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.

通过饮食或锻炼的变化影响健康的生物基础-增加 在没有疾病的情况下的寿命-还没有完全理解。最近关于苍蝇和蠕虫的数据显示， 脂肪分解的潜在作用，储存在脂滴（LD）中的三酰甘油（TAG）的催化剂，作为一个因素， that promotes促进healthspan健康.然而，将脂解作用与健康寿命改变联系起来的机制并不明确。 知道的此外，还没有研究评估脂解在哺乳动物健康寿命调节中的作用， 脂解和饮食的相互作用，这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，本申请的目的是定义脂解作用通过其的机制。 影响健康寿命，并确定膳食脂质组成对这些影响的贡献。我们 假设脂解是一个关键信号节点，通过改变脂肪酸来驱动健康 信号我们的假设基于我们实验室的初步数据， 脂肪甘油三酯脂肪酶（ATGL）催化的脂解成沉默调节蛋白1（SIRT 1）活性和下游信号传导， 激活叉头盒蛋白01（FOXO 1）。我们还表明，果蝇同源基因的过表达， ATGL，布鲁默（Bmm），增加寿命一致的已知作用SIRT 1和FOXO 1作为关键监管机构 生命周期为了检验我们的假设，我们将利用果蝇和小鼠模型的优势来检验 以下具体目标：目的1：描绘脂解影响的信号通路 果蝇的健康寿命我们将使用果蝇模型来剖析Bmm-Sir 2（果蝇SIRT 1 同源物）-dFOXO（苍蝇FOXO 1同源物）信号轴调节健康寿命。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 饮食脂质组成和ATGL过表达对寿命和衰老相关的下降之间的关系， 在小鼠体内的代谢。目的3：研究ATGL与自噬的相互作用。在这一目标下， 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延长作用。这些研究将是第一个 全面定义ATGL催化的脂解在健康中的作用，以及它如何与其他 参与寿命调节的生理因素。这些研究是创新的，因为他们将使用新的 苍蝇和老鼠模型将已知影响寿命的个体因素（如饮食）联系到一个有凝聚力的模型中 这更好地解释了健康持续监管。这项拟议中的工作意义重大，因为它将大大促进 我们对脂质代谢这一未充分研究的领域的理解是导致衰老的一个因素， 提供新的或改进的饮食，饮食或药物途径的实质性见解，以促进 healthspan.