Bioenergetic Mechanisms Underlying Circadian Dietary Intervention

项目摘要 与年龄相关的代谢紊乱和肥胖症的增加已经达到流行的程度。我们已经做出了 令人兴奋的发现，昼夜节律突变的动物会患上饮食诱导的肥胖和代谢综合征， 高脂肪喂养抑制了昼夜节律的波动，增加了食物的消耗。 一天中的时间(即正常休息时间)。相比之下，限制“右派”(即活跃人士)获得高脂肪饮食 作为一种昼夜节律的饮食干预措施，可以预防肥胖和糖尿病的发生。一起， 这些发现表明，饮食节律的昼夜节律控制紊乱导致了饮食诱导的肥胖及其 合并症，类似于人类夜间进食的不良后果，并为 我们在这里建议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 干预。重要的是，我们最近发现脂肪产热是新陈代谢所必需的。 限时喂养的好处。越来越多的证据也表明，昼夜节律和能量途径 是通过NAD+的昼夜时钟控制在分子水平上耦合的，NAD+是一种营养感知的辅助因子 Sirtuin脱乙酰酶，反馈调节核心钟活动和线粒体呼吸。 值得注意的是，我们发现补充NAD+增强了昼夜节律中线粒体的氧化代谢 突变小鼠，并在衰老过程中增强节律代谢基因的转录。在这里，我们将首先测试 昼夜节律饮食干预(即，仅限黑暗喂养)通过以下方式改善代谢健康跨度的假说 增强脂肪和肝脏的产热和氧化代谢(目标1)。要做到这一点，我们将确定 限时喂养对Ucp1-/-缺陷或增强小鼠代谢健康的影响 (Zfp423-/-)生热作用；(Ii)卡路里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(BMAL1∆脂肪和BMAL1∆肝脏)中的通量；以及(Iv)转录 节奏。目标1的结果将阐明时钟和限时摄食的机制 调节膳食营养素的代谢命运和体重设定点。在目标2中，我们将检验假设 补充NAD+可以增加限时喂养作为新陈代谢下降的对策 老龄化和营养过剩(目标2)。具体地说，我们将检查NAD+补充是否有改善 昼夜节律控制的生热、代谢通量和核心时钟的转录活动 在限时进食期间的老动物。AIM 2的结果将阐明NAD+在昼夜节律控制中的作用 食物营养、产热和健康寿命的代谢命运。总体而言， 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，导致保存理想的治疗设计的重大进展 体重和新陈代谢健康随着年龄的增长。

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.