Physiological role of PRDM16 in brown fat development and energy balance

描述（由申请人提供）： 肥胖是美国的一个公共卫生危机，因为它在各种疾病中起因果作用和/或与各种疾病相关，包括：2型糖尿病、代谢综合征、心脏病和癌症。肥胖是由能量平衡缺陷引起的，从食物中摄入的热量长期超过支出。白色脂肪组织高度适应于以甘油三酯（脂肪）的形式储存多余的食物能量。哺乳动物也有棕色脂肪，可以消耗化学能产生热量。许多研究证明棕色脂肪通过提高全身能量消耗来对抗肥胖和糖尿病。我们最近发现PRDM16是一种选择性表达于棕色脂肪和白色脂肪的转录调节因子。引人注目的是，当在白色脂肪祖细胞中表达时，PRDM 16能够诱导棕色脂肪分化的接近完整的程序。因此，确定通过PRDM16特异性调节棕色脂肪发育的分子途径可以为减少肥胖提供现实的治疗靶点。 在这个提议中，我们探索PRDM16在发育和肥胖中的体内生理作用;并研究其在棕色脂肪测定中的功能的机制基础。具体地，在目的1中，使用遗传和细胞治疗方法来测试白色脂肪中的PRDM16表达是否可以防止肥胖。在目标2中，采用生物化学研究来阐明PRDM16如何通过其与PPAR转录因子的相互作用来驱动棕色脂肪分化程序。最后，目的3是通过研究PRDM16缺陷小鼠来确定PRDM16在发育和代谢中的生理作用。 公共卫生相关性：肥胖的流行及其在促进许多疾病中的作用使其成为美国头号公共卫生问题。通过增加棕色脂肪的形成或功能来提高能量消耗是减少肥胖的可行方法。在这项研究中，我们直接测试PRDM16是否可以用于对抗肥胖，并希望这将为寻找增加PRDM16功能的药物提供科学依据。此外，我们研究了PRDM16刺激棕色脂肪发育的机制基础，这可能会揭示对抗肥胖的其他治疗靶点。

DESCRIPTION (provided by applicant): Obesity is a public health crisis in the U.S. by virtue of its causal role in and/or association with a variety of diseases including: type 2 diabetes, metabolic syndrome, heart disease, and cancer. Obesity is caused by a defect in energy balance, where calorie intake from food chronically exceeds expenditure. White adipose tissue is highly adapted to store the excess food energy in the form of triglycerides (fat). Mammals are also equipped with brown adipose which dissipates chemical energy to produce heat. Many studies document the ability of brown fat to counteract obesity and diabetes by raising whole body energy expenditure. We recently identified PRDM16 as a transcriptional regulator selectively expressed in brown versus white fat. Strikingly, PRDM16 is able to induce a near complete program of brown fat differentiation when expressed in white fat progenitors. Defining the molecular pathways that specifically regulate brown adipose development through PRDM16 could thus provide realistic therapeutic targets to reduce obesity. In this proposal, we explore the in vivo physiological role of PRDM16 in development and obesity; and investigate the mechanistic basis for its function in brown fat determination. Specifically, in aim 1, a genetic and a cell therapy approach is used to test whether PRDM16 expression in white fat can protect against obesity. In aim 2, biochemical studies are employed to elucidate how PRDM16 drives the program of brown fat differentiation via its interaction with PPAR transcription factors. Finally, aim 3 is to determine the physiological role of PRDM16 in development and metabolism by studying PRDM16-deficient mice. PUBLIC HEALTH RELEVANCE: The prevalence of obesity and its role in promoting many diseases make it the number one public health issue in the U.S. Raising energy expenditure by increasing the formation or function of brown fat is a viable approach to reduce obesity. In this study, we directly test whether PRDM16 can be used to counteract obesity and hope that this will provide the scientific basis for finding pharmacological agents that increase PRDM16 function. In addition, we investigate the mechanistic basis for PRDM16 action in stimulating brown fat development, which is likely to reveal additional therapeutic targets for fighting obesity.