Research Interests

I am interested in the aetiology and pathophysiology of human metabolic and endocrine disease and how such information might be used to improve in the diagnosis, therapy and prevention of these diseases. One major area of continuing interest is to better understand why some people are very susceptible to obesity and others seem resistant. We can learn quite a bit about this from human genetics but those discoveries need to be better integrated with growing fundamental knowledge regarding processes controlling energy intake and expenditure. I am also very interested in why people, particularly those who become obese, become resistant to the glucose lowering effects of the hormone insulin. Again the integration of human genetics with basic studies in cells and disease models will be necessary to advance our understanding. I am lucky to work in an environment where I can collaborate freely with a wide range of Principal Investigators, a subset of whom are previous trainees from my lab, who have complementary interests and expertise.

I co-direct the Wellcome-MRC Institute of Metabolic Science (IMS) with my colleague Professor Nick Wareham. Within the IMS, I direct the MRC Metabolic Diseases Unit. I am also Head of the University Department of Clinical Biochemistry. On the wider Cambridge Biomedical Campus, I am Scientific Director of the NIHR Biomedical Research Centre. I am also a Fellow of Pembroke College.

Harveian Oration “Some observations on the causes and consequences of obesity” given in 2016.

 

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The Society for Endocrinology have awarded Khalid Guma’a, who was a visiting student with the O’Rahilly group for summer 2022, with the Society for Endocrinology Summer Studentship Grant.

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Selected Publications

Full publication list on PubMed

Lam BYH, Williamson A, Finer S, Day FR, Tadross JA, Gonçalves Soares A, Wade K, Sweeney P, Bedenbaugh MN, Porter DT, Melvin A, Ellacott KLJ, Lippert RN, Buller S, Rosmaninho-Salgado J, Dowsett GKC, Ridley KE, Xy Z, Cimino I, Rimmington D, Rainbow K, Duckett K, Holmqvist S, Khan A, Dai , Bochukova EG; Genes & Health Research Team, Trembath RC, Martin HC, Coll AP, Rowditch DH, Wareham NJ, van Heel DA, Timpson N, Simerly RB, Ong KK, Cone RD, Langenberg C, Perry JRB, Yeo GS, O’Rahilly S. MC3R links nutritional state to childhood growth and the timing of puberty.  Nature. 2021 Nov 3. doi: 10.1038/s41586-021-04088-9. Epub ahead of print. PMID: 34732894.

Cimino I, Kim H, Tung YCL, Pedersen K, Rimmington D, Tadross JA, Kohnke SN, Neves-Costa A, Barros A, Joaquim S, Bennett D, Melvin A, Lockhart SM, Rostron AJ, Scott J, Liu H, Burling K, Barker P, Clatworthy MR, Lee EC, Simpson AJ, Yeo GSH, Moita LF, Bence KK, Jørgensen SB, Coll AP, Breen DM, O’Rahilly S. Activation of the hypothalamic-pituitary-adrenal axis by exogenous and endogenous GD15. Proc Natl Acad Sci U S A. 2021 Jul 6;118(27):e2106868118. doi: 10.1073/pnas.2106868118. PMID: 34187898; PMCID: PMC8271778

Wade KH, Lam BYH, Melvin A, Pan W, Corbin LJ, Hughes DA, Rainbow K, Chen JH, Duckett K, Liu X, Mokrosiński J, Mörseburg A, Neaves S, Willaimson A, Zhang C, Farooqi IS, Yeo GSH, Timpson NJ, O’Rahilly S. Loss-of-function mutations in the melanocortin 4 receptor in a UK birth cohort. Nat Med. 2021 May 27. doi:10.1038/s41591-021-01349-y. Epub ahead of print. PMID: 34045736.  

