Food Entrainment of the Human Circadian Timing System

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. 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.

Technical Summary

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.

Planned Impact

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.
 
Description What were the most significant achievements from the grant?

1. Novel scientific findings. We've provided detailed analysis of the effects of feeding time on multiple aspects of human physiology including; hormone rhythms, gene expression in different tissues, subjective appetite/behavioural scores. These data should be published during 2015 and are anticipated to make a major contribution to the literature. **UPDATE** We demonstrated in a 2017 Current Biology paper that meal timing is a powerful signal that sets daily rhythms of blood sugar control. **UPDATE 2** Major new outputs (2017 PNAS, 2018 eLife) reporting rhythms of human muscle transcriptome/lipidome, via international collaboration, and (2019 Scientific Reports) reporting circadian transcriptome in human adipose tissue.

2. Development of novel collaborations with industrial and academic colleagues. I have been involved in a series of meetings with colleagues at Kellogg and multiple universities. This has lead to a collaborative experiment with one of the academic partners and consultancy work with Kellogg. I am actively pursuing further links with these individuals.

3. Experience of research management. Although I had previously run smaller human trials and been a co-Investigator on large human studies, this was the first large human study on which I've been PI. The process has been challenging and also rewarding, as I have learnt a huge amount and the experience gained will greatly help me to run future projects.

4. New technical skills in the laboratory. Completion of the project required successful implementation of experimental methods that were new to me and other members of the team. These included measurements that were not included in the original grant proposal, e.g. temperature, interstitial glucose and subjective questionnaire data.

5. Follow-on funding. The project has directly enabled me to obtain a new funded PhD studentship and explore funding links with industrial partners. I anticipate that publication of the data will also greatly assist future funding applications.

6. Production of software to aid diet design. At the start of the study, we produced new software to enable design of controlled diets tailored to individual needs in a long-term residential study. This software has already been used by two other Surrey studies and will be made freely available as an attachment to a publication.



To what extent were the grant objectives met?

The main objectives of the grant were;
1. Construct a Phase Response Curve (PRC) to timed feeding in humans.
2. Investigate the effect of a 6-hour shift in meal times on central and peripheral circadian rhythms.

Laboratory work for both objectives is now complete and we are completing final data analysis before publication of the resulting papers. I have deliberately delayed publication in a strategic move to ensure that the core papers from the grant are as comprehensive as possible and thus achieve greatest scientific impact.

In addition to the main objectives described above, we have produced many other data and/or outputs that will be made available in the near future. These include the diet design software mentioned above, detailed physiological characterisation of an 'ultradian routine' protocol, addition of data sets not described in the original grant proposal (see 'new technical skills in the laboratory' above) and the ability to extend other aspects of the project via the associated PhD studentship.
Exploitation Route How might the findings be taken forward and by whom?

The scientific field linking circadian rhythms and sleep physiology with metabolism and nutrition is an extremely active and topical area of international research. The scientific outputs of this study will therefore be of immense interest to many research groups around the world. This interest will in part be stimulated by recent presentations by me and members of the research team, in addition to future presentations that I have been invited to give at major conferences in e.g. Boston and Edinburgh.

The timeliness of the work also makes it very popular with the media and I will ensure that media coverage of forthcoming outputs is maximised via our University's Media Relations team and other vehicles, such as the Science Media Centre.

Finally, the work is demonstrably of great interest to the food industry, as demonstrated by my existing links with Kellogg and possible future links with Nestle and smaller research institutions. I will explore these industrial opportunities with existing contacts and also by collaboration with nutritional scientists at Surrey and potentially elsewhere.
Sectors Agriculture, Food and Drink,Education,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description My research into the concept of timed feeding (chrononutrition) resulted in a major contribution to a recent BBC television programme, Trust Me I'm A Doctor (series 4, episode 2) and BBC iWonder web page. As a result of a major publication in 2017, I was interviewed by multiple national and international (e.g. from USA, Canada, Brazil, Spain) media agencies. The work was reported by 43 different news agencies, according to Altmetric (overall Altmetric score > 500). I have also been invited to speak at a meeting of the UK 'Nutritionists in Industry' group. **UPDATE** I have also written a related article for The Conversation that has been read over 500,000 times.
First Year Of Impact 2017
Sector Agriculture, Food and Drink,Education,Culture, Heritage, Museums and Collections,Other
Impact Types Cultural,Societal

