Bioenergetic Mechanisms Underlying Circadian Dietary Intervention

项目摘要 与年龄有关的代谢紊乱和肥胖症的增加已达到流行病的程度。我以黑夜做 令人兴奋的发现是，生物钟突变动物会发展饮食诱导的肥胖和代谢综合征， 高脂肪喂养会抑制昼夜节律振荡，并在“错误”时间增加食物消耗。 一天中的时间（即，正常的休息时间）。相反，限制高脂肪饮食的“权利”（即，活跃） 作为昼夜节律饮食干预的一天中的时间可以防止肥胖和糖尿病的发展。在一起， 这些发现表明，进食节律的昼夜节律控制中断有助于饮食诱导的肥胖， 合并症，类似于人类夜间进食的不良后果，并提供了一个跳板 我们在此提出的研究旨在阐明这种昼夜节律饮食的生物能量学机制， 干预重要的是，我们最近发现，脂肪产热是代谢所必需的。 限制进食时间的好处越来越多的证据也表明，昼夜节律和能量途径 在分子水平上通过NAD+的生物钟控制偶联，NAD+是营养感应的辅因子 去乙酰化酶，其反馈调节核心时钟活性和线粒体呼吸。 值得注意的是，我们发现NAD+补充增强了昼夜节律中的线粒体氧化代谢。 突变小鼠和增强节奏代谢基因转录在衰老过程中。在这里，我们将首先测试 假设昼夜节律饮食干预（即，黑暗喂养）改善代谢健康， 增强脂肪和肝脏中的产热和氧化代谢（目的1）。为此，我们将确定 时间限制喂养（i）对缺陷型（Ucp 1-/-）或增强型（Ucp 1-/-）小鼠代谢健康的影响 （Zfp 423-/-）产热;（ii）对热量限制后动物体重维持的影响;（iii）对代谢的影响。 脂肪和肝脏特异性时钟缺陷小鼠（Bmal 1脂肪和Bmal 1肝脏）中的通量;和（iv）对转录的影响 节奏目标1的结果将阐明生物钟和限时摄食的机制 调节膳食营养素的代谢去向和体重设定值。在目标2中，我们将检验假设 补充NAD+可以增加限时喂养，作为代谢下降的对策 衰老和营养过剩（目标2）。具体来说，我们将研究补充NAD+是否能改善 昼夜节律控制的产热，代谢通量，和转录活性的核心时钟在年轻和 在有限的时间内喂养动物。目的2的结果将阐明NAD+在昼夜节律控制中的作用 饮食营养、产热和健康寿命的代谢命运。总的来说， 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以下方面的作用： 营养通量和产热，导致在处理设计方面取得重大进展，以保持理想的 体重和代谢健康与衰老。

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.