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.

 说明(申请人提供)：sirtuin 1(SIRT1)是一种蛋白质脱乙酰酶，具有抗糖尿病和促进健康衰老的作用。因此，SIRT1是减少代谢性疾病和延长寿命的主要治疗目标。与SIRT1类似，地中海生活方式，即结合地中海饮食的高水平体力活动，显著降低了新陈代谢和衰老相关疾病的风险。白藜芦醇是红葡萄酒中的一种生物活性化合物，它能激活SIRT1，这一发现被认为解释了地中海饮食的一个主要生物学机制。然而，数据显示白藜芦醇对SIRT1的影响是间接的和非特异性的，这一热情被冲淡了。另一个看似合理但尚未探索的机制与油酸有关，油酸是橄榄油中的主要单不饱和脂肪酸。油酸盐产生良好新陈代谢益处的机制尚不清楚，特定的饮食脂质是否会与身体活动相互作用影响新陈代谢仍不清楚。这一知识差距为进一步确定推动地中海生活方式/饮食新陈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，本研究的目的是描述脂肪分解和油酸代谢在胰岛素抵抗和能量代谢中的生理意义，并确定影响ATGL介导的油酸信号的细胞因素。我们将测试这样一种假设，即ATGL催化的脂解作用，或影响脂解作用的因素，如运动，将与油酸盐的主要饮食来源橄榄油协同作用，通过激活SIRT1促进胰岛素敏感性、氧化代谢和代谢健康。为了验证我们的假设，我们将进行以下具体目标：1)确定全球ATGL过表达、饮食橄榄油和SIRT1对能量代谢和胰岛素抵抗的协同作用；2)确定运动、饮食橄榄油和SIRT1对能量代谢和胰岛素抵抗的协同作用；以及3)确定油酸代谢相关蛋白如何影响ATGL介导的SIRT1激活。目的1在db/db和饮食诱导的肥胖小鼠中，描述饮食油酸组成与胰岛素抵抗和能量代谢的全球ATGL过度表达之间的相互作用。目标2将探索运动和饮食油酸盐之间的协同作用，以此作为促进代谢健康的一种手段。目标3将使用细胞模型来表征油酸代谢的变化，这些变化影响其对SIRT1的调节。这些研究具有创新性，因为它们将回答有关SIRT1调节、运动和饮食的新问题，并确定地中海生活方式产生影响的主要机制。这项工作具有重要意义，因为它为治疗胰岛素抵抗及其共病的饮食、行为和药物方法开辟了新的方向。