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Professor Sir Stephen O'Rahilly


Co-Director, IMS; Director, University of Cambridge Metabolic Research Laboratories; Director, MRC Metabolic Diseases Unit

Professor of Clinical Biochemistry and Medicine

Department of Clinical Biochemistry

Group members


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 hold a number of leadership positions. I co-direct the Wellcome Trust-MRC Institute of Metabolic Science (IMS) with my colleague Professor Nick Wareham. Within the IMS, I direct the MRC Metabolic Diseases Unit which is part of the broader University of Cambridge Metabolic Research Laboratories. On the wider Cambridge Biomedical Campus, I am Scientific Director of the NIHR Biomedical Research Centre and Head of the University Department of Clinical Biochemistry.


Selected Publications

Click here for full list of publications


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.


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.


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.


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.


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.


Ramachandrappa S, Raimondo A, Cali AM, Keogh JM, Henning E, Saeed S, Thompson A, Garg S, Bochukova EG, Brage S, Trowse V, Wheeler E, Sullivan AE, Dattani M, Clayton PE, Datta V, Bruning JB, Wareham NJ, O'Rahilly S, Peet DJ, Barroso I, Whitelaw ML, Farooqi IS.  Rare variants in single-minded 1 (SIM1) are associated with severe obesity.  J Clin Invest 2013; 123(7):3042-50.  doi: 10.1172/JCI68016.


Weedon MN, Ellard S, Prindle MJ, Caswell R, Lango Allen H, Oram R, Godbole K, Yajnik CS, Sbraccia P, Novelli G, Turnpenny P, McCann E, Goh KJ, Wang Y, Fulford J, McCulloch LJ, Savage DB, O'Rahilly S, Kos K, Loeb LA, Semple RK, Hattersley AT.  An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy.  Nat Genet 2013; 45(8):947-50.  doi: 10.1038/ng.2670.


Wheeler E, Huang N, Bochukova EG, Keogh JM, Lindsay S, Garg S, Henning E, Blackburn H, Loos RJ, Wareham NJ, O'Rahilly S, Hurles ME, Barroso I, Farooqi IS.  Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity.  Nat Genet 2013; 45(5):513-7.  doi: 10.1038/ng.2607.


Gulati P, Cheung MK, Antrobus R, Church CD, Harding HP, Tung YC, Rimmington D, Ma M, Ron D, Lehner PJ, Ashcroft FM, Cox RD, Coll AP, O'Rahilly S, Yeo GS.  Role for the obesity-related FTO gene in the cellular sensing of amino acids.  Proc Natl Acad Sci USA 2013; 110(7):2557-62.  doi: 10.1073/pnas.1222796110.


Doche ME, Bochukova EG, Su HW, Pearce LR, Keogh JM, Henning E, Cline JM, Saeed S, Dale A, Cheetham T, Barroso I, Argetsinger LS, O'Rahilly S, Rui L, Carter-Su C, Farooqi IS.  Human SH2B1 mutations are associated with maladaptive behaviors and obesity.  J Clin Invest 2012; 122(12):4732-6.  doi: 10.1172/JCI62696.


Lindhurst MJ, Parker VE, Payne F, Sapp JC, Rudge S, Harris J, Witkowski AM, Zhang Q, Groeneveld MP, Scott CE, Daly A, Huson SM, Tosi LL, Cunningham ML, Darling TN, Geer J, Gucev Z, Sutton VR, Tziotzios C, Dixon AK, Helliwell T, O'Rahilly S, Savage DB, Wakelam MJ, Barroso I, Biesecker LG, Semple RK.  Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA.  Nat Genet 2012; 44(8):928-33.  doi: 10.1038/ng.2332.


Sleigh A, Raymond-Barker P, Thackray K, Porter D, Hatunic M, Vottero A, Burren C, Mitchell C, McIntyre M, Brage S, Carpenter TA, Murgatroyd PR, Brindle KM, Kemp GJ, O'Rahilly S, Semple RK, Savage DB.  Mitochondrial dysfunction in patients with primary congenital insulin resistance.  J Clin Invest 2011; 121(6):2457-61.  doi: 10.1172/JCI46405.


Gandotra S, Le Dour C, Bottomley W, Cervera P, Giral P, Reznik Y, Charpentier G, Auclair M, Delépine M, Barroso I, Semple RK, Lathrop M, Lascols O, Capeau J, O'Rahilly S, Magré J, Savage DB, Vigouroux C.  Perilipin deficiency and autosomal dominant partial lipodystrophy.  N Engl J Med 2011; 364(8):740-8.  doi: 10.1056/NEJMoa1007487.


