Time-of-Day-Dependent Feeding Influences Myocardial Function

描述（由申请人提供）：西方社会中常见的环境因素，如过量的热量摄入，缺乏身体活动和睡眠不足，与现代流行病的发展密切相关，包括肥胖，2型糖尿病和心血管疾病（CVD）。在饮食方面，研究工作主要集中在摄入卡路里的数量和/或质量（即营养成分）上，以此作为询问饮食引起病理的机制的一种手段。尽管人类在不同的膳食中消耗了大部分卡路里，但迄今为止，旨在调查营养对心脏代谢疾病影响的动物研究已经允许大鼠/小鼠连续获得具有不同营养成分的单一饮食。我们的实验室最近强调了忽视人类和实验室啮齿动物摄食行为差异的后果；在活动/清醒期结束时喂食高热量高脂肪膳食的小鼠，与在活动/清醒期开始时喂食相同膳食的小鼠相比，会出现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、高甘油三酯血症和高瘦素血症）。这种膳食喂养效果与每日摄入的卡路里总量或质量无关。然而，目前尚不清楚在清醒期结束时暂时不成比例的卡路里消耗是否会显著影响心血管疾病的易感性。这些观察结果导致了本提案的以下广泛目标：测试摄入高热量食物的时间显著影响心脏功能（基线和/或缺血/再灌注后）的创新假设，并揭示这种情况发生的分子机制。在后一种情况下，我们假设心肌细胞固有的一种机制，即生物钟，起着关键作用。心肌细胞生物钟不仅影响心肌代谢和收缩功能，而且对饮食行为的变化也非常敏感。我们计划通过完成以下具体目标来解决本提案的广泛目标：具体目标1 -阐明一天中限制时间的西方饮食喂养是否以心肌细胞生物钟依赖的方式影响心肌收缩；特定目的2 -确定限制进食时间是否能拯救db/db小鼠肥胖和糖尿病引起的心肌收缩功能障碍。就心脏功能/疾病而言，成功完成拟议的研究将确定摄入卡路里的时间是否与摄入卡路里的数量和质量同等重要。饮食干预的概念，很容易转化为人类，可以改善心脏功能独立于热量的数量或质量是前所未有的。这些发现可能会极大地重塑人类营养指南，包括关于一天中摄入高热量食物的适当时间的信息。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Diet strongly influences the development of obesity, type 2 diabetes mellitus, and cardiovascular disease in humans. Studies to date have mainly focused on the quantity and quality (i.e. nutritional content) of calories consumed, as opposed to the time of day at which meals are eaten. The current proposal outlines studies designed to investigate whether the time of day at which caloric-dense meals are eaten significantly influences heart function.