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

desnutrin/ATGL 在棕色脂肪组织的维持和功能中的作用

• 批准号: 8775662
• 负责人: Hei Sook Sul
• 金额: $ 31.78万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-12 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8775662
• 关键词: 5' -AMP-activated protein kinase; Ablation; Adenoviruses; Adipocytes; Adipose tissue; Adult; Affect; Age; Agonist; Binding; Blood Circulation; Body Temperature; Brown Fat; Cell Line; Cells; Data; Development; Diabetes Mellitus; Disease; Dominant-Negative Mutation; Embryonic Development; Employee Strikes; Energy-Generating Resources; Enzymes; Fasting; Fatty Acids; Fatty acid glycerol esters; Future; Genes; Health; Heating; Human; In Vitro; Infant; Knockout Mice; Lead; Ligands; Lipase; Lipolysis; Maintenance; Mediating; Mitochondria; Morphology; Mus; Obesity; Organ; Oxygen Consumption; Pattern; Peroxisome Proliferator-Activated Receptors; Phenocopy; Phenotype; Phosphorylation; Play; Prevention; Process; Reporter; Research; Role; Signal Pathway; Small Interfering RNA; Stimulus; Testing; Thermogenesis; Time; Tissues; Transgenic Mice; Triglycerides; in vivo; insight; interest; novel; obesity treatment; overexpression; precursor cell; prevent; promoter; therapeutic target; uncoupling protein 1

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.

描述（由申请人提供）：白色脂肪组织（WAT）专门用于储存三酰基甘油（TAG），以将脂肪酸（FA）释放到循环中，以使其他器官用作能源。相比之下，棕色脂肪组织（BAT）使用FA激活解偶联蛋白1（UCP1），以进行非震动的热生成，以将能量作为热量散发。在人类婴儿中，有大量的蝙蝠最终随着年龄的增长而转化为WAT。但是，最近发现成人存在功能性蝙蝠的存在引起了人们对蝙蝠的研究，以预防和治疗肥胖症。然而，尚不了解维持蝙蝠表型或蝙蝠转化为WAT的过程和基本机制。在这里，我们提供了初步数据，该数据显示了Desnutrin的先前未知的作用，Desnutrin是BAT表型和功能中主要的脂肪标记水解酶。也就是说，小鼠中DESNutrin的脂肪特异性消融会导致蝙蝠的惊人转化为Wat样组织，抑制UCP-1和其他富含蝙蝠的基因并改变线粒体形态，从而损害了热生成。相反，脂肪组织中DESNutrin的过表达增加了UCP1的表达和热生成。为了解释这些观察结果，我们假设desnutrin-催化的脂解是维持BAT表型和功能所必需的。我们的研究将阐明在BAT和WAT的相互作用中反映脂肪组织可塑性的基础机制以及DESNutrin在维持BAT表型和功能中至关重要的信号传导途径。提出的三个特定目的是：1。确定脱二霉素催化的脂解对维持蝙蝠表型和功能的需求。 2。检查AMP激活蛋白激酶通过磷酸化和激活DESNutrin在调节BAT功能中的作用。 3。研究PPARA作为DESNUTRIN催化脂解的下游效应子，以维持BAT表型和功能。 这些研究将清楚地表明，脱发蛋白催化的脂解在维持蝙蝠的功能和表型中起着至关重要的作用。这项研究将强调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标参与功能性BAT。我们的发现可能会提供基本的机制，以证明在冷暴露后自适应的热能能力增加。了解这一过程可能会提供未来的治疗靶标，以通过维持或诱导成人的蝙蝠来控制肥胖症。