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

描述(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)进行非颤抖产热，以热量的形式消耗能量。人类婴儿体内有大量的蝙蝠，随着年龄的增长，蝙蝠最终会转化为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潜在研究的兴趣。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，我们提供了一些初步数据，这些数据显示了蝙蝠表型和功能中的主要脂肪标签水解酶Desnutrin的一个以前未知的作用。也就是说，脂肪专一性地去除小鼠的Desnutrin会导致BAT显著转变为Wat样组织，抑制UCP-1和其他富含BAT的基因，并改变线粒体的形态，严重损害产热。相反，Desnutrin在脂肪组织中的过度表达增加了UCP1的表达和产热。为了解释这些观察，我们假设Desnutrin催化的脂解作用是维持BAT表型和功能所必需的。我们的研究将阐明BAT和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.确定维持BAT表型和功能所需的Desnutrin催化的脂解作用。2.探讨AMP激活的蛋白激酶通过激活Desnutrin对BAT功能的调节作用。3.研究PPARa作为Desnutrin催化的脂解下游效应因子，维持BAT的表型和功能。这些研究将清楚地证明去甲肾上腺素催化的脂解在维持BAT的功能和表型方面发挥的关键作用。这项研究将强调AMP激活的蛋白激酶参与激活Dessutrin，以及PPARa作为Desnutrin催化的脂解下游靶点参与维持BAT的功能。我们的发现可能为寒冷暴露后适应性产热能力的增加提供了潜在的机制。了解这一过程可能会为通过维持或诱导成人BAT来控制肥胖提供未来的治疗目标。

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.