Balance of sleep and circadian metabolic switches in Drosophila

项目摘要 睡眠不足越来越被认为是许多代谢疾病的重要风险因素， 如糖尿病、肥胖症、代谢综合征、癌症和心脏代谢紊乱。临床和模型研究 已经证实了睡眠不足对新陈代谢的负面影响。有趣的是，睡眠不足也会抑制周围神经系统的功能。 这就提出了一个问题，即代谢与睡眠的联系是否 通过昼夜节律调节。对代谢变化的时间依赖性分析显示， 在人类和其他模型系统中，代谢物池在昼夜节律过程中的振荡 例如啮齿动物和苍蝇。分子钟的破坏，无论是遗传还是通过饮食干预 如高脂肪饮食或定时限制喂养，会导致胰岛素抵抗和缺乏所谓的 “代谢灵活性”，与睡眠不足共有的表型。我们假设睡眠减少对 代谢是通过能量和氧化还原代谢途径的节律变化介导的。 在对睡眠昼夜节律代谢的机制性理解中， 连接是难以测量体内一天中不同时间的代谢通量。我们的团队开发了一个 使用果蝇（果蝇）的昼夜节律通量的创新模型。此外，饮食控制， 如活动期限时进食或限制热量，维持代谢活动的幅度， 在面对昼夜节律紊乱的周期，并已与苍蝇的心脏代谢健康。在这 建议，我们将利用D.黑腹动物来检验上述假设， 相关但独立的目标： 目标1：确定睡眠不足对代谢节律的影响。 影响：睡眠不足对代谢振荡的影响将阐明理解如何影响睡眠的方法。 昼夜节律和睡眠影响着新陈代谢，目前对这两种生理节律和睡眠都进行了独立研究。 研究目标2：确定营养挑战是否会加剧睡眠不足的代谢影响， 日具体方式。 影响：这些研究将为代谢失衡的起源提供直接的机制见解， 只是在迄今为止的研究中推断出来的。未来的药物或行为干预可以有针对性地 相应地 研究目标3：确定限时喂养是否可以减轻睡眠剥夺对新陈代谢的影响。 影响：证明饮食控制减轻了睡眠不足的负面代谢后果 具有在风险现实世界人群中进行干预的潜力。

PROJECT SUMMARY Sleep loss is increasingly recognized as a significant risk factor in numerous metabolic diseases such as diabetes, obesity, metabolic syndrome, cancer, and cardiometabolic disorders. Clinical and model studies have confirmed negative metabolic effects of sleep loss. Intriguingly, sleep loss also dampens peripheral rhythms in human populations, which raises the question of whether the metabolic-sleep connection is mediated through circadian rhythms. Time-dependent analysis of metabolic changes has revealed large-scale oscillations in metabolite pools through the course of the circadian day in humans and other model systems such as rodents and flies. Disruption of the molecular clock, either genetically or through dietary intervention such as high-fat diet or mis-timed restricted feeding, causes insulin resistance and a lack of so-called `metabolic flexibility', phenotypes shared with sleep loss. We hypothesize that effects of reduced sleep on metabolism are mediated through changes in rhythms of energetic and redox metabolic pathways. One major limitation in gleaning mechanistic understanding of the sleep-circadian-metabolism connection is difficulty in measuring metabolic flux at different times of day in vivo. Our team has developed an innovative model of circadian flux using Drosophila melanogaster (fruit fly). Furthermore, dietary manipulations, such as time-restricted feeding in the active period or caloric restriction, maintain amplitudes in metabolic cycles in face of circadian disruption and have been associated with cardio-metabolic health in flies. In this proposal, we will exploit the genetic flexibility of D. melanogaster to test the above hypothesis in the following related but independent aims:  Aim 1: Determine the impact of sleep loss on metabolic rhythms. Impact: An impact of sleep loss on metabolic oscillations will clarify the approach towards understanding how circadian rhythms and sleep, each of which is currently studied independently, affect metabolism.  Aim 2: Determine if nutritional challenge exacerbates the metabolic effects of sleep loss in a time-of- day specific manner. Impact: These studies will provide direct mechanistic insights into the origin of metabolic imbalance which has only been inferred in studies to date. Future pharmacological or behavioral interventions can be targeted accordingly.  Aim 3: Determine if time-restricted feeding can mitigate effects of sleep deprivation on metabolism. Impact: Demonstration that dietary manipulation mitigates negative metabolic consequences of sleep loss has the potential for interventional applicability in at risk real-world human populations.