Role of ATGL and lipid metabolism in healthspan

ATGL 和脂质代谢在健康寿命中的作用

• 批准号: 9902277
• 负责人: Douglas G Mashek
• 金额: $ 31.88万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902277
• 关键词: Adipose tissue; Adrenergic Agents; Aging; Area; Autophagocytosis; Biogenesis; Biological; Biology; Caloric Restriction; Catabolism; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Deacetylase; Diet; Dietary Fats; Disease; Drosophila genus; Energy Metabolism; Environmental Risk Factor; Etiology; Exercise; FRAP1 gene; Fasting; Fatty Acids; Fatty acid glycerol esters; Glean; Health; Homologous Gene; Human; Individual; Insulin; Knock-in Mouse; Knowledge; Laboratories; Link; Lipase; Lipids; Lipolysis; Literature; Longevity; LoxP-flanked allele; Mammals; Mediating; Metabolic Diseases; Metabolism; Mitochondria; Modeling; Mus; Oleates; PPAR alpha; PPAR gamma; Pharmacologic Substance; Physiological; Process; Property; Proteins; Publishing; Regulation; Role; SIRT1 gene; Signal Pathway; Signal Transduction; Somatotropin; Testing; Triglycerides; Work; aged; base; cohesion; fly; healthspan; improved; innovation; insight; insulin-like signaling; lipid metabolism; mouse model; mutant; novel; novel therapeutics; overexpression; synergism

The biological underpinnings through which changes in diet or exercise influence healthspan - increased lifespan in the absence of disease - are not fully understood. Recent data in flies and worms have highlighted a potential role for lipolysis, the catabolism of triacylglycerol (TAG) stored within lipid droplets (LDs), as a factor that promotes healthspan. However, the mechanisms linking lipolysis to alterations in healthspan are not known. In addition, no studies have evaluated the role of lipolysis in healthspan regulation in mammals or the interaction of lipolysis and diet, which largely determines the composition of LDs and, therefore, their signaling properties. Thus, the objective of this application is to define the mechanisms through which lipolysis influences healthspan and to determine the contribution of dietary lipid composition to these effects. We hypothesize that lipolysis is a key signaling node that drives healthspan through alterations in fatty acid signaling. We base this hypothesis on preliminary data from our laboratory defining a signaling axis linking adipose triglyceride lipase (ATGL)-catalyzed lipolysis to sirtuin 1 (SIRT1) activity and downstream signaling to activate forkhead box protein 01 (FOXO1). We also show that overexpression of the Drosophila homolog of ATGL, brummer (Bmm), increases lifespan consistent the known roles of SIRT1 and FOXO1 as key regulators of lifespan. To test our hypothesis, we will utilize the strengths of both Drosophila and mouse models to test the following specific aims: Aim 1: To delineate the signaling pathway through which lipolysis influences healthspan in Drosophila. We will use Drosophila models to dissect the linearity of the Bmm-Sir2 (fly SIRT1 homolog)-dFOXO (fly FOXO1 homolog) signaling axis in regulating healthspan. Aim 2: To determine the interactions between diet and ATGL on healthspan in mice. These studies will explore the synergy between dietary lipid composition and ATGL overexpression on lifespan and aging-related declines in metabolism in mice. Aim 3: To characterize the interaction between ATGL and autophagy. In this aim, will test the effects of ATGL on autophagy and the role of autophagy in mediating the signaling and lifespan extending effects of ATGL/Bmm in both fly and mammalian models. These studies will be the first to comprehensively define the role of ATGL-catalyzed lipolysis in healthspan and how it interacts other physiological factors involved in lifespan regulation. These studies are innovative because they will use novel fly and mouse models to link individual factors known to influence lifespan such as diet into a cohesive model that better explains healthspan regulation. The proposed work is significant because it will greatly advance our understanding into the understudied area of lipid metabolism as a factor contributing to aging and will provide substantial insights into new or improved dietary, behavorial or pharmaceutical avenues to promote healthspan.

饮食或运动变化会影响健康范围的生物基础 - 增加 在没有疾病的情况下，寿命尚未完全理解。苍蝇和蠕虫的最新数据突出显示了 脂解的潜在作用，是脂肪液滴（LDS）中三酰基甘油（TAG）的分解代谢，作为一个因素 这促进了HealthSpan。但是，将脂肪分解与健康范围改变的机制不是 已知。此外，尚无研究评估脂解中脂解中哺乳动物或 脂解和饮食的相互作用，在很大程度上决定了LD的组成，因此它们的信号传导 特性。因此，该应用的目的是定义脂解的机制 影响HealthSpan并确定饮食脂质成分对这些作用的贡献。我们 假设脂解是通过改变脂肪酸来驱动HealthSpan的关键信号节点 信号。我们以实验室定义信号轴连接的实验室的初步数据为基础。 脂肪甘油三酸酯脂肪酶（ATGL）催化脂解至SIRTUIN 1（SIRT1）活性和下游信号传导至 激活叉子盒蛋白01（FOXO1）。我们还表明，果蝇同源物的过表达 ATGL，BRUMMER（BMM），增加了寿命一致，SIRT1和FOXO1作为关键调节器的已知角色一致 寿命。为了检验我们的假设，我们将利用果蝇和小鼠模型的优势进行测试 以下特定目的：目标1：描述脂肪分解影响的信号通路 果蝇的HealthSpan。我们将使用果蝇模型来剖析BMM-SIR2的线性（Fly Sirt1 同源物）-dfoxo（Fly FOXO1同源物）在调节健康范围的信号轴。目标2：确定 饮食与ATGL在小鼠健康范围内的相互作用。这些研究将探索协同作用 饮食脂质组成和寿命上的ATGL过表达与与衰老有关 小鼠的代谢。目标3：表征ATGL和自噬之间的相互作用。在这个目标中 将测试ATGL对自噬的影响以及自噬在介导信号传导和寿命中的作用 在Fly和哺乳动物模型中扩展ATGL/BMM的影响。这些研究将是第一个 全面定义ATGL催化脂解在HealthSpan中的作用及其如何相互作用 寿命调节涉及的生理因素。这些研究具有创新性，因为它们将使用小说 苍蝇和小鼠模型将已知影响寿命（例如饮食）的个体因素连接为凝聚力模型 更好地解释了HealthSpan法规。拟议的工作很重要，因为它将大大推动 我们对脂质代谢的研究研究领域的理解是导致衰老的因素，并将 对新的或改善的饮食，遗嘱或药物途径提供大量见解，以促进 HealthSpan。