Role of LRP130 in brown adipocyte determination

描述(由申请人提供)： 肥胖在美国是一种日益严重的流行病，并易患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，这突显了它在肥胖中的重要性。存在两种主要类型的脂肪组织，白色和棕色，每个储存库都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(产热作用)的形式消耗燃料。棕色脂肪的生热能力被认为是抗肥胖的。在肥胖症的治疗中，基本疗法的一个梦想是研制出化合物，将棕色脂肪的生热特性赋予白色脂肪细胞的对应物。实现这一目标的核心是对棕色脂肪细胞生物学的基本了解。PGC-1家族的辅活化子调节棕色脂肪细胞的测定，然而，这种特异性的分子基础尚不清楚。我们最近发现LRP130是PGC-1？LRP130在肝脏糖异生中的作用，并已开始探索LRP130在棕色脂肪发育中的作用。初步数据表明，LRP130在测定棕色脂肪中起着至关重要的作用。LRP130调节几个依赖于PGC-1的棕色脂肪标记物，包括解偶联蛋白1(Ucp1)，它对产热很重要，是棕色脂肪细胞决定的标志。本应用的目的是评估LRP130在棕色脂肪细胞测定中的作用，并确定其潜在的转录机制。我们推测LRP130调节对棕色脂肪细胞测定重要的PGC-1靶点的一个子集。三个特定的目标将检验这一假说如下：目的(1)评估LRP130缺失的脂肪细胞的棕色脂肪细胞测定和线粒体功能。目的(2)评价异位表达LRP130的脂肪细胞中棕色脂肪细胞的检测。目的(3)确定Ucp1启动子对LRP130的调控区域。该项目的完成将促进目前对棕色脂肪细胞检测机制的理解，并可能为寻找新的诊断和治疗干预措施提供信息。

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.