 
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 PhD studentship
Amount £80,000 (GBP)
Funding ID BB/J014451/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2012 
End 09/2016
 
Description Population and systems medicine
Amount £787,221 (GBP)
Funding ID MR/P012205/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 05/2017 
End 04/2020
 
Title Adipose biopsy 
Description Working with the medical team at the Surrey Clinical Research Centre, we modified existing biopsy procedures to enable multiple (up to 16 in a month) biopsies to be taken from the upper gluteal region of an individual. The method produces much less bruising than common needle punch methods and involves small incisions per biopsy to reduce chances of scarring and speed up healing. 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact The novel ability to take repeated serial biopsies from an individual and thus derive temporal profiles of molecular state of a human metabolic tissue. 
 
Title Human adipose transcriptome 
Description Novel transcriptomic data set from serial biopsies of human adipose tissue collected during a highly specialised circadian biology protocol. 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact None yet. A manuscript is under publication and the data will be made freely available immediately after publication. 
URL https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE87761
 
Description Collaboration with Dr James Betts 
Organisation University of Bath
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual input into experimental design and conduct; endocrine assays; input into molecular assays
Collaborator Contribution conduct of the experiment; molecular assays
Impact none yet, although there may be industrial input to expand upon the initially planned analyses
Start Year 2014
 
Description Collaboration with Nestle and University of Geneva 
Organisation Nestlé (Global)
Department Société des Produits Nestlé SA
Country Switzerland 
Sector Private 
PI Contribution Scientific expertise; provision of valuable tissue samples
Collaborator Contribution Analytical expertise and man-power; specialist laboratory analysis
Impact 1. Publication by Loizides-Mangold et al (2017) in PNAS. Collaboration also involved University of Bath (Dr James Betts). 2. Invited seminar at Nestle.
Start Year 2015
 
Description Collaboration with Nestle and University of Geneva 
Organisation University of Geneva
Country Switzerland 
Sector Academic/University 
PI Contribution Scientific expertise; provision of valuable tissue samples
Collaborator Contribution Analytical expertise and man-power; specialist laboratory analysis
Impact 1. Publication by Loizides-Mangold et al (2017) in PNAS. Collaboration also involved University of Bath (Dr James Betts). 2. Invited seminar at Nestle.
Start Year 2015
 
Description Engagement with Kellogg 
Organisation Kellogg's
Country United States 
Sector Private 
PI Contribution consultancy work in the area of circadian control of metabolism
Collaborator Contribution payment for consultancy work; ongoing discussions to identify possible areas of future research that would likely be funded in whole by the company
Impact consultancy report
Start Year 2012
 
Description Engagement with Nestle and University of Bath 
Organisation Nestlé (Global)
Department Société des Produits Nestlé SA
Country Switzerland 
Sector Private 
PI Contribution I provided the major intellectual contribution to the design of a collaborative study run at Bath. Some sample analysis was also conducted at Surrey. Together with the Bath lead investigator, I am providing intellectual input to the analysis of samples that have been shipped to Nestle for -omic analyses.
Collaborator Contribution University of Bath ran our joint study and performed some sample analysis. Nestle are conducting large scale -omic analyses that are fully funded by the company.
Impact No outputs are yet available, although conference abstracts have recently been submitted and at least 1 major publication should be published in 2016. It is hoped that opportunities for industry funded research will emerge in the near future. The collaboration is multi-disciplinary involving; human physiology, transcriptomics, lipidomics and bioinformatics.
Start Year 2014
 
Description Engagement with Nestle and University of Bath 
Organisation University of Bath
Country United Kingdom 
Sector Academic/University 
PI Contribution I provided the major intellectual contribution to the design of a collaborative study run at Bath. Some sample analysis was also conducted at Surrey. Together with the Bath lead investigator, I am providing intellectual input to the analysis of samples that have been shipped to Nestle for -omic analyses.
Collaborator Contribution University of Bath ran our joint study and performed some sample analysis. Nestle are conducting large scale -omic analyses that are fully funded by the company.
Impact No outputs are yet available, although conference abstracts have recently been submitted and at least 1 major publication should be published in 2016. It is hoped that opportunities for industry funded research will emerge in the near future. The collaboration is multi-disciplinary involving; human physiology, transcriptomics, lipidomics and bioinformatics.
Start Year 2014
 
