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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：
10453740
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
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/10453740
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.

项目总结