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

描述（由申请人提供）：肥胖和代谢综合征是全球健康威胁。细胞内甘油三酯（TG）的积累与胰岛素抵抗和肥胖的代谢并发症密切相关。然而，TG蓄积的潜在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。新出现的证据表明，非TG脂质代谢物（即二酰基甘油、神经酰胺、脂肪酰辅酶A等）而不是TG本身对这些疾病是致病的，这表明旨在增强TG储存和/或减少“毒性”脂质代谢物产生的干预措施可以防止胰岛素抵抗和脂毒性代谢疾病。脂肪甘油三酯脂肪酶（ATGL）最近已被确定为介导TG水解的限速酶，因此是有毒和必需脂质代谢产物的储存/产生的关键决定因素。然而，ATGL在这些过程中的作用，特别是在ATGL也表达的非脂肪组织中，仍然知之甚少。我们的初步数据表明，i）ATGL在脂肪和非脂肪组织中表达、高度调节和功能相关，和ii）ATGL介导的TG水解的调节以组织/细胞类型特异性方式在体外和体内影响葡萄糖稳态/胰岛素作用。了解个体组织中ATGL对体内总体代谢稳态的相对贡献以及ATGL发挥这些作用的机制对于确定TG代谢是否可以通过治疗调节来保护免受脂毒性代谢疾病是至关重要的。本提案的中心目的是使用基因工程小鼠作为模型系统，确定代谢相关组织（脂肪组织和骨骼肌）中ATGL介导的TG水解对体内脂毒性和代谢综合征的组织特异性贡献。我们的总体假设是，通过调节细胞内脂质稳态，ATGL介导的TG水解失调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。为了验证这一假设，我们将评估局部和全身脂质稳态和葡萄糖稳态/胰岛素作用的小鼠与组织特异性调节ATGL在脂肪组织（AIM 1）和骨骼肌（AIM 2）。我们将通过评价导致脂毒性的特定机制（即内质网应激、线粒体功能障碍、炎症等），进一步定义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在组织特异性和全身代谢中的理解，从而为肥胖和相关代谢紊乱的发病机制和治疗提供重要见解。这是早期研究者的第一个R 01应用程序。 公共卫生相关性：脂肪和非脂肪组织（即肌肉）中脂肪的积累与肥胖症的并发症（包括糖尿病和心血管疾病）有关。脂肪甘油三酯脂肪酶（ATGL）是一种新发现的分解脂肪的酶，但这种酶在特定个体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和相关代谢紊乱的病理生理学和治疗提供重要见解。

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.