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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.

 

Selected Publications

(2007- present)

Click here for full list of publications

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 Apr 7 (epub ahead of print).  PMID: 23563609. doi: 10.1038/ng.2607.

Lindhurst M, Parker V, Payne F, Sapp J, Rudge S, Harris J et al. Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat Genet 2012;44:928-33.  PMID 22729222.

Hussain K, Challis B, Rocha N, Payne F, Minic M, Thompson A, Daly A, Scott C, Harris J, Smillie BJL, Savage DB, Ramaswami U, De Lonlay P, O'Rahilly S*, Barroso I*, Semple RK* An Activating Mutation of AKT2 and Human Hypoglycemia. Science 2011; 334(6055):474.   PMID 21979934.

Gandotra S, Le Dour C, Bottomley W, Cervera P, Giral P, Reznik Y, Guillaume Charpentier G, Auclair M, Delépine M, Barroso I, Semple R, Lathrop M, Lascols O, Capeau J, O’Rahilly S, Magre, Savage D, Vigouroux C. Perilipin Deficiency and Autosomal Dominant Partial Lipodystrophy. New Eng J Med 2011;364:740-8.  PMID 321345103.

 

Corander MP, Rimmington D, Challis BG, O'Rahilly S, Coll AP. (2011). Loss of Agouti-Related Peptide Does Not Significantly Impact the Phenotype of Murine POMC Deficiency. Endocrinology152:1819-28. PMID: 21363936.

 

Gandotra S, Le Dour C, Bottomley W, Cervera P, Giral P, Reznik Y, Charpentier G, Auclair M, Delepine M, Barroso I, Semple RK, Lathrop M, Lascols O, Capeau J, O'Rahilly S, Magre J, Savage DB, Vigouroux C. (2011). Perilpin deficiency and autosomal dominant partial lipodystrophy. N Eng J Med, 364(8):740-8. PMID: 21345103.

 

Nica AC, Parts L, Glass D, Nisbet J, Barrett A, Sekowska M, Travers M, Potter S, Grundberg E, Small K, Hedman AK, Bataille V, Tzenova Bell J, Surdulescu G, Dimas AS, Ingle C, Netle FO, di Meglio P, Min JL, Wilk A, Hammond CJ, Hassanali N, Yang TP, Montgomery SB, O'Rahilly S, Lindgren CM, Zondervan KT, Soranzo N, Barroso I, Durbin R, Ahmadi K, Deloukas P, McCarthy MI, Dermitzakis ET, Spector TD, MuTHER Consortium. (2011). The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. PLoS Genet, 7(2):e1002003. PMID: 21304890. PMCID: PMC3033383.

 

Huang-Doran I, Bicknell LS, Finucane FM, Rocha N, Porter KM, Tung YC, Szekeres F, Krrok A, Nolan JJ, O'Driscoll M, Bober M, O'Rahilly S, Jackson AP, Semple RK: for the Majewski Osteodysplastic Primordial Dwarfism Study Group. (2011). Genetic Defects in Human Pericentrin Are Associated With Severe Insulin Resistance and Diabetes. Diabetes, 60(3):925-935. PMID: 21270239. PMCID: PMC3046854.

 

Fletcher PC, Napolitano A, Skeggs A, Miller SR, Delafont B, Cambridge VC, de Wit S, Nathan PJ, Brooke A, O'Rahilly S, Farooqi IS, Bullmore ET. (2010). Distinct modulatory effects of satiety and sibutramine on brain responses to food images in humans: a double dissociation across hypothalamus, amygdala and ventralstriatum. J Neurosci, 30(43):14346-55. PMID: 20980590.

 

Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU, Allen HL, Lindgren CM, Luan J, Mägi R, Randall JC, Vedantam S, Winkler TW, Qi L, Workalemahu T, Heid IM, Steinthorsdottir V, Stringham HM, Weedon MN, Wheeler E, Wood AR, Ferreira T, Weyant RJ, Segrè AV, Estrada K, Liang L, Nemesh J, Park JH, Gustafsson S, Kilpeläinen TO, Yang J, Bouatia-Naji N, Esko T, Feitosa MF, Kutalik Z, Mangino M, Raychaudhuri S, Scherag A, Smith AV, Welch R, Zhao JH, Aben KK, Absher DM, Amin N, Dixon AL, Fisher E, Glazer NL, Goddard ME, Heard-Costa NL, Hoesel V, Hottenga JJ, Johansson A, Johnson T, Ketkar S, Lamina C, Li S, Moffatt MF, Myers RH, Narisu N, Perry JR, Peters MJ, Preuss M, Ripatti S, Rivadeneira F, Sandholt C, Scott LJ, Timpson NJ, Tyrer JP, van Wingerden S, Watanabe RM, White CC, Wiklund F, Barlassina C, Chasman DI, Cooper MN, Jansson JO, Lawrence RW, Pellikka N, Prokopenko I, Shi J, Thiering E, Alavere H, Alibrandi MT, Almgren P, Arnold AM, Aspelund T, Atwood LD, Balkau B, Balmforth AJ, Bennett AJ, Ben-Shlomo Y, Bergman RN, Bergmann S, Biebermann H, Blakemore AI, Boes T, Bonnycastle LL, Bornstein SR, Brown MJ, Buchanan TA, Busonero F, Campbell H, Cappuccio FP, Cavalcanti-Proença C, Chen YD, Chen CM, Chines PS, Clarke R, Coin L, Connell J, Day IN, Heijer M, Duan J, Ebrahim S, Elliott P, Elosua R, Eiriksdottir G, Erdos MR, Eriksson JG, Facheris MF, Felix SB, Fischer-Posovszky P, Folsom AR, Friedrich N, Freimer NB, Fu M, Gaget S, Gejman PV, Geus EJ, Gieger C, Gjesing AP, Goel A, Goyette P, Grallert H, Grässler J, Greenawalt DM, Groves CJ, Gudnason V, Guiducci C, Hartikainen AL, Hassanali N, Hall AS, Havulinna AS, Hayward C, Heath AC, Hengstenberg C, Hicks AA, Hinney A, Hofman A, Homuth G, Hui J, Igl W, Iribarren C, Isomaa B, Jacobs KB, Jarick I, Jewell E, John U, Jørgensen T, Jousilahti P, Jula A, Kaakinen M, Kajantie E, Kaplan LM, Kathiresan S, Kettunen J, Kinnunen L, Knowles JW, Kolcic I, König IR, Koskinen S, Kovacs P, Kuusisto J, Kraft P, Kvaløy K, Laitinen J, Lantieri O, Lanzani C, Launer LJ, Lecoeur C, Lehtimäki T, Lettre G, Liu J, Lokki ML, Lorentzon M, Luben RN, Ludwig B; MAGIC, Manunta P, Marek D, Marre M, Martin NG, McArdle WL, McCarthy A, McKnight B, Meitinger T, Melander O, Meyre D, Midthjell K, Montgomery GW, Morken MA, Morris AP, Mulic R, Ngwa JS, Nelis M, Neville MJ, Nyholt DR, O'Donnell CJ, O'Rahilly S, Ong KK, Oostra B, Paré G, Parker AN, Perola M, Pichler I, Pietiläinen KH, Platou CG, Polasek O, Pouta A, Rafelt S, Raitakari O, Rayner NW, Ridderstråle M, Rief W, Ruokonen A, Robertson NR, Rzehak P, Salomaa V, Sanders AR, Sandhu MS, Sanna S, Saramies J, Savolainen MJ, Scherag S, Schipf S, Schreiber S, Schunkert H, Silander K, Sinisalo J, Siscovick DS, Smit JH, Soranzo N, Sovio U, Stephens J, Surakka I, Swift AJ, Tammesoo ML, Tardif JC, Teder-Laving M, Teslovich TM, Thompson JR, Thomson B, Tönjes A, Tuomi T, van Meurs JB, van Ommen GJ, Vatin V, Viikari J, Visvikis-Siest S, Vitart V, Vogel CI, Voight BF, Waite LL, Wallaschofski H, Walters GB, Widen E, Wiegand S, Wild SH, Willemsen G, Witte DR, Witteman JC, Xu J, Zhang Q, Zgaga L, Ziegler A, Zitting P, Beilby JP, Farooqi IS, Hebebrand J, Huikuri HV, James AL, Kähönen M, Levinson DF, Macciardi F, Nieminen MS, Ohlsson C, Palmer LJ, Ridker PM, Stumvoll M, Beckmann JS, Boeing H, Boerwinkle E, Boomsma DI, Caulfield MJ, Chanock SJ, Collins FS, Cupples LA, Smith GD, Erdmann J, Froguel P, Grönberg H, Gyllensten U, Hall P, Hansen T, Harris TB, Hattersley AT, Hayes RB, Heinrich J, Hu FB, Hveem K, Illig T, Jarvelin MR, Kaprio J, Karpe F, Khaw KT, Kiemeney LA, Krude H, Laakso M, Lawlor DA, Metspalu A, Munroe PB, Ouwehand WH, Pedersen O, Penninx BW, Peters A, Pramstaller PP, Quertermous T, Reinehr T, Rissanen A, Rudan I, Samani NJ, Schwarz PE, Shuldiner AR, Spector TD, Tuomilehto J, Uda M, Uitterlinden A, Valle TT, Wabitsch M, Waeber G, Wareham NJ, Watkins H; Procardis Consortium, Wilson JF, Wright AF, Zillikens MC, Chatterjee N, McCarroll SA, Purcell S, Schadt EE, Visscher PM, Assimes TL, Borecki IB, Deloukas P, Fox CS, Groop LC, Haritunians T, Hunter DJ, Kaplan RC, Mohlke KL, O'Connell JR, Peltonen L, Schlessinger D, Strachan DP, van Duijn CM, Wichmann HE, Frayling TM, Thorsteinsdottir U, Abecasis GR, Barroso I, Boehnke M, Stefansson K, North KE, McCarthy MI, Hirschhorn JN, Ingelsson E, Loos RJ. (2010). Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet, 42(11):937-48. PMID: 20935630. PMCID: PMC3014548.

