Anticipation of meal time in humans

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 (e.g. in liver, pancreas and fat). 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 long-term health.

The time of feeding is an important signal for synchronising peripheral clocks in animals and we have recently shown for the first time that some human rhythms (e.g. of glucose control) are also synchronised by meal timing. It is also apparent from animal studies that internal clocks are essential to be able to anticipate meal timing. However, the underlying metabolic pathways involved in this meal anticipation occurs is not fully understood. Furthermore, no experiments on meal anticipation have been performed in humans, in part because very few places in the world can perform well-controlled human circadian experiments. In addition, technological advances have only recently enabled large-scale high-resolution analysis of multiple rhythmic metabolic pathways in a single set of experimental samples.

At the University of Surrey, we have the benefit of world class human biology facilities, experts in circadian rhythms, and experts in nutritional science. Through our recent research, we have become world leaders in the analysis of metabolite rhythms in samples from human volunteers using state-of-the-art technology called metabolomics. Importantly, we have also produced preliminary information that shows the ability of human metabolism to anticipate a regularly administered meal. We therefore propose to build upon our preliminary data by conducting an extremely timely experiment to discover exactly how meal time is anticipated by human biology.

Understanding the processes underlying food anticipation will answer a fundamental question in human physiology, with a (wide ranging) impact on weight balance and metabolic health. This knowledge will ultimately help scientists and clinicians to design better dietary strategies to regulate body weight and improve metabolic health.

Circadian food anticipation has been described in animal species, but no experiments on meal anticipation have been performed in humans. We will test the hypothesis that repeated exposure to a single large meal at the same time each day will result in circadian anticipatory changes in the pre-prandial time points in the absence of any meal pattern. We will recruit 24 healthy volunteers (12 males/12 females) and bring them into our Clinical Research Centre for 8 days. Prior to the laboratory phase, participants will adhere to a regular sleep-wake and meal pattern to ensure good synchronisation of their biological rhythms. In the laboratory, we will apply a parallel design. Half the participants will be given a single, large, daily meal comprising 50% of their habitual daily energy intake, with the other 50% intake evenly spread over 16, once-hourly, equal snacks in the wake period. The other half of the participants will not receive any main meal but will instead ingest the full 100% of their energy intake in these 16, once-hourly snacks.

After 6 days, all participants will undergo a 37-hour 'constant routine' protocol that enables measurement of endogenous human circadian rhythms. Blood samples will be collected every 30 minutes over 28 hours (hours 4 to 31) for analysis, capturing both the first and second clock time at which a meal is anticipated. High-resolution time courses of 183 known plasma metabolites will be determined using our established, in-house UPLC-MS/MS metabolomics approach. Other measures will include melatonin, markers related to glucose homeostasis (e.g. glucose, insulin, c-peptide, cortisol), and appetite. We will also acquire continuous measurements of interstitial glucose (via continuous glucose monitors), skin temperature (via i-buttons), wrist actigraphy (via Actiwatches) and heart rate variability. The deliverables generated in this state-of-the-art study will for the first time expose food anticipation in humans.

The proposal will have an immediate impact through the advancement of basic science and its dissemination to the public via the media, which has great interest in topics related to nutrition and chronobiology. The longer-term wider impact will stem from healthcare professionals, the food industry and policy makers and is hoped to contribute to improvement of human health.



Scientific Knowledge Base and Academic Beneficiaries

Biological rhythms are critical to everyday life and disruption of the 24-hour circadian system, for example, is associated with many disorders and diseases. The generation of publicly available datasets of circadian metabolite profiling (metabolomics), and the metabolic pathways specifically driven by food-entrainment will allow the wider research community to identify whether their research areas are impacted by anticipation and timing of these biological processes. All datasets, analytical tools and biobanked plasma/tissue samples will be made publically available after publication of the initial findings as described in the pathways to impact section.

The unique deliverables of this proposal, all of which are novel, will be of substantial benefit to the advancement in these fields of chronobiology, metabolism, signal processing and systems biology. Particular value be in the area of biological timing and metabolism, as our research will fill a critical gap in our knowledge. One of the main impacts of the proposed research will be the precise characterisation of pre-prandial food anticipatory changes in the human metabolome. Understanding the (underlying) physiological mechanisms and temporal dynamics of food anticipation in humans will lead to the need to explore how pre-prandial food anticipation regulates metabolism and nutritional physiology in the real world.

Benefit of the research will also be found in other disciplines. Biological rhythms research has moved from a specific discipline into a research area cutting across a wide range of bioscience and medical disciplines. Circadian timing of biological processes such as metabolism, cognitive performance, endocrine biology, and cancer is now widely recognised, and there is persuasive evidence that circadian rhythmicity is important for human health and well-being. The generated high-resolution metabolomics datasets will be made publicly available. The control group in which there is no large meal in the 6 days before sample collection will itself be of value and generate novel insights into the relevance of biological rhythms in human metabolism.





Health and Well-being of the Public

The Health and Safety Executive and the Office of National Statistics estimate that almost 15% of the UK working population regularly works shifts, which is associated with known metabolic health risks such as obesity, diabetes that have a huge and increasing cost in today's 24/7 society. Although it is currently unclear how abnormal feeding times, as occurs in shift workers, and the associated mistimed food anticipatory responses contribute to these metabolic disorders, characterising the metabolic pathways involved in food anticipation will be an important first step.

We anticipate continued public interest in our research, via media work that all three Investigators are regularly involved in. The longer term health benefits will derive from interactions between the research team, healthcare professionals, the food industry and policy makers.