Role of Muscle Ketone Metabolism in Mediating the Metabolic Benefits of Weight Loss

肌肉酮代谢在调节减肥代谢益处中的作用

• 批准号: 10668419
• 负责人: Ashley Silberman Williams
• 金额: $ 11.08万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668419
• 关键词: Ablation; Acceleration; Acetoacetates; Acute; Advisory Committees; Applied Genetic Engineering; Award; Bioenergetics; Body Weight decreased; Brain; Buffers; Caloric Restriction; Cell Culture System; Charge; Citric Acid Cycle; Clinical; Couples; Data; Development Plans; Diet; Disease; Electron Transport; Ensure; Environment; Enzymes; Epidemic; Equilibrium; Fasting; Fatty Acids; Fatty acid glycerol esters; Food; Generations; Genetic; Genetic Engineering; Glucose; Goals; Health; Health Benefit; Heart; Heart failure; Homeostasis; Human; Hydrogen Peroxide; Hypoglycemia; Insulin Resistance; Ketones; Laboratories; Life Style Modification; Link; Liver; Mass Spectrum Analysis; Mediating; Membrane Potentials; Mentors; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Mitochondria; Modeling; Molecular; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle Mitochondria; Myocardium; NADH; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Outcome; Overweight; Oxidation-Reduction; Oxidoreductase; Oxygen Consumption; Peripheral; Phenotype; Physiological; Physiology; Play; Positioning Attribute; Process; Production; Pyruvate; Reaction; Reactive Oxygen Species; Regimen; Research; Research Personnel; Role; Site; Skeletal Muscle; Soleus Muscle; Source; Sucrose; Tamoxifen; Technology; Testing; Tissues; Training; Work; beta-Hydroxybutyrate; career; career development; cellular engineering; dietary; dietary restriction; exercise intolerance; feeding; genetic approach; glucose metabolism; glucose uptake; heart function; improved; insight; ketogenesis; ketogentic; loss of function; member; metabolic phenotype; mouse model; multiple omics; new therapeutic target; novel; novel therapeutic intervention; nutrient metabolism; obese person; obesity prevention; oxidation; physical inactivity; respiratory; response; stable isotope; stem; therapeutic target; training opportunity; western diet

PROJECT SUMMARY Dietary regimens that promote ketone production are gaining popularity due to their ability to facilitate weight loss and improve metabolic health. Ketones (e.g. acetoacetate and 3-hydroxybutyrate (3OHB)) are produced by the liver and oxidized by the brain and peripheral tissues when glucose is low. Whereas the field has largely focused on the positive effects of ketones on the brain and heart, the role of ketone oxidation in skeletal muscle has been largely overlooked and under investigated. Data from our laboratory suggests that the skeletal muscle is a major site of 3OHB clearance, therefore we postulate that skeletal muscle 3OHB oxidation is necessary for optimal metabolic benefits of ‘ketogenic’ dietary weight loss regimens. To this end, this application links the enzyme that catalyzes the first step of 3OHB oxidation, D-ꞵ-hydroxybutyrate dehydrogenase (BDH1), to improved whole-body glucose metabolism and energy homeostasis due to post-obesity weight loss. The central objective of this proposal is to determine if skeletal muscle BDH1 plays a key role in mediating the health benefits of dietary regimens that promote ketogenesis and weight loss. BDH1 catalyzes a near-equilibrium reaction that couples ketone oxidation to the mitochondrial NAD(H) redox state. Herein, we propose a novel conceptual model that positions BDH1 as a mitochondrial redox buffer that promotes optimal skeletal muscle health during fasting and refeeding. Our conceptual model and central objective will be rigorously tested by the following studies. First, we use a novel mouse model with an inducible skeletal muscle-specific deletion of BDH1 to determine the impact of BDH1 on skeletal muscle mitochondrial bioenergetics and glucose metabolism in response to fasting and refeeding. Second, we will test the hypothesis that muscle BDH1 is required for the metabolic benefits of calorie-restricted feeding of a typical Western diet. Third, we will apply genetic engineering in primary human skeletal muscle cells test the hypothesis that ketone-induced shifts in the myocellular redox state impact glucose uptake and downstream metabolism. Results from these studies will expand our understanding of the functional relevance of skeletal muscle BDH1 and ketone oxidation with the long term goal of identifying new therapeutic targets for the prevention of obesity-induced metabolic disease. Importantly, this project will provide advanced training and mentoring in ketone metabolism, cellular genetic engineering, 13C stable isotope tracing, and computational 13C metabolic flux analysis. The career development plan will be implemented via a team of outstanding mentors including Dr. Muoio (Duke Molecular Physiology Institute, DMPI) as the primary mentor, Dr. Newgard (DMPI) as the co-mentor, and Drs. Zhang (DMPI) and Crawford (UMN) as members of the advisory committee. The DMPI is an ideal environment for training as it contains a diverse team of researchers with expertise in nutrient metabolism and multi-omics technologies; including stable isotope tracing all within a single building. The opportunities for training and career development provided by this award will ensure Dr. Williams has an exceptional start to her independent career as a metabolic researcher.

