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），以将脂肪酸（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（UCP 1），用于非颤抖性产热，以热量形式耗散能量。在人类婴儿中，有大量的BAT，最终随着年龄的增长转化为WAT。然而，最近在成人中发现功能性BAT的存在，重新引起了人们对BAT用于预防和治疗肥胖的研究的兴趣。然而，维持BAT表型或将BAT转化为WAT的过程和潜在机制尚不清楚。在这里，我们提出了初步的数据，显示了一个以前未知的作用去营养素，主要的脂肪TAG水解酶的BAT表型和功能。也就是说，小鼠中去营养素的脂肪特异性消融导致BAT向WAT样组织的显著转化，抑制UCP-1和其他BAT富集基因并改变线粒体形态，严重损害产热。相反，去营养素在脂肪组织中的过度表达增加UCP 1的表达和产热。为了解释这些观察结果，我们假设去营养素催化的脂解是维持BAT表型和功能所必需的。我们的研究将阐明反映在BAT和WAT的相互转化中的脂肪组织可塑性的潜在机制，以及去营养素在维持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.以确定维持BAT表型和功能所需的脱营养素催化的脂解。 2.研究AMP激活的蛋白激酶通过去营养素的磷酸化和激活在调节BAT功能中的作用。 3.研究PPARa作为desnutrin催化的脂解的下游效应物以维持BAT表型和功能。 这些研究将清楚地证明脱营养素催化的脂解在维持BAT的功能和表型中发挥的关键作用。这项研究将突出AMP激活的蛋白激酶参与激活desnutrin，以及PPARa作为desnutrin催化的脂解的下游靶点参与维持功能性BAT。我们的研究结果可能为有充分证据表明的冷暴露后适应性产热能力增加提供了潜在机制。了解这一过程可能会提供未来的治疗目标，以控制肥胖的维持或诱导BAT的成人。 公共卫生相关性：在两种类型的脂肪组织中，白色脂肪组织将能量储存为脂肪以增加肥胖，而棕色脂肪组织将脂肪作为热量耗散以产热，并且可以减少肥胖。这项研究旨在了解白色和棕色脂肪组织之间的转换过程，该过程由一种启动脂肪分解的酶控制。了解这种酶的作用机制和信号通路将为我们提供新的靶点，以制定控制肥胖及其相关疾病（如糖尿病）的策略。

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. PUBLIC HEALTH RELEVANCE: Of the two types of adipose tissue, white adipose tissue stores energy as fat to increase adiposity, whereas brown adipose tissue uses fat to dissipate as heat for thermogenesis and may decrease adiposity. This research is directed toward understanding the process of conversion between white and brown adipose tissue controlled by an enzyme that starts breakdown of fat. Understanding the mechanism and signaling pathway for the action of this enzyme will provide us novel targets to develop strategies to control obesity and its related diseases such as diabetes.