Bioenergetic Mechanisms Underlying Circadian Dietary Intervention

昼夜节律饮食干预的生物能量机制

• 批准号: 10426118
• 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/10426118
• 关键词: ARNTL gene; Adipocytes; Adipose tissue; Aging; Animals; Bioenergetics; Body Weight; Caloric Restriction; Cell Respiration; Circadian Dysregulation; Circadian Rhythms; Coupled; 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; adverse outcome; age related; aged; base; behavioral genomics; 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.

项目摘要 与年龄相关的代谢障碍和肥胖症的增加已达到流行比例。我们做了 令人兴奋的发现，昼夜节律突变动物会发展饮食引起的肥胖和代谢综合征， 高脂肪的喂养会抑制昼夜节律的振荡，并增加了“错误”期间的食物消耗量 一天中的时间（即正常休息时间）。相反，将高脂饮食的获取限制在“右”（即活动）中 一天中的时间作为昼夜节律干预，可以阻止肥胖和糖尿病的发展。一起， 这些发现表明，昼夜节律的昼夜节律中断，有助于饮食引起的肥胖症及其肥胖症 合并症，类似于人类夜间吃的不利后果，并为 我们在这里提出的研究旨在阐明这种昼夜节律饮食的生物能机制 干涉。重要的是，我们最近发现代谢需要脂肪生热。 时间限制的饲料的好处。越来越多的证据也表明昼夜节律途径 通过NAD+的昼夜节律控制在分子水平上耦合，NAD+是一种营养感应的辅助因子 Sirtuin脱乙酰基酶反馈以调节核心时钟活动和线粒体呼吸。 值得注意的是，我们发现NAD+补充增加了昼夜节律的线粒体氧化代谢 突变小鼠并增强衰老过程中的节奏代谢基因转录。在这里，我们将首先测试 假设昼夜节律干预（即仅黑暗喂养）可以通过 脂肪和肝脏中的热生成和氧化代谢增强（AIM 1）。为此，我们将确定 时间限制喂养（i）对有缺陷（UCP1 - / - ）的代谢健康或增强的影响 （ZFP423 - / - ）热生成； （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）； （iv）转录 节奏。 AIM 1的结果将阐明时钟和时间限制的馈送的机制 调节饮食营养素和体重设定点的代谢命运。在AIM 2中，我们将检验假设 NAD+补充可以增加时间限制的喂养，以作为代谢下降的对策 随着衰老和营养不良（AIM 2）。特别是，我们将检查NAD+补充是否有所改善 昼夜节律控制年轻人和核心时钟的热生成，代谢通量和转录活性 在时间限制的喂养过程中，老动物。 AIM 2的结果将阐明NAD+在昼夜节律中的作用 饮食养分，热生成和健康状况的代谢命运。共同的整合 本提案中的行为，基因组和生理分析将定义当天时间的作用 营养通量和热生成，导致处理的设计显着前进，以保留理想 体重和代谢健康，衰老。