Synergistic effects of diet, lipolytic signaling and SIRT1 on energy metabolism

饮食、脂肪分解信号和 SIRT1 对能量代谢的协同作用

• 批准号: 9076468
• 负责人: Douglas G Mashek
• 金额: $ 37.11万
• 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: 2016-05-16 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9076468
• 关键词: Adipose tissue; Adrenergic Agents; Affect; Aging; Animal Model; Automobile Driving; Behavioral; Biological; Biology; Cell Respiration; Cell model; Comorbidity; Complex; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Deacetylase; Development; Diet; Dietary Fats; Diglycerides; Disease; Dose; Energy Metabolism; Environmental Risk Factor; Enzymes; Exercise; Figs - dietary; Genetic; Glean; Gold; Health; Health Benefit; Human; Hydrolysis; Impairment; Insulin Resistance; Knock-in Mouse; Knockout Mice; Knowledge; Life Style; Link; Lipase; Lipolysis; Longevity; Mediating; Mediator of activation protein; Mediterranean Diet; Metabolic; Metabolic Diseases; Metabolism; Modeling; Monounsaturated Fatty Acids; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuts; Obese Mice; Obesity; Olive oil preparation; Pharmacologic Substance; Physical activity; Physiological; Post-Translational Protein Processing; Proteins; Reducing diet; Regulation; Resveratrol; Risk; Signal Transduction; Source; Substrate Specificity; Testing; Transferase; Triglycerides; Work; aged; base; cofactor; db/db mouse; diabetic; diet and exercise; disorder risk; feeding; healthy aging; improved; innovation; insight; insulin sensitivity; mode of exercise; mouse model; novel; novel therapeutics; overexpression; perilipin; public health relevance; red wine; therapeutic target; trafficking

 DESCRIPTION (provided by applicant): Sirtuin 1 (SIRT1) is a protein deacetylase that has anti-diabetic effects and promotes healthy aging. Consequently, SIRT1 is a major therapeutic target to reduce metabolic diseases and increase lifespan. Similar to SIRT1, the Mediterranean Lifestyle, defined as high levels of physical activity in conjunction with the Mediterranean Diet, significantly reduces the risk of metabolic and aging-associated diseases. The discovery that resveratrol, a bioactive compound in red wine, activates SIRT1 was thought to explain a major biological mechanism of the Mediterranean Diet. However, this enthusiasm has been tempered by data showing that the effects of resveratrol on SIRT1 are indirect and non-specific. Another plausible, yet unexplored, mechanism involves oleate, the main monounsaturated fatty acid in olive oil. The mechanism by which oleate produces its well-established metabolic benefits is not well understood and whether specific dietary lipids may interact with physical activity to affect metabolism remains unknown. This knowledge gap presents an opportunity to further define the underlying biology driving the metabolic benefit of the Mediterranean Lifestyle/Diet. Based upon strong preliminary data linking lipolytically-derived oleate to SIRT1 activation, the objective of this proposal is to characterize the physiological significance of lipolysis and oleate metabolism in insulin resistance and energy metabolism and to identify the cellular factors that influence ATGL-mediated oleate signaling. We will test the hypothesis that ATGL-catalyzed lipolysis, or factors that influence lipolysis such as exercise, will synergize with a major dietary source of oleate, olive oil, to promote insulin sensitivity, oxidative metabolism and metabolic health via SIRT1 activation. To test our hypothesis, we will conduct the following specific aims: 1) to determine the synergistic effects of global ATGL overexpression, dietary olive oil and SIRT1 on energy metabolism and insulin resistance, 2) to determine the synergistic effects of exercise, dietary olive oil and SIRT1 on energy metabolism and insulin resistance, and 3) to determine how proteins involved in oleate metabolism influence ATGL-mediated SIRT1 activation. Aim 1 will characterize interactions between dietary oleate composition and global ATGL overexpression on insulin resistance and energy metabolism in db/db and diet-induced obese mice. Aim 2 will explore the synergy between exercise and dietary oleate as a means to promote metabolic health. Aim 3 will employ cell models to characterize changes in oleate metabolism that influence its regulation of SIRT1. These studies are innovative in that they will answer novel questions about SIRT1 regulation, exercise and diet and define a major mechanism through which the Mediterranean Lifestyle elicits its effects. This work is significant as it opens new directions for dietary, behavioral and pharmaceutical approaches to treat insulin resistance and its comorbidities.

 描述（申请人提供）：Sirtuin 1 (SIRT1) 是一种蛋白质脱乙酰酶，经测试具有抗糖尿病作用并促进健康衰老，与地中海生活方式 SIRT1 类似，SIRT1 是减少代谢疾病和延长寿命的主要治疗靶点。定义为高水平的身体活动与地中海饮食相结合，可显着降低代谢和衰老相关疾病的风险白藜芦醇（一种生物活性化合物）的发现。红葡萄酒中的白藜芦醇激活 SIRT1 被认为可以解释地中海饮食的一个主要生物学机制，然而，有数据表明白藜芦醇对 SIRT1 的影响是间接的、非特异性的，这也解释了这种热情。涉及油酸，橄榄油中的主要单不饱和脂肪酸。油酸产生其公认的代谢益处的机制尚不清楚，并且特定的膳食脂质是否可能与身体活动相互作用以影响新陈代谢仍然未知。这一知识差距为进一步定义驱动地中海生活方式/饮食的代谢益处的潜在生物学提供了机会。基于将脂肪分解衍生的油酸与 SIRT1 激活联系起来的强有力的初步数据，该提案的目的是表征脂肪分解的生理意义。和油酸代谢在胰岛素抵抗和能量代谢中的作用，并确定影响 ATGL 介导的油酸信号传导的细胞因素，我们将检验 ATGL 催化脂肪分解的假设，或影响脂肪分解的因素，例如运动，将与油酸的主要饮食来源橄榄油产生协同作用，通过 SIRT1 激活促进胰岛素敏感性、氧化代谢和代谢健康。为了检验我们的假设，我们将进行以下具体目标：1）确定的协同效应。全球 ATGL 过度表达、膳食橄榄油和 SIRT1 对能量代谢和胰岛素抵抗的影响，2) 确定运动、膳食橄榄油和 SIRT1 对能量代谢和胰岛素抵抗的协同作用，以及3) 确定参与油酸代谢的蛋白质如何影响 ATGL 介导的 SIRT1 激活，目标 1 将表征饮食油酸成分与整体 ATGL 过度表达对 db/db 和饮食诱导的肥胖小鼠的胰岛素抵抗和能量代谢之间的相互作用。探索运动和膳食油酸之间的协同作用作为促进代谢健康的一种手段，目标 3 将利用细胞模型来表征影响 SIRT1 调节的油酸代谢变化。创新之处在于他们将回答有关 SIRT1 调节、运动和饮食的新问题，并定义地中海生活方式产生其影响的主要机制。这项工作意义重大，因为它为治疗胰岛素抵抗和药物治疗开辟了新的方向。它的合并症。