Physiological role of PRDM16 in brown fat development and energy balance

描述(由申请人提供)： 在美国，肥胖是一种公共健康危机，因为它在多种疾病中起着因果作用和/或与之相关，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，即从食物中摄入的卡路里长期超过支出。白色脂肪组织非常适合以甘油三酯(脂肪)的形式储存多余的食物能量。哺乳动物身上也有棕色脂肪，这种脂肪能消耗化学能产生热量。许多研究证明，棕色脂肪通过增加全身能量消耗来对抗肥胖和糖尿病。我们最近发现PRDM16是一种转录调节因子，选择性地在棕色脂肪和白色脂肪中表达。值得注意的是，当PRDM16在白色脂肪祖细胞中表达时，能够诱导出几乎完整的棕色脂肪分化程序。因此，通过PRDM16确定特定调控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目标。 在这个提案中，我们探索了PRDM16在体内发育和肥胖中的生理作用，并探讨了其在棕色脂肪测定中作用的机制基础。具体地说，在目标1中，使用了遗传和细胞治疗方法来测试白色脂肪中PRDM16的表达是否可以预防肥胖。在目标2中，利用生化研究来阐明PRDM16是如何通过其与PPAR转录因子的相互作用来驱动棕色脂肪分化的程序。最后，目标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。 与公共健康相关：肥胖的流行及其在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增加能量消耗是减少肥胖的可行方法。在本研究中，我们直接测试了PRDM16是否可以用来对抗肥胖，希望这将为寻找增加PRDM16功能的药物提供科学依据。此外，我们还研究了PRDM16在刺激棕色脂肪发育中作用的机制基础，这可能揭示抗击肥胖的其他治疗目标。

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.