Title Adipose biopsies 
Description Bespoke forceps were designed by the lead clinical at the Surrey Clinical Research Centre for the purpose of taking repeated adipose biopsies (see section on new research methods for detail) 
Type Therapeutic Intervention - Medical Devices
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2012
Development Status Closed
Impact n/a 
 
Title Diet design software 
Description Software/macro in Excel to enable design of controlled diets for long-term residential laboratory studies. NB We have explored the possibility of filing IP on this product. However, our IP team don't consider there to be a significantly large market available to warrant commercialisation. We will therefore make the resource freely available as downloadable content associated with a forthcoming research paper. 
Type Of Technology Software 
Year Produced 2012 
Impact It has already been used by two other large studies at the Surrey Clinical Research Centre, including BBSRC grant BB/I019405/1. 
 
Description BBC News website 
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 Provision of information to the public; possible increase in study volunteers due to increased exposure of the research area

The story has been mentioned by journalists who've subsequently contacted me and so has presumably increased the interest in me as a potential science communicator, in addition to the work itself.
Year(s) Of Engagement Activity 2011
URL http://www.bbc.co.uk/news/uk-england-surrey-14716475
 
Description BBC Television: Trust Me I'm A Doctor (series 4, episode 2) 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Based on my expertise from BBSRC-funded research on the subject of timed feeding, I was asked to run a 'big experiment' and two smaller demonstration experiments for the BBC's Trust Me I'm A Doctor television programme. The programme (series 4, episode 2) was first aired on BBC2 in January 2016. The build-up work spanned the previous 12 months. I have received a number of emails from members of the public as a result of the work, and will use the data as the basis for a research paper and 1-2 research grant applications.
Year(s) Of Engagement Activity 2015,2016
URL http://www.bbc.co.uk/programmes/articles/zBx3JZJCKfNBrWgT0Qyj93/the-big-experiment-could-i-lose-fat-...
 
Description BBC iWonder website 
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 Two of my PhD students (one of whom is BBSRC-funded) and I worked with the BBC to develop an interactive web site relating to my BBSRC-funded research in timed feeding.
Year(s) Of Engagement Activity 2015,2016
URL http://www.bbc.co.uk/guides/zyd34j6
 
Description Interview for BBC Radio Surrey 
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 Interview based upon results of Current Biology paper
Year(s) Of Engagement Activity 2017
 
Description Interview for national/international science broadcaster (Naked Scientists) 
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 Interview for Naked Scientists radio programme and podcast
Year(s) Of Engagement Activity 2017
 
Description Open days - University of Surrey 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Students and parents were extremely appreciative of the opportunity to talk to an academic member of staff about undergraduate study, professional training etc

There was very good feedback on the value of the events
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012,2013,2014,2015,2016
 
Description Press release for 2017 Current Biology paper 
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 Media (as a channel to the public)
Results and Impact Over 40 international and national news outlets picked up the story and the overall Altmetric score is > 500.
Year(s) Of Engagement Activity 2017
URL https://www.surrey.ac.uk/mediacentre/press/2018/delaying-meals-impacts-sugar-levels-body
 
Description Press release for 2019 Scientific Reports paper 
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 Media (as a channel to the public)
Results and Impact Over 10 international news outlets have currently picked up the story, with an overall Altmetric score currently at > 130 (within 1 week of publication).
Year(s) Of Engagement Activity 2019
URL https://www.surrey.ac.uk/news/fat-cells-work-different-shifts-throughout-day
 
Description Radio interview for Talk Radio Europe 
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 Interview about recent Current Biology paper
Year(s) Of Engagement Activity 2017
 
Description Telegraph interview - jet lag 
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 Provision of expert opinion about a topical media story

No obvious impacts to me personally
Year(s) Of Engagement Activity 2013
URL http://www.telegraph.co.uk/science/science-news/10409645/Brain-chemical-helps-beat-jet-lag.html
 
Description Video interview - Kellogg/NutSoc 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Strengthening of working relationship with Kellogg; discussion was generated at the meeting where the interview took place
Year(s) Of Engagement Activity 2012
URL https://www.youtube.com/watch?v=K-7aPvtKs14
 
Description Written article for The Conversation 
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 Written article based on 2017 Current Biology research paper. Over 500,000 reads logged.
Year(s) Of Engagement Activity 2017
URL https://theconversation.com/changing-your-meal-times-could-help-you-beat-jet-lag-and-shift-work-7906...