Molecular and pathophysiological mechanisms in human obesity

Lead Research Organisation: University of Cambridge
Department Name: Clinical Biochemistry

Abstract

Obesity is an important medical problem as it can lead to early death from diabetes, heart attacks and strokes and also causes considerable chronic ill health and a lowered quality of life. While it is clear that the reasons behind the recent increase in the frequency of obesity in most populations must lie in changes in factors such as the availability, cost and quality of food and the reduction in the need for physical activity it is also important to ask why, in the face of these environmental factors some people stay slim while others gain weight. We know from studies of twins and adopted children that genetics is a very important factor in determining the risk of becoming obese. Indeed in some children with very severe obesity from a young age we have found mutations in single genes that are sufficient in themselves to result in the child?s obesity. In one case we have been able to completely cure obesity by replacing the ?broken? gene product. We study a group of ~3500 severely obese children and so far have found a single gene mutation causing obesity in about 10% of these. New techniques for finding disease genes are now available and we want to use a range of novel approaches to try to find the causes of obesity in the rest of these children. We hope that by knowing the cause we will be able to better target treatment. As well as the severe mutations that result in morbid obesity in children there are other more recently discovered subtle genetic variants each of which are common and alter a person?s weight by a few pounds. Some of these variants are in genes that were not expected to have an effect on body weight. We also plan to better understand how those genes contribute to body weight and whether manipulating them by drugs, diet or exercise might provide new approaches to treating obesity.

Technical Summary

While the modern ?obesogenic environment is clearly driving secular trends in the prevalence of obesity, inter-individual differences in susceptibility to such influences are largely genetically determined. With MRC Programme grant support since 1999 we have developed a comprehensive programme of research into molecular and pathophysiological factors in human obesity, discovering several monogenic causes of severe, early-onset human obesity, utilizing the detailed study of such individuals to gain novel insights into control mechanisms underlying energy balance and other phenotypes in humans, and targeting therapy to genotypically defined subgroups. We have, more recently contributed to global efforts in discerning the set of more common genetic variants which underpin variation in adiposity across populations and are deeply engaged in attempts to understand the biology linking such variants to adiposity.
In relation to severe early-onset obesity we propose i) To use targeted candidate gene analysis to discover and subsequently fully characterise novel, highly penetrant genetic causes of extreme early-onset obesity in three specific subphenotypes a) obesity with developmental delay b) obesity with neuroendocrine dysfunction c) obesity with disordered sleep/arousal ii) Having recently detected leptin receptor mutations in 2% of our GOOS cohort, to establish the contribution of such mutations to the obese phenotype and to exploit a series of naturally-occurring mutations to gain insights into structure/functional relationships within the leptin receptor iii) Having recently demonstrated a key role for the MC4R in the control of human blood pressure through the examination of MC4R haploinsufficient patients vs. matched equally obese controls to explore the longer term effects of MC4R deficiency on cardiovascular health.

In relation to the biology of common human obesity we propose i) To better understand the role of the gene (FTO) variants in which are most strongly associated with common human obesity, in the control of mammalian energy balance through studies in rodents and humans ii) To build on our recently reported discovery that FTO is a 2OG-dependent dioxygenase to understand the fundamental functions of FTO including its interactions with other proteins and its targets and how this relates to its physiological functions iii) To apply similar approaches to the understanding of the biology of other novel and highly validated obesity genes emerging from ongoing hypothesis-free approaches.

We will bring a comprehensive, multidisciplinary approach to these problems using studies in vitro, in cellular systems, in rodent models and in humans.
 
Description Biomedical Research Centre
Amount £6,493,079 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2012 
End 03/2017
 
Description gy prader -w
Amount £30,668 (GBP)
Organisation Foundation for Prader-Willi Research (FPWR) 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2011 
End 06/2012
 
Description sf Neurofast
Amount £211,500 (GBP)
Funding ID 245009 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 05/2010 
End 04/2015
 
Description collaboration to understand a novel model of obesity 
Organisation University of Edinburgh
Department MRC Centre for Inflammation Research
Country United Kingdom 
Sector Academic/University 
PI Contribution understanding mechanisms in driving obesity in a novel mouse model
Collaborator Contribution we will host a colleague form edinburgh who can undertake laser capture microdissection of relevant tissue
Impact none to date
Start Year 2017
 
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 sf Rhythm pharmaceuticals 
Organisation Rhythm Pharmaceuticals
Country United States 
Sector Private 
PI Contribution Advised on development of a melanocortin agonist to treat obesity. The compound has been approved for phase 1 clinical trial. If sucessful, PI will lead a subsequent phase 2 trial
Collaborator Contribution Advised on development of a melanocortin agonist to treat obesity. The compound has been approved for phase 1 clinical trial. If sucessful, PI will lead a subsequent phase 2 trial
Impact phase 1 clinical trial will start in next few months
Start Year 2010
 
Description SOR Academy of Medical Sciences 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Raised awareness of research and IMS

None
Year(s) Of Engagement Activity 2013
 
Description SOR Award Lecture for Zulch prize 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Raised awareness of research and IMS

Prestigious award of Zulch prize
Year(s) Of Engagement Activity 2014
URL http://www.mpg.de/8406171/zuelch_award_2014_orahilly_friedman
 
Description SOR BBC TV and Radio Interviews 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Raise awareness of research and IMS to the public

None
Year(s) Of Engagement Activity 2013
 
Description SOR CSAR talk, University of Cambridge 
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 talk at Cambridge Society for the Application of Research on "Human Metabolic Disease, Lessons from the Extremes"

Raised awareness of research and of IMS
Year(s) Of Engagement Activity 2014
URL http://www.csar.org.uk/index.html
 
Description SOR CSaP 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Member of Centre for Science & Policy Executive Committee, University of Cambridge

None
Year(s) Of Engagement Activity 2013,2014
 
Description SOR Doha talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Invited guest speaker at Academic Health System lecture series at Hamad Medical Corporation, Doha, Qatar

Raise awareness of research and IMS
Year(s) Of Engagement Activity 2014
 
Description SOR Dublin Science Gallery 
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 speaker at Trinity College Dublin Science Gallery as part of exhibition and 'Lab in the Gallery' FAT LAB. The goal of FAT LAB is to initiate a widespread re-evaluation of the perception of fat by inviting visitors to the gallery to participate in real research experiments and by creating a series of talks and events to engage our target audience of 15-25 year olds.