 

Jovanovic Z, Tung YC, Lam BY, O'Rahilly S, Yeo GS. (2010). Identificationo f the global transcriptomic response of the hypothalamic arcuate nucleus to fasting and leptin. J Neuroendocrinol, 22(8):915-25. PMID: 20553370.

 

Tschöp J, Nogueiras R, Haas-Lockie S, Kasten KR, Castañeda TR, Huber N, Guanciale K, Perez-Tilve D, Habegger K, Ottaway N, Woods SC, Oldfield B, Clarke I, Chua S Jr, Farooqi IS, O'Rahilly S, Caldwell CC, Tschöp MH. (2010). CNS leptin action modulates immune response and survival in sepsis. J Neurosci, 30(17):6036-47. PMID: 20427662. PMCID: PMC2868384.

 

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. (2010). Large, rare chromosomal deletions associated with severe early-onset obesity. Nature, 463(7281):666-70. PMID: 19966786.

 

Rubio-Cabezas O, Puri V, Murano I, Saudek V, Semple RK, Dash S, Hyden CS, Bottomley W, Vigouroux C, Magré J, Raymond-Barker P, Murgatroyd PR, Chawla A, Skepper JN, Chatterjee VK, Suliman S, Patch AM, Agarwal AK, Garg A, Barroso I, Cinti S, Czech MP, Argente J, O'Rahilly S, Savage DB; LD Screening Consortium. (2009). Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC. EMBO Mol Med, 1(5):280-7. PMID: 20049731. PMCID: PMC2891108.

 

O'Rahilly S. (2009). Human genetics illuminates the paths to metabolic disease. Nature, 462(7271):307-14. Review. PMID: 19924209.

 

Richards JB, Waterworth D, O'Rahilly S, Hivert MF, Loos RJ, Perry JR, Tanaka T, Timpson NJ, Semple RK, Soranzo N, Song K, Rocha N, Grundberg E, Dupuis J, Florez JC, Langenberg C, Prokopenko I, Saxena R, Sladek R, Aulchenko Y, Evans D, Waeber G, Erdmann J, Burnett MS, Sattar N, Devaney J, Willenborg C, Hingorani A, Witteman JC, Vollenweider P, Glaser B, Hengstenberg C, Ferrucci L, Melzer D, Stark K, Deanfield J, Winogradow J, Grassl M, Hall AS, Egan JM, Thompson JR, Ricketts SL, König IR, Reinhard W, Grundy S, Wichmann HE, Barter P, Mahley R, Kesaniemi YA, Rader DJ, Reilly MP, Epstein SE, Stewart AF, Van Duijn CM, Schunkert H, Burling K, Deloukas P, Pastinen T, Samani NJ, McPherson R, Davey Smith G, Frayling TM, Wareham NJ, Meigs JB, Mooser V, Spector TD; GIANT Consortium. (2009). A genome-wide association study reveals variants in ARL15 that influence adiponectin levels. PLoS Genet, 5(12):e1000768. PMID: 20011104. PMCID: PMC2781107.

 

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. (2009). A truncation mutation in TBC1D4 in a family with acanthosis nigricans and postprandial hyperinsulinemia. Proc Natl Acad Sci USA, 106(23):9350-5. PMID: 19470471. PMCID: PMC2695078.

 

Semple RK, Sleigh A, Murgatroyd PR, Adams CA, Bluck L, Jackson S, Vottero A, Kanabar D, Charlton-Menys V, Durrington P, Soos MA, Carpenter TA, Lomas DJ, Cochran EK, Gorden P, O'Rahilly S, Savage DB. (2009). Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis. J Clin Invest, 119(2):315-22. doi: 10.1172/JCI37432. PMID: 19164855. PMCID: PMC2631303.

 

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. (2009). TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet, 41(3):354-8. PMID: 19079066.

 

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. (2009). Modulation of blood pressure by central melanocortinergic pathways. N Engl J Med, 360(1):44-52. PMID: 19092146.

 

Payne VA, Grimsey N, Tuthill A, Virtue S, Gray SL, Dalla Nora E, Semple RK, O'Rahilly S, Rochford JJ. (2008). The human lipodystrophy gene BSCL2/seipin may be essential for normal adipocyte differentiation. Diabetes, 57(8):2055-60. PMID: 18458148. PMCID: PMC2494687.

 

Savage DB, Zhai L, Ravikumar B, Choi CS, Snaar JE, McGuire AC, Wou SE, Medina-Gomez G, Kim S, Bock CB, Segvich DM, Solanky B, Deelchand D, Vidal-Puig A, Wareham NJ, Shulman GI, Karpe F, Taylor R, Pederson BA, Roach PJ, O'Rahilly S, DePaoli-Roach AA. (2008). A prevalent variant in PPP1R3A impairs glycogen synthesis and reduces muscle glycogen content in humans and mice. PLoS Med, 5(1):e27. PMID: 18232732.

 

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. (2007). The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science, 318(5855):1469-72. PMID: 17991826. PMCID: PMC2668859.