Bioenergetic Mechanisms Underlying Circadian Dietary Intervention

昼夜节律饮食干预的生物能量机制

• 批准号: 10661568
• 负责人: Joseph Bass
• 金额: $ 39.5万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10661568
• 关键词: ARNTL gene; Adipocytes; Adipose tissue; Aging; Animals; Behavioral; Bioenergetics; Body Weight; Caloric Restriction; Cell Respiration; Circadian Dysregulation; Circadian Rhythms; Coupled; Darkness; Data; Deacetylase; Diabetes Mellitus; Diet; Dietary Intervention; Eating; Energy Metabolism; Epidemic; Fatty acid glycerol esters; Feedback; Genetic; Genetic Transcription; Genomics; Goals; Health; Health Benefit; High Fat Diet; Human; Liver; Maintenance; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic syndrome; Mitochondria; Molecular; Mus; Mutant Strains Mice; Nutrient; Obesity; Overnutrition; Pathway interactions; Periodicity; Physiological; Play; Process; Public Health; Regulation; Respiration; Rest; Ribosomal RNA; Role; Sirtuins; Societies; Supplementation; Testing; Thermogenesis; Time; Time-restricted feeding; Weight Gain; Wild Type Mouse; access restrictions; adverse outcome; age related; aged; aging nutrition; circadian; circadian pacemaker; cofactor; comorbidity; detection of nutrient; diet-induced obesity; dietary; dietary manipulation; enzyme feedback; feeding; food consumption; healthspan; human old age (65+); improved; mitochondrial metabolism; mutant; novel; obesity development; obesogenic; preservation; prevent; therapy design; transcriptome sequencing; uncoupling protein 1; weight maintenance

Project Summary The rise in age-related metabolic disorders and obesity has reached epidemic proportions. We have made the exciting discoveries that circadian clock mutant animals develop diet-induced obesity and metabolic syndrome, and that high fat feeding dampens circadian oscillations and increases food consumption during the `wrong' time of day (i.e., the normal rest period). In contrast, restricting access to high fat diet to the `right' (i.e., active) time of day as a circadian dietary intervention prevents the development of obesity and diabetes. Together, these findings suggest disrupted circadian control of feeding rhythms contributes to diet-induced obesity and its comorbidities, similar to the adverse consequences of night-eating in humans, and provide a springboard for our proposed studies here to elucidate the bioenergetics mechanisms underlying this circadian dietary intervention. Importantly, we recently discovered that adipose thermogenesis is required for the metabolic benefits of time-restricted feeding. Mounting evidence has also indicated that circadian and energetic pathways are coupled at the molecular level through circadian clock control of NAD+, a cofactor for nutrient-sensing sirtuin deacetylases which feedback to regulate both core clock activity and mitochondrial respiration. Remarkably, we found that NAD+ supplementation augments mitochondrial oxidative metabolism in circadian mutant mice and enhances rhythmic metabolic gene transcription during aging. Here, we will first test the hypothesis that circadian dietary intervention (i.e., dark-only feeding) improves metabolic healthspan through enhanced thermogenesis and oxidative metabolism in adipose and liver (Aim 1). To do so, we will determine the impact of time-restricted feeding (i) on the metabolic health of mice with defective (Ucp1-/-) or enhanced (Zfp423-/-) thermogenesis; (ii) on weight maintenance in animals following caloric restriction; (iii) on metabolic flux in adipose- and liver-specific clock deficient mice (Bmal1∆adipose and Bmal1∆liver); and (iv) on transcriptional rhythms. Results of Aim 1 will elucidate the mechanism through which the clock and time-restricted feeding regulate the metabolic fate of dietary nutrient and body weight setpoint. In Aim 2, we will test the hypothesis that NAD+ supplementation can augment time-restricted feeding as a countermeasure for metabolic decline with aging and overnutrition (Aim 2). Specifically, we will examine whether NAD+ supplementation improves circadian control of thermogenesis, metabolic flux, and transcriptional activity of the core clock in young and old animals during time-restricted feeding. Results of Aim 2 will elucidate the role of NAD+ in circadian control of the metabolic fate of dietary nutrient, thermogenesis, and healthspan. Collectively, the integration of behavioral, genomic, and physiologic analyses in the present proposal will define the role of time-of-day in nutrient flux and thermogenesis, leading to significant advance in the design of treatments to preserve ideal body weight and metabolic health with aging.

项目总结