Melvin A, Chantzichristos D, Kyle CJ, MacKenzie S, Walker BR, Johannsson G, Stimson RH, O’Rahilly S. GDF15 is elevated in conditions of glucocorticoid deficiency and is modulated by glucocorticoid replacement. JCEM 2019;105:dgz277. doi:10.1210/clinem/dgz277. PMID: 31853550 PMCID: PMC7105349

Coll AP*, Chen M, Taskar P, Rimmington D, Patel S, Tadross JA, Cimino I, Yang M, Welsh P, Virtue S, Goldspink DA, Miedzybrodzka EL, Konopka AR, Esponda RR, Huang JT, Tung YCL, Rodriguez-Cuenca S, Tomaz RA, Harding HP, Melvin A, Yeo GSH, Preiss D, Vidal-Puig A, Vallier L, Nair KS, Wareham NJ, Ron D, Gribble FM, Reimann F, Sattar N, Savage DB, Allan BB, O’Rahilly S*. GDF15 mediates the effects of metformin on body weight and energy balance.  Nature 2020;578:E24. doi:10.1038/s41586-020-2031-4. PMID:32051582  (*co-corresponding authors).

Patel S, Alvarez-Guaita A, Melvin A, Rimmington D, Dattilo A, Miedzybrodzka EL, Cimino I, Maurin AC, Roberts GP, Meek CL, Virtue S, Sparks LM, Parsons SA, Redman LM, Bray GA, Liou AP, Woods RM, Parry SA, Jeppesen PB, Kolnes AJ, Harding HP, Ron D, Vidal-Puig A, Reimann F, Gribble FM, Hulston CJ, Farooqi IS, Fafournoux P, Smith SR, Jensen J, Breen D, Wu Z, Zhang BB, Coll AP, Savage DB, O’Rahilly S.  GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans. Cell Metab. 2019 doi: 10.1016/j.cmet.2018.12.016. [Epub ahead of print]. PMID: 30639358. PMCID: PMC6408327

Polex-Wolf J, Lam BY, Larder R, Tadross J, Rimmington D, Bosch F, Cenzano VJ, Ayuso E, Ma MK, Rainbow K, Coll AP, O’Rahilly S, Yeo GS. Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome. J Clin Invest. 2018 Jan 29. pii: 97007. doi: 10.1172/JCI97007. PMID: 29376887.

Larder R, Sim MFM, Gulati P, Antrobus R, Tung YCL, Rimmington D, Ayuso E, Polex-Wolf J, Lam BYH, Dias C, Logan DW, Virtue S, Bosch F, Geo GSH, Saudek V, O’Rahilly S, Coll AP. Obesity-associated gene TMEM18 has a role in the central control of appetite and body weight-regulation. Proc Natl Acad Sci U S A. 2017 Aug 15. pii: 201707310. doi: 10.1073/pnas.1707310114. PMID: 28811369. PMCID: PMC5584443

Lotta LA, Gulati P, Day FR, Payne F, Ongen H, van de Bunt M, Gaulton KJ, Eicher JD, Sharp SJ, Luan J, De Lucia Rolfe E, Stewart ID, Wheeler E, Willems SM, Adams C, Yaghootkar H; EPIC-InterAct Consortium.; Cambridge FPLD1 Consortium., Forouhi NG, Khaw KT, Johnson AD, Semple RK, Frayling T, Perry JR, Dermitzakis E, McCarthy MI, Barroso I, Wareham NJ, Savage DB, Langenberg C, O’Rahilly S, Scott RA. Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance. Nat Genet. 2016 14. doi: 10.1038/ng.3714. PMID: 27841877. PMCID: PMC5774584

Raffan E, Dennis RJ, O’Donovan CJ, Becker JM, Scott RA, Smith SP, Withers DJ, Wood CJ, Conci E, Clements DN, Summers KM, German AJ, Mellersh CS, Arendt ML, Iyemere VP, Withers E, Söder J, Wernersson S, Andersson G, Lindblad-Toh K, Yeo GS, O’Rahilly S. A Deletion in the Canine POMC Gene Is Associated with Weight and Appetite in Obesity-Prone Labrador Retriever Dogs. Cell Metab. 2016 May 10;23(5):893-900. doi: 10.1016/j.cmet.2016.04.012. Epub 2016 May 3. PMID: 27157046; PMCID: PMC4873617.

