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Balance of sleep and circadian metabolic switches in Drosophila

果蝇的睡眠平衡和昼夜代谢开关

基本信息

批准号：
10407604
负责人：
AMITA SEHGAL
金额：
$ 50.59万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10407604
关键词：
Address Affect Behavior Therapy Biological Models Bolus Infusion Caloric Restriction Carbon Dioxide Cardiometabolic Disease Cells Circadian Dysregulation Circadian Rhythms Clinical Clinical Research Data Desegregation Diabetes Mellitus Dietary Intervention Drosophila genus Drosophila melanogaster Electronics Energy Intake Equilibrium Face Future Generations Genetic Glean Glucose Health High Fat Diet Human Impairment Injections Insulin Resistance Intervention Jet Lag Syndrome Label Light Link Lipids Malignant Neoplasms Mass Spectrum Analysis Measures Mechanics Mediating Metabolic Metabolic Diseases Metabolic Marker Metabolic Pathway Metabolic syndrome Metabolism Methods Modeling Molecular Mus Neurons Neurotransmitters Nutrient Nutritional Obesity Oxidation-Reduction Oxidative Stress Pathway Pathway interactions Peripheral Pharmacology Phenotype Physiological Population Research Resolution Risk Risk Factors Rodent Rodent Model Sleep Sleep Deprivation Sleeplessness Standardization Stress Study models System Testing Time Time-restricted feeding Tracer Transcript Unhealthy Diet Work cardiometabolism circadian dietary manipulation dietary restriction experimental study feeding flexibility fly in vivo innovation insight insulin signaling metabolic abnormality assessment metabolic rate molecular clock mutant neurochemistry response shift work temporal measurement

项目摘要

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.

项目总结睡眠不足日益被认为是许多代谢性疾病的重要风险因素，如如糖尿病、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。耐人寻味的是，睡眠不足也会抑制外设人类群体的节律，这引发了代谢-睡眠联系是否通过昼夜节律调节。对代谢变化的时间依赖分析揭示了大规模的人体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。通过基因或饮食干预扰乱分子时钟如高脂肪饮食或不适当的限制喂养，会导致胰岛素抵抗和缺乏所谓的 “新陈代谢灵活性”，这一表型与睡眠不足有共同之处。我们假设睡眠减少对新陈代谢是通过能量代谢途径和氧化还原代谢途径的节律变化来调节的。收集睡眠-昼夜节律-新陈代谢机制方面的一个主要限制在活体内测量一天中不同时间的代谢流量时，连接是困难的。我们的团队已经开发出一种利用果蝇(果蝇)研究昼夜节律通量的创新模型。此外，饮食控制，如在活动期限时喂食或限制热量摄入，保持代谢的幅度面对昼夜节律紊乱的循环，并与果蝇的心脏新陈代谢健康有关。在这建议，我们将利用黑腹小球藻的遗传灵活性在以下几个方面验证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澄清理解如何目前独立研究的昼夜节律和睡眠都会影响新陈代谢。 目标2：确定营养挑战是否会在一段时间内加剧睡眠不足的代谢影响特定日期的方式。影响：这些研究将为代谢失衡的起源提供直接的机械性见解只有在迄今为止的研究中才能推断出来。未来的药物或行为干预可以有针对性相应地。 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：证明饮食控制可以减轻睡眠不足带来的负面代谢后果有可能对处于危险中的真实世界的人类人群进行干预。