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

基本信息

批准号：
10670534
负责人：
Ashley Silberman Williams
金额：
$ 5.4万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10670534
关键词：
Acetoacetates Acute Advisory Committees 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 Hydroxybutyrates Hypoglycemia Institutes Insulin Resistance Ketones Laboratories Lead 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 Obesity Outcome Overweight Oxidation-Reduction Oxides 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 base 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 nutrition related genetics obese person obesity prevention oxidation physical inactivity respiratory response stable isotope stem therapeutic target training opportunity western diet

项目摘要

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.

项目摘要促进酮产量的饮食方案由于能够促进体重而越来越受欢迎损失并改善代谢健康。酮（例如，乙酸乙酸酯和3-羟基丁酸（3OHB））由当葡萄糖低时，肝脏和外周组织氧化。而该领域的大部分专注于酮对大脑和心脏的积极作用，酮氧化在骨骼肌中的作用在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间隙的主要部位，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，此应用程序链接催化3OHB氧化的第一步D-ꞵ-羟基丁酸脱氢酶（BDH1）的酶由于肥胖后体重减轻而改善了全身葡萄糖代谢和能量稳态。中央该建议的目的是确定骨骼肌BDH1在介导健康中是否起关键作用饮食方案的益处，促进生酮发生和体重减轻。 BDH1催化近平衡伴侣酮氧化与线粒体NAD（H）氧化还原状态的反应。在这里，我们提出了一本小说将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参考期间的健康。我们的概念模型和中心目标将由以下研究。首先，我们使用具有诱导骨骼肌肉特异性缺失的新型鼠标模型确定BDH1对骨骼肌线粒体生物能和葡萄糖代谢的影响对禁食和参考的响应。其次，我们将检验以下假设：典型的西方饮食的卡路里限制喂养的代谢益处。第三，我们将应用基因工程在原发性人类骨骼肌细胞中，检验了酮诱导的心肌氧化还原移位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大我们的了解骨骼肌BDH1和酮氧化的功能相关性与长期目标确定预防肥胖引起的代谢疾病的新治疗靶标。重要的是，这个项目将在酮代谢，细胞基因工程，13C中提供高级培训和心理化稳定的同位素跟踪和计算13C代谢通量分析。职业发展计划将是通过包括Muoio博士（DMPI杜克分子生理研究所）在内的杰出心理团队实施作为主要导师，Newgard博士（DMPI）作为院长，博士。 Zhang（DMPI）和Crawford（Umn）咨询委员会成员。 DMPI是培训的理想环境，因为它包含了潜水员团队具有营养代谢和多词技术技术专业知识的研究人员；包括稳定的同位素在单个建筑物中追踪所有。该奖项提供的培训和职业发展的机会将确保威廉姆斯博士作为代谢研究人员独立的独立职业开头。