Raise awareness of research and IMS
Year(s) Of Engagement Activity 2014
URL https://dublin.sciencegallery.com/video/2014/07/sciencefatstephenorahillyanddonaloshea
 
Description SOR Irish Medical News feature 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Raised awareness of research and IMS

None
Year(s) Of Engagement Activity 2013
URL http://www.imn.ie/index.php?option=com_content&view=article&id=5418:arise-sir-orahilly&catid=57:clin...
 
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Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Raised awareness of research and IMS

None
Year(s) Of Engagement Activity 2013
URL http://www.jci.org/videos/cgms
 
Description SOR Lancet article 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Raised awareness of research and IMS

None
Year(s) Of Engagement Activity 2013
URL http://download.thelancet.com/pdfs/journals/lancet/PIIS0140673613616220.pdf
 
Description SOR MRC Centenary Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Raised awareness of research and IMS among public

None
Year(s) Of Engagement Activity 2013
 
Description SOR MedSOC talk, Cambridge 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Invited speaker at MedSOC talk, University of Cambridge

Raise awareness of research and of IMS
Year(s) Of Engagement Activity 2014
 
Description SOR Naked Scientist Question of the Week 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact Raised awareness of research and IMS to public

None
Year(s) Of Engagement Activity 2013
URL http://www.thenakedscientists.com/HTML/podcasts/qotw/show/20130307/
 
Description SOR National Health and Medical Research Council (NHMRC) CEO Obesity Roundtable 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Health professionals
Results and Impact Participated in roundtable discussion with members of Australian Government National Health and MRC and others

Raise awareness of research and IMS
Year(s) Of Engagement Activity 2014
 
Description SOR Pharmacology tea club talk 
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 University of Cambridge Department of Pharmacology tea club talk

Raise awareness of research and of IMS
Year(s) Of Engagement Activity 2014
 
Description SOR RTE interviews 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Raised awareness of research and IMS to the public

None
Year(s) Of Engagement Activity 2013
 
Description SOR Research Lecture Karolinska Institute, Stockholm 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Raised awareness of research and IMS among peers

None
Year(s) Of Engagement Activity 2013
 
Description SOR SAC Fondation Leducq 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Scientific Advisory Committee

None
Year(s) Of Engagement Activity 2013,2014
 
Description SOR UCD MGA presentation lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Gave presentation when awarded Medical Graduates Association Distinguished Graduate Award from University College Dublin for 2014

Raised awareness of research and IMS
Year(s) Of Engagement Activity 2014
URL http://www.ucd.ie/medicine/ourcommunity/ouralumni/
 
Description SOR University of Bristol talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Invited speaker at University of Bristol MRC IEU Seminar Series

Raise awareness of research and IMS
Year(s) Of Engagement Activity 2014
 
Description SOR University of Leuven 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Gave talk at University of Leuven, Belgium in seminar series for high profile scientists aimed at broad audience

Raised awareness of research and IMS
Year(s) Of Engagement Activity 2014
 
Description SOR University of Manchester talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Invited speaker at University of Manchester at Faculty's Life Science 'Leaders in Science' Lecture Series

Raise awareness of research and IMS
Year(s) Of Engagement Activity 2014
 
Description SOR University of the Third Age, Cambridge 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Invited to give talk at University of the Third Age in Cambridge

Raise awareness of research and IMS
Year(s) Of Engagement Activity 2014
 
Description SOR, Galway Diabetes Research Centre 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact http://www.conference.ie/Conferences/menu.asp?menu=1088&Conference=190

raised awareness of research are and IMS among peers
Year(s) Of Engagement Activity 2012
 
Description gy Group to encourage ethnic minority applications (GEEMA) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Schools
Results and Impact Took part in a summer school for 40 15-year-olds from ethnic minorities to encourage applications to Cambridge University

Several students commented that they enjoyed meeting such a good role model, and were encouraged to apply to the University as a result. Ethnic minority applications are steadily increasing
Year(s) Of Engagement Activity 2010,2011,2012
 
Description sf Cheltenham 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact gave a public lecture at the Cheltenham Science Festival, stimulating questions and debate with the audience

Raised awareness and stimulated debate about the biological basis of obesity
Year(s) Of Engagement Activity 2011
 
Description sf Dana Centre lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Evening lecture at the Dana Centre, followed by public debate with Sadaf Farooqi, University of Cambridge, Kevin Murphy, Imperial College London and Jane Landon, National Heart Forum
Event organised by the Global Medical Excellence Cluster

Stimulated a lively debate between lay audience and the speakers
Year(s) Of Engagement Activity 2011
 
Description sor, 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 public lecture to >300 people, at the Cambridge Science Festiva, March 2011

Several audience members visited the related display to learn more about the area
Year(s) Of Engagement Activity 2011