Dalgaard K, Landgraf K, Heyne S, Lempradl A, Longinotto J, Gossens K, Ruf M, Orthofer M, Strogantsev R, Selvaraj M, Lu TT, Casas E, Teperino R, Surani MA, Zvetkova I, Rimmington D, Tung YC, Lam B, Larder R, Yeo GS, O’Rahilly S, Vavouri T, Whitelaw E, Penninger JM, Jenuwein T, Cheung CL, Ferguson-Smith AC, Coll AP, Körner A, Pospisilik JA. Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity. Cell. 2016 Jan 28;164(3):353-64. doi: 10.1016/j.cell.2015.12.025. PMID: 26824653; PMCID: PMC4735019.

Van der Klaauw AA, Keogh JM, Henning E, Stephenson C, Kelway S, Trowse VM, Subramanian N, O’Rahilly S, Fletcher PC, Farooqi IS. Divergent effects of central melanocortin signalling on fat and sucrose preference in humans. Nat Commun. 2016 Oct 4;7:13055. doi: 10.1038/ncomms13055. PMID:27701398. PMCID: PMC5059464

Tung YC, Gulati P, Liu CH, Rimmington D, Dennis R, Ma M, Saudek V, O’Rahilly S, Coll AP, Yeo GS. FTO is necessary for the indication of leptin resistance by high-fat feeding.  Mol Metab 2015; 4(4):287-98. doi: 10.1016/j.molmet.2015.01.011. eCollection 2015. PMID: 25830092. PMCID: PMC4354923

Simonds SE, Pryor JT, Ravussin E, Greenway FL, Dileone R, Allen AM, Bassi J, Elmquist JK, Keogh JM, Henning E, Myers MG Jr, Licinio J, Brown RD, Enriori PJ, O’Rahilly S, Sternson SM, Grove KL, Spanswick DC, Farooqi IS, Cowley MA. Leptin mediates the increase in blood pressure associated with obesity.  Cell 2014; 159(6):1404-16.  doi: 10.1016/j.cell.2014.10.058.  PMID:25480301

Payne F, Colnaghi R, Rocha N, Seth A, Harris J, Carpenter G, Bottomley WE, Wheeler E, Wong S, Saudek V, Savage D, O’Rahilly S, Carel JC, Barroso I, O’Driscoll M, Semple R. Hypomorphism in human NSMCE2 linked to primordial dwarfism and insulin resistance.  J Clin Invest 2014; 124(9):4028-38.  doi: 10.1172/JCI73264. PMID:2510536 PMCID: PMC4151221

Grosse J, Heffron H, Burling K, Akhter Hossain M, Habib AM, Rogers GJ, Richards P, Larder R, Rimmington D, Adriaenssens AA, Parton L, Powell J, Binda M, Colledge WH, Doran J, Toyoda Y, Wade JD, Aparicio S, Carlton MB, Coll AP, Reimann F, O’Rahilly S, Gribble FM. Insulin-like peptide 5 is an orexigenic gastrointestinal hormone.  Proc Natl Acad Sci USA 2014; 111(30):11133-8.  doi: 0.1073/pnas.1411413111. PMID: 25028498 PMCID: PMC4121845

Payne F, Lim K, Girousse A, Brown RJ, Kory N, Robbins A, Xue Y, Sleigh A, Cochran E, Adams C, Dev Borman A, Russel-Jones D, Gorden P, Semple RK, Saudek V, O’Rahilly S, Walther TC, Barroso I, Savage DB. Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease.  Proc Natl Acad Sci USA 2014; 111(24):8901-6.  doi: 10.1073/pnas.1408523111. PMID: 24889630 PMCID: PMC4066527

Pearce LR, Atanassova N, Banton MC, Bottomley B, van der Klaauw AA, Revelli JP, Hendricks A, Keogh JM, Henning E, Doree D, Jeter-Jones S, Garg S, Bochukova EG, Bounds R, Ashford S, Gayton E, Hindmarsh PC, Shield JP, Crowne E, Barford D, Wareham NJ; UK10K consortium, O’Rahilly S, Murphy MP, Powell DR, Barroso I, Farooqi IS. KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation.  Cell 2013; 155(4):765-77. PMID: 24209692 PMCID: PMC3898740