Food Entrainment of the Human Circadian Timing System

Most living organisms possess internal clocks that regulate daily (circadian) rhythms in many key biological 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. There is increasing evidence to show that abnormal timing of these clocks leads to defects in normal biology. The effects of this abnormal timing can be short lived (e.g. in jet lag) or present over a number of years (e.g. in shift workers). In the second scenario, the long term effects of abnormal rhythms is thought to be a causative factor in many industrial accidents and can lead to increased incidence of major contributors to ill health, such as heart and metabolic diseases. In order 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 light is the main synchroniser of the 'master' clock in the brain, the synchronisation of peripheral clocks is poorly understood. Evidence from animal studies suggests that the time of feeding is an important signal for peripheral clocks. However, these animal experiments have not been performed in humans because; 1) very few places in the world can perform well controlled human circadian experiments, and 2) it is difficult to obtain multiple samples of human tissue other than blood. At the University of Surrey, we have the benefit of excellent human biology facilities, experts in circadian rhythms, and experts in nutritional science. Moreover, in our recent research, we have optimised a method for taking multiple samples of fat from human volunteers. We therefore propose to conduct a set of extremely important and timely experiments to discover whether the time of feeding can regulate human clocks. 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. If food is found to be able to regulate circadian timing then this would identify novel treatment strategies that may lead to novel dietary interventions to reduce the burden of shift work and jet lag on health and performance. There has been a lot of public and media interest in both body clocks and nutrition over recent years and so this research is likely to be of broad interest. In particular, we hope to discover new scientific findings that will underpin non-drug treatment for sufferers of circadian disorders including air travellers, shift workers and the totally blind.

The mammalian circadian timing system consists of a master clock in the hypothalamic suprachiasmatic nuclei (SCN) and many other peripheral clocks throughout the body. Light is thought to be the predominant time cue (zeitgeber) for entrainment of the SCN, which is then thought to synchronise the peripheral clocks via as yet poorly defined mechanisms. One of the primary candidates for entrainment of peripheral clocks is timed feeding. It has long been known in animal experiments that temporal restriction of food availability induces various circadian changes, e.g. food anticipatory activity. Moreover, molecular studies indicate that temporal food restriction has a profound effect on the phase of peripheral clocks. However, there are very few data investigating the effect of timed feeding in humans. In this study, we will conduct two key experiments; firstly the construction of a phase response curve to food, and secondly a meal shift protocol. These experiments will for the first time test the hypothesis that timed feeding entrains human circadian clocks and will study a combination of endocrine and molecular markers of both central (SCN) and peripheral clocks. Furthermore, the second experiment will compare the relative ability of light and food to entrain central and peripheral clocks. Our ability to measure human peripheral clocks is demonstrated by our published data on leukocyte gene expression and our recent unpublished study that has pioneered the use of serial adipose biopsies in circadian biology. These experiments will provide a timely and high impact addition to the fields of chronobiology and nutrition/metabolism. Moreover, they will have clear relevance for sufferers of circadian disorders including air travellers, shift workers and the totally blind.

This project will provide impact in many key areas identified by the BBSRC; 1. Scientific advancement and supporting excellent research in the science base. The understanding of circadian physiology and its underpinning molecular biology has been an area of major development in the biosciences. It is now appreciated that circadian rhythms interact with many essential biological processes and circadian dysregulation is believed to be an important contributor to multiple disease states. One important area of circadian manipulation that is still poorly understood is how timed feeding regulates human circadian physiology. The combination of the University of Surrey's state-of-the-art facilities and our recent technical developments now permit us to undertake these key experiments. This project will therefore provide major scientific advances that will be at the cutting edge of circadian and nutritional biology. 2. Knowledge and knowledge economy. In addition to its detrimental effect on health, circadian dysregulation in shift workers is thought to reduce performance and may be an important contributor to industrial accidents. By investigating putative mechanisms to reset human circadian rhythms, our study will provide novel knowledge that has the potential to improve worker performance and therefore produce great economic benefit. 3. Training and delivering highly skilled people. We have proposed a named postdoctoral researcher in this application to maximise the efficiency of the project. Although the individual concerned has some of the key skills required to complete the work (e.g. subject recruitment, conducting human trials, data analysis), she will greatly expand her theoretical understanding of circadian biology and also learn a great deal of new practical skills. She will therefore mature into a highly trained researcher who will be able to continue her career in either academic or industrial research. 4. Policy development. The new scientific understanding that will derive from this work has great potential in the development of policy surrounding lifestyle and occupational health. For example, demonstration of the ability of timed feeding to reduce internal circadian desynchrony could inform future research and policy relating to the minimisation of the risks associated with shift work. 5. Public engagement, public health and societal issues. It is anticipated that the current application will also be of great interest to the media and public, so providing opportunity for public engagement. All of the applicants already have experience of public engagement, ranging from newspaper interviews to television appearances, and would be extremely willing to continue this work. As well as providing an interesting scientific story, the research also relates to public health and contemporary societal issues, including nutrition and energy balance. 6. International development. As many of the issues mentioned above (e.g. shift work, energy balance, and scientific advancement) are relevant internationally, the research should have wide-reaching impact both within and outside the UK.