Mechanisms in Disorders of Energy Balance

Lead Research Organisation: University of Cambridge

Abstract

We aim to understand the biological processes controlling what we eat and how we store and use energy. These pathways are disturbed in obesity and related metabolic conditions such as Type 2 diabetes. This knowledge will, ultimately, lead to development of new treatments for these disorders.

We know that an individual’s genetic make-up has a significant role in determining susceptibility to developing obesity and its deleterious consequences. Recent advances have made it substantially easier to analyse human genetic code. We aim to exploit data from human genetic studies to gain fundamental insights into what causes human obesity, and propose to combine these genetic studies with laboratory studies based around cell lines and whole animal models to better understand the pathways involved.

This programme builds on our previous work centred around a large group of patients from around the world who developed severe obesity as children and formed the basis for subsequent detailed studies on food intake and energy use. While humans will always be our experimental subject of choice, there are important mechanistic questions that require alternative approaches. We will use rodent models to explore aspects of disease processes that cannot be readily addressed in humans. Further, rodents have the advantage of being readily susceptible to genetic manipulation allowing precise alteration of specific genes and, importantly, creation of animal models of relevant, specific, human diseases.

Technical Summary

Obesity and its metabolic consequences are major threats to public health with an unmet need for improved therapy and prevention. Understanding the mechanisms involved in the control of human energy balance is essential to develop new treatments. By focusing upon a cohort of patients with severe early onset obesity, we have previously uncovered novel, highly penetrant alleles causing childhood obesity and gone on to establish the mechanisms of molecular dysfunction in many of these conditions.
Over this quinquennium our work on the biology of energy balance and its disorders will have three broad aims:
i) To continue to explore how human genetic variation that strongly predisposes to disorders of energy balance such as obesity exerts its effects at the molecular, cellular, organismal and human level and, where possible, to translate that knowledge into improved diagnosis or treatment
ii) To further understand how disruption of particular imprinted genes can lead to obesity phenotypes. This will include further exploration of the bi-stable, potentially stochastic pattern of obesity seen with loss of Nnat and the development of a murine model of PWS that exhibits hyperphagia and obesity
iii) To explore aspects of the basic biology underlying variation in leptin production and secretion, and to establish the extent to which a potentially clinically relevant phenotype of partial leptin deficiency might exist within the broader population of people with obesity

Publications

10 25 50
 
Description Mapping the human hypothalamic functional architecture underlying food intake control
Amount £625,065 (GBP)
Funding ID BB/S017593/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 07/2019 
End 06/2022
 
Description Molecular characterization in human neurons of genes associated with severe obesity identified from consanguineous pedigrees.
Amount £1,014,003 (GBP)
Funding ID MR/S026193/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2019 
End 09/2022
 
Description SOR - Bei Zhang and Kendra Bence, Pfizer Boston 
Organisation Pfizer Global R & D
Country United States 
Sector Private 
PI Contribution Collaboration
Collaborator Contribution Collaboration
Impact N/A
Start Year 2018
 
Description SOR - Bristol MC4R 
Organisation University of Bristol
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaborative exchange
Collaborator Contribution Collaborative exchange
Impact N/A
Start Year 2019
 
Description SOR - Ghent 
Organisation University of Ghent
Country Belgium 
Sector Academic/University 
PI Contribution Collaboration
Collaborator Contribution Collaboration
Impact N/A
Start Year 2019
 
Description SOR - Novo 
Organisation Novo Nordisk Foundation
Country Denmark 
Sector Charity/Non Profit 
PI Contribution Collaboration
Collaborator Contribution Collaboration
Impact N/A
Start Year 2018
 
Description collaboration with Anne White and team to understand role of hypthothalmic Agrp in development of glucocorticoid induced metabolic complications 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution intellecula input into study design and data analysis
Collaborator Contribution funding and undertaking mouse work
Impact series of manuscripts published
Start Year 2014
 
Description collaboration with colleagues in CRUK to better define metabolic problems in pancreatic cancer 
Organisation Cancer Research UK
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution intellectual l input into the design and concepts of a clinical study to look to better characterise energy balance and hormoneal milieu in patients with pancreatic cancer
Collaborator Contribution study design and study delivery
Impact still undergoing set up and ethical review- likely to be active in 2020
Start Year 2017
 
Description BBC2 programme 'Who Are You Calling Fat?' - Expert 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact In a 'fly on the wall' primetime programme on BBC2, nine people who live with obesity, or who choose to call themselves fat, move in together to explore what it means to be larger bodied in Britain today. I appeared on the second episode to offer my expert opinion on the role of genetics on obesity. 3 million live viewers
Year(s) Of Engagement Activity 2019
URL https://www.bbc.co.uk/programmes/m0009tvl
 
