Novel Thermogenic Factors to Combat Obesity and Metabolic Disease

项目总结 肥胖是糖尿病和心血管等慢性疾病发展的重要危险因素 疾病。考虑到全球肥胖率的上升到现在的流行，目前的治疗方法是无效的 比例。世界卫生组织(WHO)报告称，全球有19亿人(三分之一)是 超重和管理肥胖相关疾病的成本上升占每年1470亿美元 2008年美国医疗保健支出。需要更多的治疗选择是至关重要的。这样做的目的是 提议是开发针对肥胖和相关代谢性疾病的分子治疗方法。我们利用这个机会 产生热量的棕色和米色脂肪生物学，当靶向时，可以增加能量消耗和提供 通过解偶联蛋白1(UCP1)的作用预防肥胖。这个过程的机制， 然而，还没有完全理解。揭示新的途径和调控因素，可以激活这一点 该过程将最大限度地为患有肥胖症和相关代谢性疾病的个人提供治疗选择。 我们之前在小鼠模型中的工作表明，转录因子阴阳1(YY1)是关键的 用于棕色脂肪的功能。脂肪特异性消融YY1(YY1bKO)导致明显的生热缺陷 棕色脂肪组织，但机制尚不清楚。为了深入了解其作用机制，我们 在YY1bKO棕色脂肪中进行了无偏转录谱分析，以寻找新的生热调节剂和 鉴定了NipSnap1(4-硝基苯基磷酸酶结构域和非神经性SNAP-25蛋白) 同源基因1)。NipSnap1在进化上在物种中是保守的，但一个明确的功能注释仍有待于 已分配。我们的初步数据显示，NipSnap1显示出很强的生热特性，并显著改变了 UCP1蛋白水平。因此，这项建议的目标是确定NipSnap1的分子功能 生热脂肪组织，以验证NipSnap1在 生热作用。建议的研究将在原代棕色和米色脂肪细胞中使用生化方法。 详细说明NipSnap1转录和翻译动态对各种生热刺激的响应 (目标1)。然后，我们将继续通过增益-和CRISPR-损失-来描述NipSnap1的功能。 除了测试连接和非连接的线粒体呼吸能力外，还进行功能研究 系统。还将评估使用高效LC-MS/MS进行生热脂肪代谢组谱分析 (目标2)。我们的研究将是第一次表征分子功能以及与代谢组学相关的 NipSnap1在生热脂肪组织中的网络。这项提案的发现将决定NipSnap1 可用于治疗肥胖症和相关的代谢紊乱。

PROJECT SUMMARY Obesity is a significant risk factor for the development of chronic disorders such as diabetes and cardiovascular disease. Current treatments are ineffectual given the worldwide increase in obesity rates to now epidemic proportions. The World Health Organization (WHO) reports that 1.9 billion (1 in 3) individuals globally are overweight and the rising cost to manage obesity-related diseases represented $147 billion dollars of the annual U.S. healthcare expenditure in 2008. The need for additional treatment options is critical. The goal of this proposal is to develop molecular treatments for obesity and associated metabolic disease. We take advantage of the thermogenic brown and beige fat biology that, when targeted, can increase energy expenditure and confer protection against obesity through the action of uncoupling protein 1 (UCP1). The mechanisms of this process, however, are not completely understood. Unveiling novel pathways and regulatory factors that can activate this process will maximize treatment options for individuals suffering from obesity and associated metabolic disease. Our previous work in murine models demonstrated that the transcription factor Yin Yang 1 (YY1) is critical for brown fat function. Adipose-specific ablation of YY1 (YY1bKO) results in significant thermogenic defects in the brown fat tissue, but the mechanism is unknown. In order to gain insight into the mechanism of action, we performed unbiased transcriptomic profiling in YY1bKO brown fat in search for novel thermogenic regulators and identified the gene nipsnap1 (4-nitrophenyl phosphatase domain and non-neuronal SNAP-25 like protein homolog1). Nipsnap1 is evolutionarily conserved across species, yet a clear functional annotation remains to be assigned. Our preliminary data show that Nipsnap1 exhibits a strong thermogenic profile and dramatically alters UCP1 protein levels. The goal of this proposal therefore is to identify the molecular function of Nipsnap1 in thermogenic adipose tissue in order to test the hypothesis that Nipsnap1 plays a significant role in thermogenesis. The studies proposed will use biochemical approaches in primary brown and beige adipocytes to detail the transcription and translation dynamics of Nipsnap1 in response to various thermogenic stimuli (Aim1). We will then continue with the functional characterization of Nipsnap1 through gain- and CRISPR-loss- of-function studies in addition to testing the coupled and uncoupled mitochondrial respiratory capacity of the system. Thermogenic adipose metabolomic profiling using high performance LC-MS/MS will also be assessed (Aim 2). Our studies will be the first to characterize the molecular function as well as the metabolomic-linked network of Nipsnap1 in thermogenic adipose tissue. The findings from this proposal will determine if Nipsnap1 can be leveraged towards a treatment for obesity and associated metabolic disorders.