Uncovering sleep and circadian mechanisms contributing to adverse metabolic health

项目摘要/摘要 肥胖症和糖尿病在现代社会中已经达到了流行的程度，治疗和共病 每年花费数十亿美元的医疗费用。在肥胖和糖尿病增加的同时， 数百万美国人每晚的睡眠时间一直在减少。通过联想 睡眠不足和代谢健康不良之间的关系是明确的，导致健康不良的确切机制并不是很好- 明白了。例如，导致睡眠限制本身就会导致许多令人困惑的变量，大多数 值得注意的是昼夜节律紊乱，这也独立地损害了健康。因此，很难有针对性地开发 没有首先确定慢性睡眠限制和昼夜节律的单独和综合影响的干预措施 新陈代谢紊乱。这个项目的目标是系统地确定慢性睡眠的影响。 对新陈代谢健康的限制和昼夜节律扰乱，无论是独立的还是联合的。我们的特定 目的是：1)揭示长期睡眠限制、昼夜节律以及它们的组合对能量的影响 摄取方式；2)确定长期睡眠限制对食物选择的影响 有机会在所有昼夜节律时间进食；以及3)揭示长期睡眠限制、昼夜节律、 以及它们的组合，对葡萄糖耐量的影响。为了实现我们的目标，我们设计了14天的随机- 控制机制研究，在所有活动期间，参与者将被长期限制睡眠或不被限制 计划在20小时的“一天”内均匀地发生在所有昼夜节律阶段，并可随意获取食物。我们 假设当每个人在所有昼夜时间都有平等的进食机会时，他们将消费 在昼夜节律的夜晚，更多的卡路里与睡眠状况无关，2)睡眠限制将 导致晚间碳水化合物消耗量较高，这将与较高的内源性大麻素有关 浓度，以及3)长期睡眠限制会导致昼夜节律后更多的糖耐量受损 颠覆。这些数据将提供对慢性睡眠限制和昼夜节律的基本理解 干扰会影响新陈代谢健康。重要的是，这些数据将产生深远的影响，特别是在 制定干预措施，不仅在超重/肥胖的个人中促进健康体重， 也包括那些睡眠时间较短和/或工作时间较长、轮换、 或者永久上夜班。该项目还符合以下优先研究领域，以供未来研究 在NIH国家睡眠障碍研究中心(NCSDR)计划中。目标1：阐明睡眠和 健康和疾病的昼夜节律机制，特别是在识别睡眠和昼夜节律影响方面 关于人类肥胖和心脏代谢风险的生物学基础，以及更好地量身定做临床干预措施- 翻译研究和目标2：改善睡眠和昼夜节律障碍的治疗并降低风险 与睡眠不足和昼夜节律失调有关，特别是在阐明 昼夜节律生物学、睡眠健康和进食时间对心脏代谢健康和肥胖的影响。

Project Summary/Abstract Obesity and diabetes have reached epidemic proportions in modern society, with treatments and comorbidities costing billions of dollars in health care costs each year. Concurrent with increases in obesity and diabetes have been decreases in the amount of sleep millions of Americans obtain on a nightly basis. Though associations between short sleep and poor metabolic health are clear, exact mechanisms driving poor health are not well- understood. For example, inducing sleep restriction inherently results in a number of confounding variables, most notably circadian disruption, which also independently impairs health. It is thus difficult to develop targeted interventions without first identifying the individual and combined effects of chronic sleep restriction and circadian disruption on metabolism. The goal of this project is to systematically determine the influence of chronic sleep restriction and circadian disruption, both independently and in combination, on metabolic health. Our specific aims are to: 1) uncover the impact of chronic sleep restriction, circadian timing, and their combination on energy intake patterns; 2) determine the influence of chronic sleep restriction on food choice when there is equal opportunity to eat at all circadian times; and 3) uncover the impact of chronic sleep restriction, circadian timing, and their combination, on glucose tolerance. To accomplish our aims, we have designed a 14-day randomized- control mechanistic study in which participants will be either chronically sleep restricted or not while all activities are scheduled to occur evenly across all circadian phases on a 20-h “day” with ad libitum food access. We hypothesize that when individuals have equal opportunities to eat at all circadian times, they will 1) consume greater amounts of calories during the circadian evening independent of sleep condition, 2) sleep restriction will result in higher evening carbohydrate consumption, which will be associated with higher endocannabinoid concentrations, and 3) chronic sleep restriction will result in more impaired glucose tolerance after circadian disruption. These data will provide a fundamental understanding of how chronic sleep restriction and circadian disruption impacts metabolic health. Importantly, these data will have far-reaching implications, particularly in the development of interventions to promote healthy weight in not only individuals that are overweight/obese, but also those at risk for obesity who live on short sleep schedules and/or work on extended duration, rotating, or permanent nightshifts. This project also meets the following High-Priority Research Areas for future research in the NIH National Center on Sleep Disorders Research (NCSDR) plan. Goal 1: Elucidate the Sleep and Circadian Mechanisms Underlying Health and Disease, particularly in identifying sleep and circadian influences on the biology underlying obesity and cardiometabolic risk in humans and to better tailor interventions in clinical- translational studies, and Goal 2: Improve the Treatment of Sleep and Circadian Disorders and Reduce the Risks Associated with Sleep Deficiency and Circadian Misalignment, particularly in elucidating the relationship between circadian biology, sleep health, and the timing of food intake on cardiometabolic health and obesity.