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.
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.
Publications

Asai M
(2013)
Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity.
in Science (New York, N.Y.)

Bochukova EG
(2010)
Large, rare chromosomal deletions associated with severe early-onset obesity.
in Nature

Bradfield JP
(2012)
A genome-wide association meta-analysis identifies new childhood obesity loci.
in Nature genetics

Cheung MK
(2013)
FTO expression is regulated by availability of essential amino acids.
in International journal of obesity (2005)

Coll AP
(2013)
The hypothalamus and metabolism: integrating signals to control energy and glucose homeostasis.
in Current opinion in pharmacology

Coll AP
(2013)
"Are melanocortin receptors constitutively active in vivo?".
in European journal of pharmacology

Collet TH
(2017)
Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency.
in Molecular metabolism

Corander MP
(2011)
Loss of agouti-related peptide does not significantly impact the phenotype of murine POMC deficiency.
in Endocrinology

Dalgaard K
(2016)
Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity.
in Cell

Doche ME
(2012)
Human SH2B1 mutations are associated with maladaptive behaviors and obesity.
in The Journal of clinical investigation
Description | Biomedical Research Centre |
Amount | £6,493,079 (GBP) |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 03/2012 |
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 | 06/2011 |
End | 06/2012 |
Description | sf Neurofast |
Amount | £211,500 (GBP) |
Funding ID | 245009 |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 04/2010 |
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... |
Description | SOR JCI Interview-Conversations with Giants in Medicine |
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 |