Uncovering the Impact of Diet on the Human Circadian Timing System

摘要/摘要 生物过程和行为与24小时明暗周期的同步是最佳的基础 生理、认知功能和健康。因为人类平均有超过24小时的 时钟，大多数人必须每天执行这一同步过程。不能充分纠缠 内部昼夜节律对外部环境的影响，即使是很小的错位，也可能会产生严重的影响 后果包括心脏代谢结果不佳(即心血管疾病、糖尿病、肥胖)， 睡眠受损，认知能力下降，甚至在经济上处于不利地位。据信，夹带作用 完全是通过暴露在晨光下来协调的，因为已经假设非光的外源性刺激 对人体的昼夜节律夹带几乎没有影响。然而，来自动物模型的新证据 表明昼夜节律对光的夹带可能会受到饮食组成的阻碍。具体地说，给小鼠喂食 高脂肪饮食对光的吸收速度慢20%，昼夜节律期更长。如果这些发现成立 这对人类来说是正确的，这将挑战人类昼夜节律生理学领域的现有理论，并将 有巨大的公共健康影响，因为如此多的美国人消费高脂肪饮食。因此，量化 典型的饮食选择和昼夜节律夹带之间的相互作用非常重要。这样做的目的是 该项目的目的是确定这些与饮食有关的啮齿动物昼夜节律效应是否也适用于人类。我们的具体目标 是为了确定高脂肪饮食对以下方面的影响：1)昼夜节律系统对光的夹带速度；2) 昼夜节律周期和由此产生的日常行为的昼夜节律时序，即，夹带的相角(时间 褪黑素和睡眠的区别)；以及3)吃高脂肪饮食和睡眠的结合 昼夜节律阶段(即昼夜节律对错)影响心脏新陈代谢健康和认知。 功能。为了达到我们的目标，我们设计了一项对照的随机交叉机制研究 实验室环境。我们假设，当习惯吃低脂肪饮食的人被提供一种 等卡路里高脂肪饮食(与提供等卡路里低脂肪饮食相比)，他们需要更长的时间才能适应转变 在明暗循环中，有一个较窄的夹带相角，并增加了昼夜失调 以及心脏新陈代谢健康和认知功能的相关损害。这些数据将提供一个 基本了解常见的饮食模式如何改变人类与 环境。重要的是，这些数据将对社会的大部分人产生深远的影响 忍受：1)跨多个时区旅行(时差)；2)需要重新调整工作日的睡眠/起床时间(社交 时差)；以及3)工作和学校开学时间太早，对于大多数年轻人的自然生物钟时间来说 成年人和青少年。这项研究很重要，因为昼夜节律调整的必要性无处不在，而且 事实上，即使饮食对昼夜节律的影响很小，也会对人类的健康和认知产生重大影响 功能。

Summary/Abstract Synchronization of biological processes and behaviors with the 24-hour light-dark cycle is fundamental to optimal physiology, cognitive function, and health. Because humans have, on average, a longer than 24-hour internal clock, most people must perform this synchronization process on a daily basis. An inability to adequately entrain internal circadian rhythms to the external environment, even a small misalignment, can have severe consequences including poor cardiometabolic outcomes (i.e., cardiovascular disease, diabetes, obesity), impaired sleep, reduced cognitive performance, and even economic disadvantage. Entrainment is believed to be entirely orchestrated by exposure to morning light, as it has been assumed that non-photic exogenous stimuli have little influence on circadian entrainment in humans. However, emerging evidence from animal models indicates that circadian entrainment to light could be hampered by dietary composition. Specifically, mice fed a high-fat diet have a 20% slower rate of entrainment to light and a longer circadian period. If these findings hold true in humans, this would challenge current theory within the field of human circadian physiology and would have vast public health implications because so many Americans consume high-fat diets. Thus, quantifying the interaction between typical dietary choices and circadian entrainment has great importance. The goal of this project is to determine if these diet-related circadian effects in rodents translate to humans. Our specific aims are to establish the impact of a high-fat diet on the: 1) rate of entrainment of the circadian system to light; 2) circadian period and the resultant circadian timing of daily behaviors i.e., phase angle of entrainment (time difference between melatonin and sleep onsets); and 3) how the combination of eating a high-fat diet and circadian phase (i.e., circadian alignment vs misalignment) impacts cardiometabolic health and cognitive function. To accomplish our aims, we have designed a randomized cross-over mechanistic study in controlled laboratory settings. We hypothesize that when individuals that habitually eat a low-fat diet are provided an isocaloric high-fat diet (versus when provided an isocaloric low-fat diet), they will take longer to entrain to a shift in the light-dark cycle, have a narrower phase angle of entrainment, and have increased circadian misalignment and associated impairments in cardiometabolic health and cognitive function. These data will provide a fundamental understanding of how common dietary patterns alter the way humans synchronize to the environment. Importantly, these data would have far-reaching implications for the large portions of society that endure: 1) travel across multiple time zones (jet-lag); 2) a need to readjust sleep/wake timing on workdays (social jet-lag); and 3) work and school start times that are too early for the natural internal clock timing of most young adults and teens. This study is important because of the ubiquity of the need for circadian adjustments and the fact that even slight effects of diet on circadian entrainment can have large effects on human health and cognitive function.