Impact of circadian misalignment on energy balance regulation

这项拟议的研究将测试进食时间与睡眠时间的错位是否会导致 正能量平衡和身体成分的变化。睡到很晚、吃到很晚的人 患肥胖症和代谢紊乱的风险增加。这可能是由于神经肽的活性 激活大脑奖赏区域和刺激食物摄取，这也参与了睡眠-觉醒循环。我们 研究表明，睡眠限制会激活大脑奖赏区域，如脑岛和额眶皮质，以及 增加食物摄入量，但也有越来越多的证据表明，在一天中的错误时间进食(即在 动物的休息期或人类的休息期)，可能会促进体重增加/阻碍体重减轻。 然而，对晚餐时间的研究仅限于观察性研究，并受到不同饮食习惯的影响 睡眠时间和时间。由于饮食是一个强大的外部计时器，我们假设改变 睡眠和用餐时间的协调会导致调节能量平衡的荷尔蒙发生变化。的目标是 这项拟议的研究旨在确定外出就餐与睡眠不同步是否会对 体重管理。这项拟议的研究既有机械性的目标，也有翻译的目标。首先，我们将测试 一天中晚些时候进食会促进正能量平衡的假设(机械目标1和2)通过 增强食物的有益特性，改变调节食欲的荷尔蒙和能量消耗 与早先吃东西相比。这将通过测量神经元对食物的反应来进行评估(功能 磁共振成像)、食欲调节激素(瘦素、Ghrelin、胰高血糖素样肽1、肽 YY)，以及受控饲养条件下的24小时能量消耗(代谢室)。接下来，我们将测试 假设4周的自由生活条件下错位的餐点相对于调整好的餐点将导致 增加能量摄入和身体脂肪(翻译目标3)。44名超重的男性和女性将 被招募参加两阶段交叉研究，有恒定的睡眠周期。阶段的不同只是在 用餐与睡眠时间相一致：对齐=醒后1小时开始进餐；不对齐=用餐 从醒来后5小时开始。机械目标将通过在第3天和第14天后进行的测量来实现 干预行动。血液样本将被检测褪黑激素和皮质醇作为昼夜节律的标志。这个 翻译目标将在每个人规定的用餐时间后的4周自由生活期后实现 相位。这项拟议中的研究将在不影响总睡眠时间的情况下操纵进餐时间，这项研究很重要 因为它将提供有关昼夜节律失调影响肥胖风险的机制的信息， 与睡眠时间无关。它还将提供信息，帮助解释肥胖症发病率更高的原因 在倒班工人中，受时差/社交时差影响的人，以及不吃早餐的人。因此，拟议的研究将 成为建立个性化时型的生活方式建议或疗法的垫脚石 改善体重管理和降低心脏代谢风险。

The proposed study will test whether the misalignment of eating occasions to the sleep period leads to positive energy balance and body composition changes. Individuals who sleep and eat late into the day are at increased risk of obesity and metabolic disorders. This may be due to the activity of neuropeptides that activate brain reward areas and stimulate food intake, which are also involved in the sleep-wake cycle. We have shown that sleep restriction activates brain reward areas, such as the insula and orbitofrontal cortex, and enhances food intake but there is also increasing evidence that eating at the wrong time of day (i.e. during resting periods in animals or later in the day in humans), may promote weight gain/hinder weight loss. However, studies of late meal timing are limited to observational studies and confounded by differences in sleep duration and timing. Since eating is a strong external time keeper, we hypothesize that altering the alignment of sleep and meal times will cause changes in hormones that regulate energy balance. The goal of the proposed study is to determine whether eating out of synchrony with sleep has negative consequences for weight management. The proposed study has both mechanistic and translational objectives. First, we will test the hypothesis that eating late in the day will promote positive energy balance (mechanistic aims 1 & 2) by enhancing the rewarding properties of food, altering appetite-regulating hormones, and energy expenditure compared to eating at earlier times. This will be assessed by measuring neuronal responses to food (functional magnetic resonance imaging), appetite-regulating hormones (leptin, ghrelin, glucagon-like peptide 1, peptide YY), and 24-h energy expenditure (metabolic chamber) under controlled feeding conditions. Next, we will test the hypothesis that 4 wk of free-living conditions of misaligned meals, relative to aligned meals, will lead to increases in energy intake and body fat (translational aim 3). Forty-four overweight men and women will be recruited to participate in a 2-phase, crossover study, with constant sleep periods. Phases will only differ in the alignment of meals to the sleep period: aligned = meals starting 1 h after awakening; misaligned = meals starting 5 h after awakening. Mechanistic aims will be addressed from measurements taken after 3 and 14 d of the intervention. Blood samples will be assayed for melatonin and cortisol as markers of circadian rhythm. The translational aim will be addressed after a 4 wk free-living period following the prescribed meal times for each phase. This proposed study, which will manipulate meal timing, without affecting total sleep time, is important because it will provide information on the mechanism by which circadian misalignment influences obesity risk, independent of sleep duration. It will also provide information to help explain the greater prevalence of obesity in shift workers, those affected by jetlag/social jetlag, and breakfast skippers. As such, the proposed study will be a stepping-stone in the establishment of lifestyle recommendations or therapies to personalize chronotype to improve weight management and cardio-metabolic risk reduction.