Description Genetics Society 2019 JBS Haldane Award Lecture 
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 This lecture 'Is Obesity A Choice?' took place at the Royal Institution in London on November 1, 2019. There were 300 people in the audience. The lecture was recorded and uploaded onto the Royal Institution YouTube Channel, where it has (as of Feb 27, 2020) been viewed 26,088 times.
Year(s) Of Engagement Activity 2019
URL https://www.youtube.com/watch?v=88tWJ1p5d4o
 
Description Interview on Scandinavian Talk Show 'Skavlan' 
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 This was an interview on Scandinavia's largest talkshow 'Skavlan', which broadcasts to Sweden, Norway and Finland. Each episode has more than 2 million live viewers.
Year(s) Of Engagement Activity 2020
URL https://www.youtube.com/watch?v=tqXccq2jLkc
 
Description Neuronal Control of Metabolism symposium, 12th February 2020 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact outline of role of GDF15 in control of food intake and how this knowledge may affect drug design in the future
Year(s) Of Engagement Activity 2020
 
Description SOR - Academy of Medical Sciences Fellows Event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact Invited by Regional Champion of Academy of Medical Sciences to give keynote lecture at Fellows' event which was combined with THIS (The Healthcare Improvement Studies) Institute in Cambridge. The event was an opportunity for early and mid career researchers to present their work and to network with the fellows and peers and bring the East Anglia fellows together.
Year(s) Of Engagement Activity 2018
 
Description SOR - EMBO Basel Life mtg, Switzerland 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Invited to speak at EMBO Basel Life meeting on "Molecules in Biology and Medicine". A new EMBO meeting which is intended to combine general and medical biology. This meeting is a joint initiative of EMBO and a newly founded, not-for-profit organization, the European Association for Life Sciences. The scientific advisory committee envisions a top level, broad scope meeting and aims to establish it as one of the premier meetings in the life sciences. The meeting was held in conjunction with Basel Life Science Week.
Year(s) Of Engagement Activity 2018
 
Description SOR - Helmholtz conference, Munich (2018) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Plenary speaker at 6th annual Helmholtz Diabetes Conference, Munich. Helmholtz Zentrum München and Nature Medicine have combined forces to organize this annual high-impact conference series now for the sixth time. At this meeting, international top scientists interact to facilitate the identification of, and potential solutions to, the preeminent scientific challenges facing the prevention and treatment of diabetes. For this 6th conference, the main focus will be on the role of the brain in metabolic control.
Year(s) Of Engagement Activity 2018
URL https://www.hd-conference.com/about-the-conference/index.html
 
Description SOR - ICE Cape Town 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Plenary speaker at International Congress of Endocrinology (ICE), Cape Town, South Africa which was held in conjunction with SEMDSA, the Society for Endocrinology,  Metabolism and Diabetes of Southern Africa. ICE is the premier global scientific gathering for endocrinology.
Year(s) Of Engagement Activity 2018
URL http://www.ice2018.org/
 
Description SOR - Italian Debate for Endocrinology Experts (IDEE), Rome 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Invited to give plenary lecture given involvement with 100K Genomes UK project at "Italian Debate for Endocrinology Experts 2018" meeting in Rome for Italian delegates. All speakers international.
Year(s) Of Engagement Activity 2018
 
Description SOR - MTB Zurich 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Invited as keynote speaker to give a talk at the annual retreat of the PhD Programme in Molecular and Translational Biomedicine (MTB), University of Zurich, Switzerland
Year(s) Of Engagement Activity 2018
 
Description SOR - Manchester Literary and Philosophical Society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Invited by Science and Technology Committee of the The Manchester Literary and Philosophical Society, which was founded in 1781, to give a talk.
Year(s) Of Engagement Activity 2018
URL http://www.manlitphil.ac.uk
 
Description SOR - Medical Alumni Biennial Lecture, St Andrews 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Invited guest speaker at Medical Alumni Biennial Lecture at University of St Andrews, Fife
Year(s) Of Engagement Activity 2018
 
Description SOR - Milner Therapeutics Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Invited speaker at Milner Therapeutics Symposium which is a one day event, with speakers from Academia and Pharma/Biotech.
#MilnerSymp18
Year(s) Of Engagement Activity 2018
 
Description SOR - NIH OxCam Workshop, Cambridge 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Invited to give keynote talk at the annual NIH OxCam Workshop held at Homerton College, Cambridge - a 3 day meeting that brings together supervisors and students from the NIH-OxCam PhD programme.
Year(s) Of Engagement Activity 2018
 
