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: 9344823
• 负责人: Douglas G Mashek
• 金额: $ 19.83万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9344823
• 关键词: Adipose tissue; Adrenergic Agents; Aging; Aging-Related Process; Area; Autophagocytosis; Biogenesis; Biological; Biology; Boxing; 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; FOXO1A gene; 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; PPAR alpha; PPAR gamma; Pharmacologic Substance; Physiological; Property; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Somatotropin; Testing; Triglycerides; Work; age related; aged; base; feeding; fly; improved; innovation; insight; insulin signaling; lipid metabolism; mouse model; mutant; novel; novel therapeutics; overexpression

PROJECT SUMMARY 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.

项目概要 饮食或运动的改变影响健康寿命的生物学基础 - 增加 在没有疾病的情况下的寿命 - 尚未完全了解。苍蝇和蠕虫的最新数据突出显示 脂肪分解的潜在作用，即储存在脂滴 (LD) 内的三酰甘油 (TAG) 的分解代谢，作为一个因素 促进健康寿命。然而，脂肪分解与健康寿命改变之间的联系机制尚不明确。 已知。此外，还没有研究评估脂肪分解在哺乳动物或人类健康寿命调节中的作用。 脂肪分解和饮食的相互作用，很大程度上决定了 LD 的组成，从而决定了它们的信号传导 特性。因此，本申请的目的是确定脂肪分解的机制 影响健康寿命并确定膳食脂质成分对这些影响的贡献。我们 假设脂肪分解是通过脂肪酸的改变驱动健康寿命的关键信号节点 发信号。我们的这一假设基于我们实验室定义的信号轴链接的初步数据 脂肪甘油三酯脂肪酶 (ATGL) 催化脂肪分解产生沉默调节蛋白 1 (SIRT1) 活性和下游信号转导 激活叉头盒蛋白 01 (FOXO1)。我们还表明，果蝇同源物的过度表达 ATGL、brummer (Bmm) 可延长寿命，这与 SIRT1 和 FOXO1 作为关键调节因子的已知作用一致 的寿命。为了验证我们的假设，我们将利用果蝇和小鼠模型的优势来测试 具体目标如下： 目标 1：描绘脂肪分解影响的信号通路 果蝇的健康寿命。我们将使用果蝇模型来剖析 Bmm-Sir2（果蝇 SIRT1 同源物）-dFOXO（果蝇 FOXO1 同源物）信号轴在调节健康寿命中的作用。目标 2：确定 饮食和 ATGL 之间的相互作用对小鼠健康寿命的影响。这些研究将探讨协同作用 膳食脂质成分和 ATGL 过度表达对寿命和衰老相关下降的影响 小鼠的新陈代谢。目标 3：表征 ATGL 与自噬之间的相互作用。为了这个目标， 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 ATGL/Bmm 在果蝇和哺乳动物模型中的扩展效应。这些研究将首先 全面定义 ATGL 催化脂肪分解在健康寿命中的作用以及它如何与其他物质相互作用 参与寿命调节的生理因素。这些研究具有创新性，因为他们将使用新颖的 苍蝇和小鼠模型将已知影响寿命的个体因素（例如饮食）连接到一个有凝聚力的模型中 这更好地解释了健康寿命的调节。拟议的工作意义重大，因为它将极大地推进 我们对脂质代谢作为导致衰老和意志的因素这一尚未研究的领域的理解 提供有关新的或改进的饮食、行为或药物途径的实质性见解，以促进 健康寿命。