Perilipin 5 in the Regulation of Adipose Tissue Function

项目摘要/摘要 肥胖和2型糖尿病患病率的上升威胁到限制人类的健康寿命，因为它增加了 增加癌症和心脏代谢性疾病的风险，并造成压倒性的经济负担。新的 迫切需要治疗策略。自发现功能性棕色和米色脂肪细胞以来， 成年人类，很多注意力都集中在开发这些产热脂肪细胞的能力上 通过非偶联的线粒体呼吸将多余的能量以热量的形式释放出去。人类的先进成像技术 已经揭示了棕色脂肪质量和心脏代谢风险因素之间的良好相关性。一个巨大的差距 是一种安全有效的药理策略，可以激活棕色和/或米色脂肪细胞 促进能量负平衡，逆转肥胖，缓解肥胖相关的代谢紊乱，如 2型糖尿病、心血管疾病和非酒精性脂肪肝。这个项目的总体目标是 应用程序是为实验室长期以来提出的一种这样的策略提供概念验证- Perilipin 5(PLIN5)的长期研究计划，Perilipin 5(PLIN5)是Perilipin脂滴蛋白家族的成员 它在氧化组织中表达，包括棕色脂肪组织(BAT)。越来越多的文学作品 来自我们实验室和其他实验室的研究表明，PLIN5不仅参与调节脂滴的脂解作用 在核内与SIRT1和PGC1a的相互作用也参与了基因表达的调控 以及将脂滴拴在线粒体上。我们在小鼠身上发表的研究表明，PLIN5是 蝙蝠新陈代谢、转录和线粒体适应冷胁迫所必需的。我们有 BAT小鼠体内PLIN5功能增强可预防糖耐量减低和脂肪肝。 高脂饮食和促进白色脂肪组织(WAT)健康重塑并预防脂肪细胞 肥大。在这一更新申请中，我们建议测试促进PLIN5表达的假设 在BAT中，联合b3肾上腺素能受体激动剂治疗饮食诱导的肥胖小鼠将逆转 WAT的脂肪细胞肥大、逆转肥胖和逆转糖耐量异常。目标1将阐明 PLIN5对线粒体形态和功能影响的代谢和信号通路 BAT以及通过遗传小鼠模型对全身脂肪和葡萄糖代谢的影响，体内结构-- 功能研究和机械线粒体实验。目标2将询问信号通路 以及与通过两次干预治疗饮食诱导的肥胖相关的生理反应 B3肾上腺素能受体激动剂协同作用对BAT细胞plin5表达的影响。 这些目标的成功完成可能会为新的治疗方法奠定概念基础 治疗肥胖症的范例是有效的，但现有药物的剂量较低，无毒。

Project Abstract/Summary The rising prevalence of obesity and type 2 diabetes threatens to limit human healthspan by increasing the risks for cancer and cardiometabolic disease and to impose overwhelming economic burdens. New therapeutic strategies are urgently needed. Since the discovery of functional brown and beige adipocytes in adult humans, much attention has focused on exploiting the ability of these thermogenic adipocytes to dissipate excess energy as heat through uncoupled mitochondrial respiration. Advanced imaging in humans has revealed a favorable correlation between brown fat mass and cardiometabolic risk factors. A major gap in the field is a safe and effective pharmacological strategy to activate brown and/or beige adipocytes to promote negative energy balance, reverse obesity, and mitigate obesity-related metabolic disorders, such type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease. The overall goal of this application is to provide proof-of-concept for one such strategy that has been suggested by the lab’s long- standing research program on Perilipin 5 (PLIN5), a member of the Perilipin family of lipid droplet proteins that is expressed in oxidative tissues, including brown adipose tissue (BAT). A growing body of literature from our lab and others has implicated PLIN5 not only in the regulation of lipolysis at the lipid droplet surface, but also in the regulation of gene expression via interactions in the nucleus with SIRT1 and PGC1a and in the tethering of lipid droplets to mitochondria. Our published work in mice has shown that PLIN5 is required for the metabolic, transcriptional, and mitochondrial adaptations of BAT to cold stress. We have also shown that PLIN5 gain-of-function in BAT of mice can prevent glucose intolerance and fatty liver from high-fat diet and promote healthy remodeling of white adipose tissue (WAT) with prevention of adipocyte hypertrophy. In this renewal application we propose to test the hypothesis that promoting PLIN5 expression in BAT in conjunction with b3 adrenergic receptor agonist treatment of diet-induced obese mice will reverse adipocyte hypertrophy in WAT, reverse obesity, and reverse glucose intolerance. Aim 1 will elucidate the metabolic and signaling pathways responsible for the effects of PLIN5 on mitochondrial form and function in BAT and on systemic lipid and glucose metabolism by means of genetic mouse models, in vivo structure- function studies, and mechanistic mitochondrial experiments. Aim 2 will interrogate the signaling pathways and physiological responses associated with treatment of diet-induced obesity with a 2-hit intervention built on augmentation of PLIN5 in BAT in synergistic combination with b3 adrenergic receptor agonist treatment. Successful completion of these Aims may establish the conceptual foundation for a new therapeutic paradigm for treatment of obesity that is efficacious but at lower, non-toxic doses of existing medications.