes to type 2 diabetes and cardiovascular disease. Adipose tissue is a central regulator of whole body energy balance underscoring its importance in obesity. Two major types of adipose tissue exist, white and brown, and each depot is comprised of its requisite adipocyte. White adipocytes store energy as triglycerides, while brown adipocytes dissipate their fuel stores as heat (thermogenesis). The thermogenic capacity of brown fat is believed to render it anti-obesity. In the treatment of obesity, one dream of rationale therapeutics is to formulate compounds that confer the thermogenic qualities of brown fat onto their white adipocyte counterpart. Central to achieving such a goal is a basic understanding of brown adipocyte biology. Coactivators of the PGC-1 family regulate brown adipocyte determination, however, the molecular basis for this specificity is unknown. We recently found that LRP130 specifies PGC-1? function in hepatic gluconeogenesis, and have begun to explore the role of LRP130 in brown fat development. Preliminarily data indicates a crucial role for LRP130 in brown fat determination. LRP130 regulates several PGC-1 dependent brown fat markers, including uncoupling protein 1 (Ucp1), which is important for thermogenesis and is a hallmark of brown adipocyte determination. The goal of this application is to evaluate the role of LRP130 in brown adipocyte determination, and identify its underlying transcriptional mechanisms. We postulate that LRP130 regulates a subset of PGC-1 targets important for brown adipocyte determination. Three specific aims will test the hypothesis as follows: Aim (1) Evaluate brown adipocyte determination and mitochondrial function in adipocytes deficient for LRP130. Aim (2) Evaluate brown adipocyte determination in adipocytes expressing ectopic LRP130. Aim (3) Identify the regulatory regions of the Ucp1 promoter responsive to LRP130. Completion of this project will advance the current understanding of mechanisms underlying brown adipocyte determination, and may inform the search for new diagnostic and therapeutic interventions.