Time-of-Day-Dependent Feeding Influences Myocardial Function

西方社会中常见的环境因素，如过量的热量摄入，身体活动不足， 睡眠不足与现代流行病的发展密切相关，包括肥胖症， 2型糖尿病和心血管疾病（CVD）。在饮食方面， 主要关注数量和/或质量（即，作为一种手段， 探究饮食导致病理的机制尽管人类 在不连续的膳食中消耗大部分卡路里，迄今为止基于动物的研究旨在 询问营养对心脏代谢疾病的影响， 获得不同营养成分的单一饮食。忽视差异的后果 最近，我们的实验室强调了人类和实验室啮齿动物喂养行为之间的关系; 在活动/清醒期结束时进食热量密集的高脂肪餐会产生心脏代谢综合征 表型（体重增加、肥胖、葡萄糖耐受不良、高胰岛素血症、高胰岛素血症和 高瘦素血症，与在活动/清醒期开始时喂食相同膳食的小鼠相比）。这 进食效果与每日摄入的热量总量或质量无关。然而，目前， 目前尚不清楚在清醒期结束时， 显著影响CVD易感性。这些意见导致了以下广泛的目标， 这个建议：测试创新的假设，在一天中的时间，热量密集的膳食是 摄入显著影响心脏功能（基线和/或缺血/再灌注后），和 以揭示其发生的分子机制。在后一种情况下，我们假设 心肌细胞固有的机制，称为昼夜节律钟，起着关键作用。的 心肌细胞生物钟不仅影响心肌代谢和收缩功能， 对饮食行为的变化非常敏感。我们计划处理这项建议的广泛目标 通过完成以下具体目标：具体目标1 -阐明是否有时间限制 西方饮食喂养影响心肌细胞昼夜节律钟依赖性心肌收缩 具体目标2 -确定一天中的时间限制喂养是否能挽救心肌 在db/db小鼠中由肥胖和糖尿病引起的收缩功能障碍。成功完成 拟议的研究将确定热量摄入的时间是否与热量摄入的数量和 在心脏功能/疾病方面，摄入的卡路里的质量。饮食干预的概念， 其可容易地转化为人类，可独立于热量改善心脏功能， 质量是前所未有的。这些发现可能会大大改变人类营养指南， 关于一天中摄入高热量膳食的适当时间的信息。

Common environmental factors within Western society, such as excess caloric intake, physical inactivity, and sleep deprivation are strongly associated with the development of modern day epidemics, including obesity, type 2 diabetes mellitus, and cardiovascular disease (CVD). In terms of diet, research efforts have focused attention primarily on the quantity and/or quality (i.e., nutritional content) of calories ingested as a means of interrogating the mechanisms responsible for diet-induced pathology. Despite the fact that humans consume the majority of their calories during discrete meals, to date animal-based studies designed to interrogate the influence of nutrition on cardiometabolic diseases have allowed rats/mice contiguous access to a single diet of distinct nutritional content. The consequence of overlooking discrepancies between human and laboratory rodent feeding behavior was recently highlighted by our laboratory; mice fed a caloric-dense high fat meal at the end of the active/awake period develop a cardiometabolic syndrome phenotype (weight gain, adiposity, glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia, compared to mice fed the same meal at the beginning of the active/awake period). This meal-feeding effect was independent of total daily quantity or quality of calories ingested. However, currently it is not known whether temporally disproportionate consumption of calories at the end of the waking period significantly influences CVD susceptibility. These observations have lead to the following broad objective of this proposal: to test the innovative hypothesis that the time-of-day at which caloric-dense meals are ingested significantly influences heart function (baseline and/or following ischemia/reperfusion), and to reveal the molecular mechanism(s) by which this occurs. In the latter case, we hypothesize that a mechanism intrinsic to the cardiomyocyte, known as the circadian clock, plays a critical role. The cardiomyocyte circadian clock not only influences myocardial metabolism and contractile function, but is also exquisitely sensitive to changes in dietary behavior. We plan to address the broad objective of this proposal through completion of the following specific aims: Specific Aim 1 - Elucidate whether time-of-day-restricted Western diet feeding influences myocardial contractile in a cardiomyocyte circadian clock dependent manner; and Specific Aim 2 - Determine whether time-of-day-restricted feeding rescues myocardial contractile dysfunction arising from obesity and diabetes in db/db mice. Successful completion of the proposed studies will establish whether timing of caloric intake is of comparable importance to the quantity and quality of calories ingested, in terms of heart function/disease. The concept that a dietary intervention, which is readily translatable to humans, can improve heart function independent of caloric quantity or quality is unprecedented. Such findings could significantly re-shape human nutritional guidelines to include information on the appropriate time-of-day at which calorie-dense meals are consumed.