Anticipation of meal time in humans

Lead Research Organisation: University of Surrey
Department Name: Biochemistry & Physiology

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

10 25 50
 
Description Nutrition Society of India (Mumbai Chapter): podcast and live video stream on "You are when you eat: Role of Chrononutrition in Metabolic Health"
Geographic Reach Asia 
Policy Influence Type Influenced training of practitioners or researchers
Impact Live talk/podcast/video stream to the Nutrition Society of India (Mumbai Chapter); attended by hundreds of nutritionists/dieticians; followed by a lengthy discussion/Q&A session in which I provided specific information and guidance to local practitioners, including how they could conduct field research/interventions on a limited budget
URL https://www.youtube.com/watch?v=41WTaEZ8SHg
 
Description Talk at UNIFESP Brazil
Geographic Reach South America 
Policy Influence Type Influenced training of practitioners or researchers
Impact Deeper, improved understanding of the links between circadian timing, restricted sleep and metabolic dysfunction.
 
Description Anticipation of meal time in humans
Amount £810,047 (GBP)
Funding ID BB/S01814X/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 08/2019 
End 09/2022
 
Description Technology Development Grant
Amount £919,761 (GBP)
Funding ID 223704/Z/21/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2022 
End 05/2024
 
Title Effect of timed meals 
Description Dataset of hormone and metabolite data before and after a 5-h shift in the timing of the meal schedule 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact Shifting the timing of the mean schedule by 5 h resulted in a mismatch between the central SCN-clock driven rhythms and the peripheral clock driven rhythms. These highly controlled laboratory data from healthy volunteers form the foundation on which to assess the effect of meals, both the timing and content, on metabolite rhythms. 
 
Description Lipidomics in constant routine study 
Organisation University of Birmingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Designed and conducted constant routine study. Collected plasma samples each hour across 33 h. The plasma samples form part of this collaboration.
Collaborator Contribution Our partners will analyse the plasma samples using their established untargeted lipidomics UPLC-MS methodology.
Impact No outputs as yet.
Start Year 2019
 
Description BBC Food web article 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Response to a media request for expert opinion on meal timing
Year(s) Of Engagement Activity 2022
URL https://www.bbc.co.uk/food/articles/eating_times
 
Description BBC Radio Surrey interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact REsponse to a media request to do a live radio interview about meal timing
Year(s) Of Engagement Activity 2021
 
Description European Academy of Neurology (EAN) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Introduced the concept of how biological rhythms may underpin neurological diseases
Year(s) Of Engagement Activity 2021
URL https://www.ean.org/congress2021
 
Description Royal Society of Medicine 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Talk at Royal Society of Medicine about adverse effects of shift work and its underlying mechanisms. Sparked questions about designing healthier shift work schedules.
Year(s) Of Engagement Activity 2021
URL https://www.rsm.ac.uk/events/respiratory-medicine/2020-21/rmp58/
 
Description Talk at University of Manchester Centre For Biological Timing 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Around 80 UK researchers attended my online Zoom talk at the University of Manchester Centre For Biological Timing.
Year(s) Of Engagement Activity 2020
 
Description UNIFESP graduate course in Chronobiology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Introduce PG and UG students at Federal University of Paraná (UFPR), Curitiba, Brazil to Chronobiology and its links to sleep and metabolism and Chrono-nutrition.
Year(s) Of Engagement Activity 2020
 
Description You and your hormones podcast 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Response to a request to provide expert opinion on the subject of meal timing in a highly regarded professional podcast series
Year(s) Of Engagement Activity 2021
URL https://www.yourhormones.info/resources/digital-library/podcasts/does-when-i-eat-affect-my-weight/