Description SOR - NOVA filming 
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 Filming at PBS/NOVA in Boston, USA. Documentary on the science of fat and obesity. Due to air on US TV as "The truth about fat" on 8.4.2020.
Year(s) Of Engagement Activity 2019
 
Description SOR - Oxford Metabolic Health symposium, Oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Invited to give keynote talk at Oxford Metabolic Health's inaugural symposium - a new cross-divisional and interdepartmental initiative at the University of Oxford that aims to bring together researchers with an interest in metabolism in its broadest sense, encourage interaction and exchange of ideas, and identify new strategic opportunities.
Year(s) Of Engagement Activity 2018
 
Description SOR - SGC TEP Symposium, Oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Invited to give keynote lecture at SGC (Structural Genomics Consortium) University of Oxford TEP 2018 Symposium on 'Exploiting disease genomics to catalyse new medicines'- serving as an opportunity to bring together collaborators, funders, and partners alike to share the vision of the TEP concept for drug discovery.
Year(s) Of Engagement Activity 2018
URL https://www.thesgc.org/tep-symposium-2018
 
Description SOR - Science Festival talk March 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Talk entitled 'Science of Fat' given at Peterhouse College, Cambridge as part of the Cambridge Science Festival
Year(s) Of Engagement Activity 2018
 
Description SOR - Sick Film 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Filming of Sick Film (hyperemesis gravidarum) for production company Good Guys Productions Ltd - filming intended for conferences, training, etc and potentially for use as part of TV production.
Year(s) Of Engagement Activity 2019
 
Description SOR - SpR training, Addenbrooke's Hospital 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other audiences
Results and Impact Talk for Regional SpR diabetes and endocrine training day, Addenbrooke's Hospital, Cambridge
Year(s) Of Engagement Activity 2018
 
Description SOR - TV (BBC Look east) interview May 2019 
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 Media (as a channel to the public)
Results and Impact Interviewed in relation to research on hyperemesis gravidarum (HG) - was shown on BBC Look East and the interview was syndicated across BBC news and used on radio
Year(s) Of Engagement Activity 2019
 
Description SOR - Talk at Harvard Medical School, USA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Invited speaker at Dr Jeffrey Flier's 70th symposium at Harvard Medical School, USA. Dr Flier was 21st Dean of the Faculty of Medicine at Harvard University for 9 years. He is also an endocrinologist and an authority on the molecular causes of obesity and diabetes and previously served as Harvard Medical School Faculty Dean for Academic Programs and Chief Academic Officer for Beth Israel Deaconess Medical Center, a Harvard teaching affiliate. He is one of the country's leading investigators in the areas of obesity and diabetes. His research has produced major insights into the molecular mechanism of insulin action, the molecular mechanisms of insulin resistance in human disease, and the molecular pathophysiology of obesity.
Year(s) Of Engagement Activity 2018
 
Description SOR - WT Researcher meeting, Hinxton 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Annual presentation of work undertaken as a Wellcome Trust funding holder
Year(s) Of Engagement Activity 2018
 
Description SOR - iBiology talk 
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 Other audiences
Results and Impact Recording talks for iBiology (www.ibiology.org), a science communication project funded by NSF/NIH and supported by the Lasker Foundation, EMBO and HHMI (recorded locally at Cambridge TV).
Year(s) Of Engagement Activity 2019
URL https://www.ibiology.org/human-disease/obesity/
 
Description SOR - radio Europe interview Apr 2018 
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 on Talk Radio Europe Lifestyle Show about lipodystrophy
Year(s) Of Engagement Activity 2018
 
Description SOR 61st Annual meeting of German Endocrine Society, Bonn, Germany 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Gave plenary lecture
Year(s) Of Engagement Activity 2018
URL http://www.dge2018.de/programm.html
 
Description SOR Cambridge Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Gave a talk 'Science of fat' at the annual Cambridge Science Festival
Year(s) Of Engagement Activity 2018
URL https://www.sciencefestival.cam.ac.uk/
 
Description SOR Life Sciences Seminar Series, University in Brno, Czech Republic 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Invited to give a talk in the Life Sciences Seminar Series in Masaryk, University in Brno, Czech Republic
Year(s) Of Engagement Activity 2018
 
Description innvited talk to Diabetes UK annual professional conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact able to share our data with colleagues and clinicians from across the UK
Year(s) Of Engagement Activity 2019
 
Description seminar to Institute of Metabolic Science in Aberdeen 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact engaged with scientists in another centre of metabolic excellence to share ideas around common research interests
Year(s) Of Engagement Activity 2018