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Professor Sir Stephen O'Rahilly

MD FRCP FRCPI FRCPath FRS FMedSci

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

so104@medschl.cam.ac.uk

Group members

 

Research Interests

Staff photo

I have a long-standing interest in the aetiology and pathophysiology of human metabolic and endocrine disease and how such information might be used to improve diagnosis, prognostication, therapy and prevention. I have a long-standing, close, collaboration with Sadaf Farooqi, Tony Coll and Giles Yeo, which focuses on Mechanisms in disorders of energy balance.

In these studies, we use human genetic and physiological approaches, accompanied by studies in cellular and animal disease models to better understand the biological causes of highly penetrant forms of human obesity and also the mechanisms whereby more common genetic variants predispose to common forms of obesity. This work has been incorporated into a research programme at the MRC Metabolic Diseases Unit (MDU) which formed in 2013.

 

I hold a Wellcome Trust Senior Investigator Award focused on Mechanisms of Human Insulin Resistance. In this work I collaborate closely with David Savage and Robert Semple. We use human genetic and physiological approaches, accompanied by studies in cellular and animal disease models to better understand the biological causes of extreme forms of human insulin resistance and also the mechanisms whereby more common genetic variants predispose to common forms of the metabolic syndrome.

 

Both of these programmes benefit greatly from extensive interactions with Ines Barroso and with Nick Wareham and colleagues in the MRC Epidemiology Unit within the IMS.

 

More recently I have developed an interest in canine models of metabolic disease and in certain hormones of the gastro-intestinal tract (in collaboration with Fiona Gribble and Frank Reimann).

 

Selected Publications

(2007- present)

Click here for full list of publications

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.  http://www.ncbi.nlm.nih.gov/pubmed/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.  http://www.ncbi.nlm.nih.gov/pubmed/25105364

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/25028498

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/24889630

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/24209692

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/23778139

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/23770608

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/23563609

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/23359686

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/23160192

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/22729222

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/21555852

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/21345103

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/19966786

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/19470471

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/19092146

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/19079066

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/17991826

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/17690262

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/17229951.

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/17130481

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/15494731

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/15166380

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/15070780

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/14617756

 

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/14573733

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/12646665

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/12118251

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/11689931

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/11574398

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/11479539

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/10903343

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/10655060

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/10622252

 

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/10486419

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/9771698

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/9486982

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/9032087

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/9399962

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/9207799

 

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.  http://www.ncbi.nlm.nih.gov/pubmed/9202122