Role of desnutrin/ATGL in maintenance and function of brown adipose tissue

描述（由申请人提供）：白色脂肪组织（WAT）专门用于储存三酰甘油（TAG），将脂肪酸（FA）释放到循环中，供其他器官用作能量来源。相比之下，棕色脂肪组织（BAT）使用FA激活解偶联蛋白1 （UCP1）进行非寒颤产热，以热量形式消耗能量。在人类婴儿中，随着年龄的增长，大量的BAT最终转化为WAT。然而，最近在成人中发现的功能性BAT引起了人们对研究BAT预防和治疗肥胖的兴趣。然而，BAT表型维持或BAT向WAT转化的过程和潜在机制尚不清楚。在这里，我们提供的初步数据显示了以前未知的脱硝蛋白（主要的脂肪TAG水解酶）在BAT表型和功能中的作用。也就是说，在小鼠中，脂肪特异性地消融脱氮素会导致BAT显著转化为类似于瓦特的组织，抑制UCP-1和其他富含BAT的基因，改变线粒体形态，严重损害产热功能。相反，脂肪组织中desnutrin的过表达增加了UCP1的表达和产热作用。为了解释这些观察结果，我们假设脱硝素催化的脂肪分解是维持BAT表型和功能所必需的。我们的研究将阐明BAT与WAT相互转化所反映的脂肪组织可塑性的机制，以及desnutrin在维持BAT表型和功能中的重要作用的信号通路。提出的三个具体目标是：1。以确定在维持BAT表型和功能的过程中是否需要地热素催化的脂肪分解。2. 探讨amp活化的蛋白激酶通过磷酸化和激活脱硝蛋白调控BAT功能的作用。3. 研究PPARa作为胰肽催化脂肪分解的下游效应因子对维持BAT表型和功能的作用。这些研究将清楚地证明，胰肽催化的脂肪分解在维持BAT的功能和表型中起着关键作用。本研究将强调amp激活的蛋白激酶在激活矮糖素中的作用，以及PPARa作为矮糖素催化脂肪分解的下游靶点在维持功能性BAT中的作用。我们的研究结果可能为冷暴露时适应性产热能力的增加提供了潜在的机制。了解这一过程可能为通过维持或诱导成人BAT来控制肥胖提供未来的治疗靶点。

DESCRIPTION (provided by applicant): White adipose tissue (WAT) is specialized for the storage of triacylglycerol (TAG) to release fatty acids (FA) into the circulation for other organs to use as an energy source. In contrast, brown adipose tissue (BAT) uses FA to activate uncoupling protein 1 (UCP1) for non-shivering thermogenesis to dissipate energy as heat. In human infants, there is an abundance of BAT that eventually converts into WAT with age. However, the recent discovery of presence of functional BAT in adults has generated renewed interest in the study of BAT for potential prevention and treatment of obesity. Nevertheless, the process and underlying mechanisms for the maintenance of BAT phenotype or the conversion of BAT to WAT are not understood. Here, we present preliminary data that show a previously unknown role for desnutrin, the major adipose TAG hydrolase in BAT phenotype and function. Namely, adipose-specific ablation of desnutrin in mice causes a striking conversion of BAT to a WAT-like tissue, repressing UCP-1 and other BAT-enriched genes and changing mitochondrial morphology, severely impairing thermogenesis. In contrast, overexpression of desnutrin in adipose tissue increases UCP1 expression and thermogenesis. To explain these observations, we hypothesize that desnutrin- catalyzed lipolysis is required for maintaining BAT phenotype and function. Our studies will elucidate the mechanisms underlying adipose tissue plasticity reflected in the interconversion of BAT and WAT and the signaling pathway for desnutrin's essential role in maintaining BAT phenotype and function. The three specific aims proposed are: 1. to determine the requirement of desnutrin-catalyzed lipolysis for maintaining BAT phenotype and function. 2. To examine the role of AMP-activated protein kinase in regulating BAT function through phosphorylation and activation of desnutrin. 3. To study PPARa as a downstream effector of desnutrin-catalyzed lipolysis for maintaining BAT phenotype and function. These studies will clearly demonstrate the critical role that desnutrin-catalyzed lipolysis plays in the maintaining the function and phenotype of BAT. This research will highlight the involvement of AMP-activated protein kinase in activating desnutrin, as well as the participation of PPARa as a downstream target of desnutrin-catalyzed lipolysis, in maintaining functional BAT. Our findings may provide underlying mechanisms for the well-documented increase in adaptive thermogenic capacity upon cold exposure. Understanding this process may provide future therapeutic targets to control obesity by maintenance or induction of BAT in adults.