Determining The Role of Photic and Non-Photic Time Cues in Resetting Lipid Circadian Rhythms in Humans

项目概要/摘要 昼夜节律紊乱是由昼夜节律睡眠-觉醒障碍患者经历的， 全世界有数百万轮班工人，这可能会增加他们患慢性疾病的风险， 心血管疾病昼夜节律紊乱的治疗需要适当的时间干预， 或者将昼夜节律系统提前（提前）或者延迟（延迟）。相位响应曲线（PRC）指示何时 管理干预，没有干预，中断可能会因相位不足而延长 复位或由于将系统切换到错误的方向而恶化。目前，该领域依赖于中国 重置褪黑激素节律作为重置整个昼夜节律系统的指南，尽管昼夜节律 节律存在于除褪黑激素之外的许多其它生理特征中。初步数据显示， 在健康的年轻人中，总胆固醇和甘油三酯的循环水平有很强的昼夜节律 这些节奏也可以改变。我们的试点研究进一步表明， 脂质节律可能对进餐时间的变化而不是光暴露更敏感。我们有 构建了这些脂质节律的初步PRCs，以响应光暴露和 在24小时内分配膳食，并检测到稳健的相位提前和延迟。此外， 这些脂质节律大于褪黑激素的脂质节律。我们不知道，然而，是否光暴露或 进餐时间是重新设定这些脂质节律的主要时间线索。如果没有这些知识， 综合治疗昼夜节律紊乱的脂质节律，可能是心脏代谢的基础 的影响，将是困难的。本提案的目标是建造三个PRC， 系统地检查光和进餐时间对重置脂质昼夜节律的贡献。年轻 将健康成人随机分为三种条件：（1）明亮的光+12小时进餐窗口，（2）昏暗的光+12小时进餐窗口， 餐窗，和（3）昏暗的灯光+6.5小时餐窗（时间重新分区进食），每个分布在24小时 天主要结果包括在以下条件下测量的脂质和褪黑素昼夜节律的相位重置 三种条件中的每一种以及6.5小时内脂质曲线下面积限制了进食。 本研究的目的是：（1）确定光是否是重置褪黑激素的主要时间线索，而不是脂质 昼夜节律，（2）确定进餐时间是否是重置脂质而不是褪黑激素的主要时间线索 昼夜节律，以及（3）评估24小时内进食对循环脂质水平的急性影响。我们 这项工作将全面评估两个日常事件--光照和饮食--如何使血脂同步 人体的昼夜节律。我们希望我们的分析范式是一种基础资源， 扩展到人类昼夜节律调节下的其他外周系统的未来研究，并具有积极的意义。 通过指导昼夜节律紊乱患者和人群的治疗策略， 他们中的许多人由于不规则的睡眠-觉醒时间表而经历反复的昼夜节律紊乱。

Project Summary/Abstract Circadian rhythm disruption is experienced by patients with Circadian Rhythm Sleep-Wake Disorders and millions of shiftworkers worldwide, which may increase their risk of developing chronic health disorders including cardiovascular disease. Treatment of circadian rhythm disruption requires appropriately-timed intervention to either shift the circadian system earlier (advance) or later (delay). A Phase Response Curve (PRC) informs when to administer the intervention, without which the disruption may either be prolonged due to inadequate phase resetting or worsened due to shifting the system in the wrong direction. Currently, the field relies on the PRC for resetting the melatonin rhythm as guide to reset the entire circadian system, despite the fact that circadian rhythms are present in many other physiological features besides melatonin. Our preliminary data show that there are robust circadian rhythms in circulating levels of total cholesterol and triglyceride in healthy young individuals and that these rhythms can also be shifted. Our pilot studies further indicate that the timing of these lipid rhythms may be more responsive to shifts in the timing of meals rather than light exposure. We have constructed preliminary PRCs of these lipid rhythms in response to a combined stimulus of light exposure and meals distributed across the 24-h day and detected robust phase advances and delays. Moreover, the shifts in these lipid rhythms are larger than those for melatonin. We do not know, however, whether light exposure or meal timing is the primary time cue for resetting these lipid rhythms. Without this knowledge, developing a comprehensive treatment for circadian rhythm disruption of lipid rhythms that likely underlies the cardiometabolic consequences of shiftwork, will remain difficult. The objective of this proposal is to construct three PRCs that systematically examine the contribution of light and meal timing on resetting lipid circadian rhythms. Young healthy adults will be randomized to three conditions: (1) bright light + 12-h meal window, (2) dim light + 12-h meal window, and (3) dim light + 6.5-h meal window (time redistricted eating), each distributed across the 24-h day. The primary outcomes include phase resetting of lipid and melatonin circadian rhythms measured under each of the three conditions, and the area-under-the curve of the lipids during the 6.5-h time restricted eating. The aims of the study are to: (1) determine if light is the primary time cue for resetting melatonin but not lipid circadian rhythms, (2) determine if meal timing is the primary time cue for resetting lipid but not melatonin circadian rhythms, and (3) evaluate the acute effects of eating across the 24-h day on circulating lipid levels. Our work will be a comprehensive evaluation of how two daily events – light exposure and meals – synchronize lipid circadian rhythms in humans. We expect our analytic paradigm to be a foundational resource that can be extended to future studies of other peripheral systems under circadian regulation in humans, and have a positive public health impact by guiding therapeutic strategies for patients with circadian disruption and the population at large, many of whom experience recurrent circadian disruption due to irregular sleep-wake schedules.