Adipose Triglyceride Lipase (ATGL) in Lipotoxicity and The Metabolic Syndrome

描述(申请人提供)：肥胖和代谢综合征是全球性的健康威胁。细胞内三酰甘油(TG)的积聚与胰岛素抵抗和肥胖的代谢并发症密切相关。然而，甘油三酯累积的机制及其与脂质诱导的毒性代谢效应(“脂毒性”)的关系仍不清楚。新的证据表明，非甘油三酯的脂质代谢产物(如甘油二酯、神经酰胺、脂酰基COAs等)而不是TGS本身是这些疾病的致病因素，这表明旨在加强甘油三酯储存和/或减少“有毒”脂代谢产物产生的干预措施可能预防胰岛素抵抗和脂毒性代谢性疾病。脂肪甘油三酯脂肪酶(ATGL)是甘油三酯(TG)水解酶的限速酶，是有毒和必需的脂类代谢物储存/生产的关键决定因素。然而，ATGL在这些过程中的作用，特别是在表达ATGL的非脂肪组织中，仍然知之甚少。我们的初步数据表明，ATGL在脂肪和非脂肪组织中表达、高度调控并具有功能相关性，以及ii)ATGL介导的甘油三酯水解酶的调节在体外和体内以组织/细胞类型特异性的方式影响葡萄糖稳态/胰岛素作用。了解单个组织中ATGL对体内整体代谢动态平衡的相对贡献以及ATGL发挥这些作用的机制对于确定是否可以通过治疗来调节TG代谢以预防脂毒性代谢性疾病至关重要。这一建议的中心目的是以基因工程小鼠为模型系统，在体内确定代谢相关组织(脂肪组织和骨骼肌)中ATGL介导的甘油三酯水解对脂肪毒性和代谢综合征的组织特异性贡献。我们的总体假设是，ATGL介导的甘油三酯水解酶的失调，通过调节细胞内脂质稳态，是组织特异性和全身葡萄糖稳态/胰岛素作用的主要决定因素。为了验证这一假说，我们将评估脂肪组织(AIM 1)和骨骼肌(AIM 2)中ATGL的组织特异性调节小鼠的局部和全身脂质稳态以及葡萄糖稳态/胰岛素作用。我们将通过评估导致脂毒性的特定机制(如内质网应激、线粒体功能障碍、炎症等)，进一步确定ATGL调节改变脂质稳态和葡萄糖稳态/胰岛素作用的分子机制。这些研究将促进对ATGL在组织特异性和系统代谢方面的了解，从而为肥胖症和相关代谢紊乱的发病机制和治疗提供重要的见解。这是早期研究人员第一次申请R01。 公共卫生相关性：脂肪和非脂肪组织(即肌肉)中的脂肪积累与肥胖的并发症有关，包括糖尿病和心血管疾病。脂肪甘油三酯脂肪酶(ATGL)是一种新近发现的分解脂肪的酶，但该酶在特定组织中分解脂肪对全身代谢的贡献尚不清楚。了解组织特异性ATGL介导的脂肪分解的生理相关性和机制基础将为肥胖症和相关代谢紊乱的病理生理学和治疗提供重要的见解。

DESCRIPTION (provided by applicant): Obesity and the metabolic syndrome are global health threats. Intracellular triacylglycerol (TG) accumulation is strongly associated with insulin resistance and metabolic complications of obesity. However, the mechanisms underlying TG accumulation and its relationship to lipid-induced toxic metabolic effects ("lipotoxicity") remain unclear. Emerging evidence suggests that non-TG lipid metabolites (i.e. diacylglycerols, ceramides, fatty-acyl CoAs, etc.) rather than TGs themselves are pathogenic for these disorders, indicating that interventions designed to enhance TG storage and/or reduce production of "toxic" lipid metabolites may protect against insulin resistance and lipotoxic metabolic disease. Adipose triglyceride lipase (ATGL) has recently been identified as the rate-limiting enzyme mediating TG hydrolysis, and is therefore a critical determinant of storage/production of toxic as well as essential lipid metabolites. Nevertheless, the role of ATGL in these processes, particularly in non-adipose tissues where ATGL is also expressed, remains poorly understood. Our preliminary data suggest that i) ATGL is expressed, highly regulated, and functionally relevant in adipose and non-adipose tissues, and ii) modulation of ATGL-mediated TG hydrolysis influences glucose homeostasis/ insulin action in vitro and in vivo in a tissue/cell type-specific manner. Understanding the relative contribution of ATGL in individual tissues to overall metabolic homeostasis in vivo as well as the mechanisms by which ATGL exerts these effects are essential for determining whether TG metabolism can be therapeutically modulated to protect against lipotoxic metabolic disease. The CENTRAL AIM of this proposal is to determine the tissue- specific contribution of ATGL-mediated TG hydrolysis in metabolically relevant tissues (adipose tissue and skeletal muscle) to lipotoxicity and the metabolic syndrome in vivo using genetically-engineered mice as model systems. Our OVERALL HYPOTHESIS is that dysregulation of ATGL-mediated TG hydrolysis, by modulating intracellular lipid homeostasis, is a major determinant of both tissue-specific and systemic glucose homeostasis/insulin action. To test this hypothesis, we will evaluate local and systemic lipid homeostasis and glucose homeostasis/insulin action in mice with tissue-specific modulation of ATGL in adipose tissue (AIM 1) and skeletal muscle (AIM 2). We will further define the molecular mechanisms by which modulation of ATGL alters lipid homeostasis and glucose homeostasis/insulin action by evaluating specific mechanisms that contribute to lipotoxicity (i.e. endoplasmic reticulum stress, mitochondrial dysfunction, inflammation, etc.). These studies will promote the understanding of ATGL in tissue-specific and systemic metabolism, thereby providing important insights into the pathogenesis and treatment of obesity and related metabolic disorders. This is the first R01 application of an early stage investigator. PUBLIC HEALTH RELEVANCE: Accumulation of fat in adipose and non-adipose tissues (i.e. muscle) is associated with complications of obesity including diabetes and cardiovascular disease. Adipose triglyceride lipase (ATGL) is a newly identified enzyme that breaks down fat, but the contribution of fat breakdown by this enzyme in specific individual tissues to whole body metabolism is not known. Understanding the physiological relevance and mechanistic underpinnings of tissue-specific ATGL-mediated fat breakdown will provide important insights into the pathophysiology and treatment of obesity and related metabolic disorders.