项目概要 促进酮产生的饮食方案由于能够减轻体重而越来越受欢迎 损失并改善代谢健康。酮（例如乙酰乙酸酯和 3-羟基丁酸酯 (3OHB)）是通过 当葡萄糖低时，肝脏会被大脑和周围组织氧化。鉴于该领域在很大程度上 重点关注酮对大脑和心脏的积极影响，酮氧化在骨骼肌中的作用 很大程度上被忽视和调查。我们实验室的数据表明骨骼肌 是 3OHB 清除的主要位点，因此我们假设骨骼肌 3OHB 氧化对于 “生酮”饮食减肥方案的最佳代谢益处。为此，该应用程序链接 催化 3OHB 氧化第一步的酶 D-ꞵ-羟基丁酸脱氢酶 (BDH1)， 由于肥胖后体重减轻，改善了全身葡萄糖代谢和能量稳态。中央 该提案的目的是确定骨骼肌 BDH1 是否在调节健康方面发挥关键作用 促进生酮和减肥的饮食方案的好处。 BDH1 催化近平衡 将酮氧化与线粒体 NAD(H) 氧化还原状态耦合的反应。在此，我们推荐一部小说 将 BDH1 定位为促进最佳骨骼肌的线粒体氧化还原缓冲液的概念模型 禁食和重新进食期间的健康。我们的概念模型和中心目标将受到严格的测试 以下研究。首先，我们使用一种新型小鼠模型，该模型具有可诱导的骨骼肌特异性 BDH1 缺失 确定 BDH1 对骨骼肌线粒体生物能学和葡萄糖代谢的影响 对禁食和重新进食的反应。其次，我们将检验以下假设：肌肉 BDH1 是 典型西方饮食的热量限制喂养的代谢益处。第三，我们将应用基因工程 在原代人骨骼肌细胞中测试了酮诱导的肌细胞氧化还原变化的假设 状态影响葡萄糖摄取和下游代谢。这些研究的结果将扩展我们的 了解骨骼肌 BDH1 和酮氧化与长期目标的功能相关性 确定预防肥胖引起的代谢疾病的新治疗靶点。重要的是，这 项目将提供酮代谢、细胞基因工程、13C 方面的高级培训和指导 稳定同位素追踪和计算 13C 代谢通量分析。职业发展计划将是 由包括 Muoio 博士（杜克分子生理学研究所，DMPI）在内的杰出导师团队实施 作为主要导师，Newgard 博士（DMPI）作为共同导师，Drs.张 (DMPI) 和克劳福德 (UMN) 作为 咨询委员会成员。 DMPI 是一个理想的培训环境，因为它拥有一支多元化的团队 具有营养代谢和多组学技术专业知识的研究人员；包括稳定同位素 追踪同一栋建筑物内的所有内容。该奖项提供的培训和职业发展机会 将确保威廉姆斯博士作为代谢研究员的独立职业生涯有一个良好的开端。