Meal timing and energy restriction as regulators of central and peripheral human rhythms

大多数生物体内都有生物钟来调节许多关键生理功能（如激素分泌、睡眠时间、新陈代谢）的昼夜节律。包括人类在内的哺乳动物的昼夜节律系统由一个位于大脑下丘脑的“主”时钟和许多遍布全身的“外围”时钟（例如肝脏、胰腺和脂肪组织）组成。越来越多的证据表明，许多生物钟在调节我们的新陈代谢方面发挥着重要作用，包括我们对一天中不同时间进餐的反应。这项工作非常重要，因为它开始解释吃饭时间（不仅仅是食物种类和数量）是如何影响我们的体重和长期健康的。为了使我们的生物钟与外部环境的变化相匹配，它们是由各种环境时间线索同步的。虽然众所周知，光/暗周期是大脑中“主”时钟的主要同步器，但其他信号对于同步整个身体的时钟也很重要。摄食时间是动物外周生物钟同步的重要信号。我们最近首次表明，一些人类节律（例如葡萄糖浓度）与进餐时间同步，甚至可以预测有规律的大餐。负能量平衡（消耗的能量少于身体基本代谢所需的能量）也会改变啮齿动物大脑中的“主”时钟。然而，主要未解决的问题包括：1)哪种膳食提供了人类主要的同步信号，以及2)负能量平衡如何影响进餐时间对人类昼夜节律生物学的影响。这些问题很重要，因为它们将使我们能够设计有效的用餐时间策略，以最好地帮助数百万因昼夜节律系统紊乱而受到疾病影响的人。这些人包括轮班工人、时差患者和盲人。世界上很少有地方可以进行控制良好的人类昼夜节律实验。在萨里大学，我们拥有世界领先的人类临床设施，以及昼夜节律和营养科学方面的专家。通过我们最近的研究，我们在时间营养（用餐时间的影响）和使用称为代谢组学的最先进技术分析人类志愿者样本中的代谢物节律领域已经成为世界领先者。因此，我们建议在我们最近成功的基础上，进行非常及时的实验，以增强我们对进餐时间如何调节人类昼夜节律和代谢生理的理解。这项工作的结果将对科学家和公众产生重要影响。科学家们将学到关于生物钟基本生物学的重要新信息，以及它们是如何受到食物时间和能量平衡的调节的。我们的工作将为设计新的饮食干预措施提供重大推动，以减轻轮班工作的负担和时差对健康的不良影响（肥胖、2型糖尿病、心血管疾病）。我们最近的研究受到了广泛的媒体和公众的关注，所以这个项目的结果很可能会引起广泛的关注。我们尤其希望发现新的科学发现，为使用定时进餐方法治疗包括航空旅客、轮班工人和全盲患者在内的昼夜节律紊乱患者提供支持。

Most living organisms possess internal biological clocks that regulate daily (circadian) rhythms in many key physiological functions (e.g. hormone secretion, sleep time, metabolism). The circadian timing system in mammals, including humans, consists of a 'master' clock within a part of the brain called the hypothalamus and many 'peripheral' clocks found throughout the body (e.g. in liver, pancreas and fat tissue). There is increasing evidence to show that many of these clocks play an important role in timing our metabolism, including how we respond to meals eaten at different times of day. This work is extremely important as it is beginning to explain how meal timing (not just food type and quantity) influences our body weight and long-term health.For our internal clocks to be matched to external changes in the environment, they are synchronised by various environmental time cues. Although it is known that the light/dark cycle is the main synchroniser of the 'master' clock in the brain, other signals are important for synchronising clocks throughout the body. The time of feeding is an important signal for synchronising peripheral clocks in animals. We have recently shown for the first time that some human rhythms (e.g. of glucose concentration) are synchronised by meal timing and can even anticipate regular large meals. The condition of negative energy balance (consuming less energy than is needed for the body's basic metabolic needs) also shifts the 'master' clock in the brain of rodents. However, major unanswered questions include: 1) which meal provides the main synchronising signal in humans, and 2) how does negative energy balance affect the influence of meal timing on human circadian biology.These questions are important as they will enable us to design effective meal timing strategies to best help the millions of people who are subject to disorders caused by a disorganised circadian system. Such individuals include shift workers, people experiencing jet-lag and the blind.Very few places in the world can perform well-controlled human circadian experiments. At the University of Surrey, we have the benefit of world leading human clinical facilities, plus experts in circadian rhythms and nutritional science. Through our recent research, we have become world leaders in the field of chrono-nutrition (effect of meal timing) and the analysis of metabolite rhythms in samples from human volunteers using state-of-the-art technology called metabolomics. We therefore propose to build upon our recent successes by conducting extremely timely experiments to enhance our understanding of how meal timing can regulate human circadian rhythms and metabolic physiology.The results of the work will have important implications for scientists and the public. Scientists will learn crucial new information about the basic biology of body clocks and how they are regulated by food timing and energy balance. Our work will provide a major boost to the design of novel dietary interventions to reduce the burden of shift work and jet lag on adverse health consequences (obesity, Type 2 diabetes, cardiovascular disease). Our recent research has received extensive media and public interest, so results from this project are highly likely to be of broad interest. In particular, we hope to discover new scientific findings that will underpin the use of timed meal approaches to treat sufferers of circadian disorders including air travellers, shift workers and the totally blind.