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

项目总结 促进酮生成的饮食方案因其促进体重的能力而越来越受欢迎 减少和改善新陈代谢健康。酮(如乙酰乙酸酯和3-羟基丁酸酯(3OHB))由 当葡萄糖含量较低时，肝脏会被大脑和周围组织氧化。鉴于该领域有很大一部分 重点阐述了酮对大脑和心脏的积极作用，以及酮在骨骼肌中的氧化作用 在很大程度上被忽视和调查不足。我们实验室的数据表明，骨骼肌 是清除3OHB的主要部位，因此我们推测骨骼肌3OHB氧化是必需的。 生酮饮食减肥方案的最佳代谢效益。为此，此应用程序将 催化3OHB氧化第一步的酶，D-ꞵ-羟丁酸脱氢酶(BDH1)，以 由于肥胖后的减肥，改善了全身的葡萄糖代谢和能量平衡。中环 这个建议的目的是确定骨骼肌BDH1是否在调节健康的过程中起关键作用 促进酮类生成和减肥的饮食方案的好处。BDH1催化了一种近平衡 将酮氧化与线粒体NAD(H)氧化还原状态偶联的反应。在这里，我们提出了一部小说 概念模型，将BDH1定位为线粒体氧化还原缓冲区，促进最佳骨骼肌 禁食和再喂食期间的健康。我们的概念模型和中心目标将由 随后进行的研究。首先，我们使用了一种新的小鼠模型，该模型具有可诱导的骨骼肌特异性BDH1缺失 探讨BDH1对小鼠骨骼肌线粒体生物能量学和糖代谢的影响 对禁食和重新进食的反应。其次，我们将检验肌肉BDH1对于 典型西式饮食的卡路里限制喂养的代谢益处。三是应用基因工程 在原代人类骨骼肌细胞中，测试了酮诱导肌细胞氧化还原转移的假设 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和酮氧化的功能与长期目标的相关性 为预防肥胖引起的代谢性疾病确定新的治疗目标。重要的是，这 项目将提供酮代谢、细胞基因工程、13C等方面的高级培训和指导 稳定同位素示踪和计算13C代谢通量分析。职业发展计划将是 通过包括Muoio博士(DMPI杜克分子生理学研究所)在内的优秀导师团队实施 作为主要导师，纽加德博士(DMPI)担任联合导师，张博士(DMPI)和克劳福德(UMN)担任 咨询委员会的成员。DMPI是一个理想的培训环境，因为它包含一个不同的团队 具有营养新陈代谢和多组学技术专长的研究人员；包括稳定同位素 在一栋楼里追踪所有的东西。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新陈代谢研究人员的独立职业生涯有一个特殊的开端。

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.