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 最佳的生理、认知功能和健康。因为人类平均有超过24小时的 内部时钟，大多数人必须每天执行这一同步过程。不能 充分地将内部昼夜节律与外部环境捆绑在一起，即使是很小的失调，也可能 有严重的后果，包括不良的心脏代谢结果(即心血管疾病、糖尿病、 肥胖)以及睡眠、认知功能和学习能力受损。据信，夹带作用完全是 通过暴露在晨光中来协调的，因为已经假设非光的外源刺激具有 对人体昼夜节律夹带的影响很小。然而，来自动物模型的新证据表明 这种昼夜节律对光线的影响可能会受到饮食构成的阻碍。具体地说，喂食高脂肪的小鼠 饮食对光的吸收速度要慢20%，昼夜节律周期更长。如果这些发现适用于 人类，这将挑战人类昼夜节律生理学领域的现有理论，并将 随着如此多的美国人食用高脂肪饮食，这对公共健康产生了巨大的影响。因此，量化相互作用 在典型的饮食选择和昼夜节律的夹带之间有着非常重要的作用。这个项目的目标是 确定这些与饮食有关的啮齿类动物的昼夜节律效应是否也适用于人类。我们的具体目标是 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率；2)昼夜节律 周期和由此产生的日常行为的昼夜节律时间，即夹带的相角(时间差 褪黑素和睡眠之间的关系)；以及3)吃高脂肪饮食和昼夜节律的结合 (即昼夜节律对齐与不对齐)以及再夹带的速度影响心脏代谢健康， 认知功能和学习。为了达到我们的目标，我们设计了一个随机交叉 在受控实验室环境中进行机械研究。我们假设，当习惯性地吃一种 低脂肪饮食提供等卡路里的高脂肪饮食(而不是提供等卡路里的低脂肪饮食)，他们将 需要更长的时间才能卷进到明暗循环中的移动，卷积的相位角更窄，并且 昼夜节律失调和相关心脏代谢健康、认知功能、 和学习。这些数据将提供一个基本的理解，即常见的饮食模式如何改变 人类与环境同步的方式。重要的是，这些数据将对 社会的很大一部分人会经历：1)跨越多个时区(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)工作和上学时间太早，对 大多数年轻人和青少年的生物钟。这项研究之所以重要，是因为人们普遍需要 昼夜节律的调整，以及饮食对昼夜节律的微小影响可能会有很大的影响这一事实 对健康、认知功能和学习的影响。

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) and impaired sleep, cognitive function, and learning. 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 as 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) and the rate of re-entrainment impacts cardiometabolic health, cognitive function, and learning. 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, cognitive function, and learning. These data will provide a fundamental understanding of how common dietary patterns alter the way humans synchronize to the environment. Importantly, these data will 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 circadian clock 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 health, cognitive function, and learning.