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.

项目概要 与年龄相关的代谢紊乱和肥胖症的增加已达到流行病的程度。 令人兴奋的发现，生物钟突变动物会出现饮食引起的肥胖和代谢综合征， 高脂肪喂养会抑制昼夜节律波动并增加“错误”期间的食物消耗 相反，将高脂肪饮食限制在“正确”的时间（即正常休息时间）。 一天中的某个时间作为昼夜节律饮食干预可以预防肥胖和糖尿病的发生。 这些发现表明，喂养节律的昼夜节律控制被破坏会导致饮食诱发的肥胖及其相关疾病。 并发症，类似于人类夜间进食的不良后果，并为 我们在这里提出的研究是为了阐明这种昼夜节律饮食背后的生物能量学机制 重要的是，我们最近发现脂肪产热是代谢所必需的。 越来越多的证据还表明，限时喂养的好处还可以改善昼夜节律和能量通路。 通过 NAD+ 的生物钟控制在分子水平上耦合，NAD+ 是营养感应的辅助因子 Sirtuin 脱乙酰酶可反馈调节核心时钟活动和线粒体呼吸。 值得注意的是，我们发现补充 NAD+ 可以增强昼夜节律中的线粒体氧化代谢 突变小鼠在衰老过程中增强节律性代谢基因转录 在这里，我们首先测试一下。 假设昼夜节律饮食干预（即仅黑暗喂养）通过以下方式改善代谢健康寿命： 增强脂肪和肝脏的产热和氧化代谢（目标 1）。 限时喂养 (i) 对有缺陷 (Ucp1-/-) 或增强的小鼠代谢健康的影响 (Zfp423-/-) 生热作用；(ii) 热量限制后动物的体重维持；(iii) 代谢； 脂肪和肝脏特异性时钟缺陷小鼠的通量（Bmal1Δadipose 和 Bmal1Δliver）；以及（iv）转录 目标 1 的结果将阐明时钟和时间限制喂养的机制。 调节膳食营养素和体重设定点的代谢命运 在目标 2 中，我们将检验假设。 补充 NAD+ 可以增强限时喂养，作为代谢下降的对策 具体来说，我们将检查补充 NAD+ 是否会改善衰老和营养过剩的情况（目标 2）。 年轻人和老年人核心时钟的产热、代谢流和转录活动的昼夜节律控制 目标 2 的结果将阐明 NAD+ 在昼夜节律控制中的作用。 膳食营养素、生热作用和健康寿命的代谢命运的综合。 本提案中的行为、基因组和生理分析将定义一天中的时间在 营养通量和生热作用，导致治疗设计的重大进步，以保持理想的状态 随着衰老的体重和代谢健康。