Bochukova EG, Huang N, Keogh J, Henning E, Purmann C, Blaszczyk K, Saeed S, Hamilton-Shield J, Clayton-Smith J, O'Rahilly S, Hurles ME, Farooqi IS.  Large, rare chromosomal deletions associated with severe early-onset obesity.  Nature 2010; 463(7281):666-70.  doi: 10.1038/nature08689.


Dash S, Sano H, Rochford JJ, Semple RK, Yeo G, Hyden CS, Soos MA, Clark J, Rodin A, Langenberg C, Druet C, Fawcett KA, Tung YC, Wareham NJ, Barroso I, Lienhard GE, O'Rahilly S, Savage DB.  A truncation mutation in TBC1D4 in a family with acanthosis nigricans and postprandial hyperinsulinemia.  Proc Natl Acad Sci USA 2009; 106(23):9350-5.  doi: 10.1073/pnas.0900909106.


Greenfield JR, Miller JW, Keogh JM, Henning E, Satterwhite JH, Cameron GS, Astruc B, Mayer JP, Brage S, See TC, Lomas DJ, O'Rahilly S, Farooqi IS.  Modulation of blood pressure by central melanocortinergic pathways.  N Engl J Med 2009; 360(1):44-52.  doi: 10.1056/NEJMoa0803085.


Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, Porter KM, Serin A, Mungan NO, Cook JR, Ozbek MN, Imamoglu S, Akalin NS, Yuksel B, O'Rahilly S, Semple RK.  TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction.  Nat Genet 2009; 41(3):354-8.  doi: 10.1038/ng.306.


Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, Hewitson KS, Yeo GS, McDonough MA, Cunliffe S, McNeill LA, Galvanovskis J, Rorsman P, Robins P, Prieur X, Coll AP, Ma M, Jovanovic Z, Farooqi IS, Sedgwick B, Barroso I, Lindahl T, Ponting CP, Ashcroft FM, O'Rahilly S, Schofield CJ.  The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase.  Science 2007; 318(5855):1469-72.


Farooqi IS, Bullmore E, Keogh J, Gillard J, O'Rahilly S, Fletcher PC.  Leptin regulates striatal regions and human eating behavior.  Science 2007; 317(5843):1355.


Farooqi IS, Wangensteen T, Collins S, Kimber W, Matarese G, Keogh JM, Lank E, Bottomley B, Lopez-Fernandez J, Ferraz-Amaro I, Dattani MT, Ercan O, Myhre AG, Retterstol L, Stanhope R, Edge JA, McKenzie S, Lessan N, Ghodsi M, De Rosa V, Perna F, Fontana S, Barroso I, Undlien DE, O'Rahilly S.  Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor.  N Engl J Med 2007; 356(3):237-47.


Gray J, Yeo GS, Cox JJ, Morton J, Adlam AL, Keogh JM, Yanovski JA, El Gharbawy A, Han JC, Tung YC, Hodges JR, Raymond FL, O'Rahilly S, Farooqi IS.  Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene.  Diabetes 2006; 55(12):3366-71.


Yeo GS, Connie Hung CC, Rochford J, Keogh J, Gray J, Sivaramakrishnan S, O'Rahilly S, Farooqi IS.  A de novo mutation affecting human TrkB associated with severe obesity and developmental delay.  Nat Neurosci 2004; 7(11):1187-9.


George S, Rochford JJ, Wolfrum C, Gray SL, Schinner S, Wilson JC, Soos MA, Murgatroyd PR, Williams RM, Acerini CL, Dunger DB, Barford D, Umpleby AM, Wareham NJ, Davies HA, Schafer AJ, Stoffel M, O'Rahilly S, Barroso I.  A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science 2004; 304(5675):1325-8.


Challis BG, Coll AP, Yeo GS, Pinnock SB, Dickson SL, Thresher RR, Dixon J, Zahn D, Rochford JJ, White A, Oliver RL, Millington G, Aparicio SA, Colledge WH, Russ AP, Carlton MB, O'Rahilly S.  Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY(3-36).  Proc Natl Acad Sci USA 2004; 101(13):4695-700.


Jackson RS, Creemers JW, Farooqi IS, Raffin-Sanson ML, Varro A, Dockray GJ, Holst JJ, Brubaker PL, Corvol P, Polonsky KS, Ostrega D, Becker KL, Bertagna X, Hutton JC, White A, Dattani MT, Hussain K, Middleton SJ, Nicole TM, Milla PJ, Lindley KJ, O'Rahilly S.  Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency.  J Clin Invest 2003; 112(10):1550-60.


Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O'Rahilly S, Carlton MB, Crowley WF Jr, Aparicio SA, Colledge WH.  The GPR54 gene as a regulator of puberty.  N Engl J Med 2003; 349(17):1614-27.


Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S.  Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene.  N Engl J Med 2003; 348(12):1085-95.


Savage DB, Agostini M, Barroso I, Gurnell M, Luan J, Meirhaeghe A, Harding AH, Ihrke G, Rajanayagam O, Soos MA, George S, Berger D, Thomas EL, Bell JD, Meeran K, Ross RJ, Vidal-Puig A, Wareham NJ, O'Rahilly S, Chatterjee VK, Schafer AJ.  Digenic inheritance of severe insulin resistance in a human pedigree.  Nat Genet 2002; 31(4):379-84.  Erratum in: Nat Genet 2002; 32(1):211.


Farooqi IS, Keogh JM, Kamath S, Jones S, Gibson WT, Trussell R, Jebb SA, Lip GY, O'Rahilly S.  Partial leptin deficiency and human adiposity.  Nature 2001; 414(6859):34-5.


Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV, O'Rahilly S.  Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans.  Diabetes 2001; 50(10):2199-202.


Magré J, Delépine M, Khallouf E, Gedde-Dahl T Jr, Van Maldergem L, Sobel E, Papp J, Meier M, Mégarbané A, Bachy A, Verloes A, d'Abronzo FH, Seemanova E, Assan R, Baudic N, Bourut C, Czernichow P, Huet F, Grigorescu F, de Kerdanet M, Lacombe D, Labrune P, Lanza M, Loret H, Matsuda F, Navarro J, Nivelon-Chevalier A, Polak M, Robert JJ, Tric P, Tubiana-Rufi N, Vigouroux C, Weissenbach J, Savasta S, Maassen JA, Trygstad O, Bogalho P, Freitas P, Medina JL, Bonnicci F, Joffe BI, Loyson G, Panz VR, Raal FJ, O'Rahilly S, Stephenson T, Kahn CR, Lathrop M, Capeau J; BSCL Working Group.  Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.  Nat Genet 2001; 28(4):365-70.


Farooqi IS, Yeo GS, Keogh JM, Aminian S, Jebb SA, Butler G, Cheetham T, O'Rahilly S.  Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency.  J Clin Invest 2000 Jul; 106(2):271-9.


Shackleton S, Lloyd DJ, Jackson SN, Evans R, Niermeijer MF, Singh BM, Schmidt H, Brabant G, Kumar S, Durrington PN, Gregory S, O'Rahilly S, Trembath RC.  LMNA, encoding lamin A/C, is mutated in partial lipodystrophy.  Nat Genet 2000; 24(2):153-6.


Barroso I, Gurnell M, Crowley VE, Agostini M, Schwabe JW, Soos MA, Maslen GL, Williams TD, Lewis H, Schafer AJ, Chatterjee VK, O'Rahilly S.  Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension.  Nature 1999; 402(6764):880-3.


Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O'Rahilly S.  Effects of recombinant leptin therapy in a child with congenital leptin deficiency.  N Engl J Med 1999; 341(12):879-84.


Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O'Rahilly S.  A frameshift mutation in MC4R associated with dominantly inherited human obesity.  Nat Genet 1998; 20(2):111-2.


Dib K, Whitehead JP, Humphreys PJ, Soos MA, Baynes KC, Kumar S, Harvey T, O'Rahilly S.  Impaired activation of phosphoinositide 3-kinase by insulin in fibroblasts from patients with severe insulin resistance and pseudoacromegaly.  A disorder characterized by selective postreceptor insulin resistance. J Clin Invest 1998; 101(5):1111-20.


Montague CT, Prins JB, Sanders L, Digby JE, O'Rahilly S.  Depot- and sex-specific differences in human leptin mRNA expression: implications for the control of regional fat distribution.  Diabetes 1997; 46(3):342-7.


Adams M, Montague CT, Prins JB, Holder JC, Smith SA, Sanders L, Digby JE, Sewter CP, Lazar MA, Chatterjee VK, O'Rahilly S.  Activators of peroxisome proliferator-activated receptor gamma have depot-specific effects on human preadipocyte differentiation.  J Clin Invest 1997; 100(12):3149-53.


Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, Montague CT, Hutton JC, O'Rahilly S.  Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene.  Nat Genet 1997; 16(3):303-6.


Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Earley AR, Barnett AH, Prins JB, O'Rahilly S.  Congenital leptin deficiency is associated with severe early-onset obesity in humans.  Nature 1997; 387(6636):903-8.