Stephen O’Rahilly
FRS, FMedSci
Co-Director of IMS and Director of IMS-MRL
Professor of Clinical Biochemistry and Medicine
Department of Clinical Biochemistry
Research Interests
The overall theme of research within the group is type 2 diabetes. In particular, we focus on two major components of type 2 diabetes, namely obesity and insulin resistance, and how these two phenomena interlink to predispose to metabolic disease. Our general aim is to provide a better molecular understanding of these disease processes so that improved therapy can be designed. We approach these issues in three general ways:
1. Human studies We have access to unique populations of subjects with extreme phenotypes of obesity and insulin resistance in addition to large populations relevant to the more common phenotypes of type 2 diabetes and obesity. Mutations which are detected in candidate gene studies are explored further for their role in human disease by linkage studies in pedigrees, functional studies of the properties of the mutant variant and detailed in vivo studies in humans.
2. Studies in cellular models We have extensive activities in functional genomics with a major focus of the laboratory on exploring the cellular consequences of mutations found in candidate genes in humans with diabetes related phenotypes. In addition, we undertake basic studies into the biology of insulin and IGF-1 signalling and adipogenesis, processes which inform our more applied work in humans.
3. In vivo models Recently we have begun to use murine models to explore certain aspects of the molecular pathogenesis of human diseases. This is a growing part of the programme.
Our research is funded by the Wellcome Trust, MRC, EU FP6 DIABESITY & EUGENE2 and Foundation for Prader-Willi Research.
Selected Publications
(from the last 10 years)
Click here for full list of publications
de Smith AJ, Purmann C, Walters RG, Ellis RJ, Holder SE, Van Haelst MM, Brady AF, Fairbrother UL, Dattani M, Keogh JM, Henning E, Yeo GS, O'Rahilly S, Froguel P, Farooqi IS, Blakemore AI. A Deletion of the HBII-85 Class of Small Nucleolar RNAs (snoRNAs) is Associated with Hyperphagia, Obesity and Hypogonadism. Hum Mol Genet. 2009 Jun 4. [Epub ahead of print] Abstract
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 U S A. 2009 Jun 9;106(23):9350-5. Epub 2009 May 22. Abstract
Boyle KB, Hadaschik D, Virtue S, Cawthorn WP, Ridley SH, O'Rahilly S, Siddle K. The transcription factors Egr1 and Egr2 have opposing influences on adipocyte differentiation. Cell Death Differ. 2009 May;16(5):782-9. Epub 2009 Feb 20. Abstract
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. Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis. J Clin Invest. 2009 Feb;119(2):315-22. doi: 10.1172/JCI37432. Epub 2009 Jan 26. Abstract
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 Jan 1;360(1):44-52. Epub 2008 Dec 17. Abstract
Willer CJ, et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Genetic Investigation of Anthropometric Traits Consortium. Nat Genet. 2009 Jan;41(1):25-34. Epub 2008 Dec 14. Abstract
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 Mar;41(3):354-8. Epub 2008 Dec 11. Abstract
Payne VA, Grimsey N, Tuthill A, Virtue S, Gray SL, Dalla Nora E, Semple RK, O'Rahilly S, Rochford JJ. The human lipodystrophy gene BSCL2/seipin may be essential for normal adipocyte differentiation. Diabetes. 2008 Aug;57(8):2055-60. Epub 2008 May 5. Abstract
Loos RJ, et al. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet. 2008 Jun;40(6):768-75. Epub 2008 May 4. Abstract
Savage DB, Zhai L, Ravikumar B, Choi CS, Snaar JE, McGuire AC, Wou SE, Medina-Gomez G, Kim S, Bock CB, Segvich DM, Vidal-Puig A, Wareham NJ, Shulman GI, Karpe F, Taylor R, Pederson BA, Roach PJ, O'Rahilly S, DePaoli-Roach AA. A prevalent variant in PPP1R3A impairs glycogen synthesis and reduces muscle glycogen content in humans and mice. PLoS Med. 2008 Jan 29;5(1):e27. Abstract
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 Nov 30;318(5855):1469-72. Epub 2007 Nov 8. Abstract
Nogueiras R, Wiedmer P, Perez-Tilve D, Veyrat-Durebex C, Keogh JM, Sutton GM, Pfluger PT, Castaneda TR, Neschen S, Hofmann SM, Howles PN, Morgan DA, Benoit SC, Szanto I, Schrott B, Schürmann A, Joost HG, Hammond C, Hui DY, Woods SC, Rahmouni K, Butler AA, Farooqi IS, O'Rahilly S, Rohner-Jeanrenaud F, Tschöp MH. The central melanocortin system directly controls peripheral lipid metabolism. J Clin Invest. 2007 Nov;117(11):3475-88. Abstract
Farooqi IS, Bullmore E, Keogh J, Gillard J, O'Rahilly S, Fletcher PC. Leptin regulates striatal regions and human eating behavior. Science. 2007 Sep 7;317(5843):1355. Epub 2007 Aug 9. Abstract
Coll AP, Farooqi IS, O'Rahilly S. The hormonal control of food intake. Cell. 2007 Apr 20;129(2):251-62. Abstract
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 and O’Rahilly S. Clinical and Molecular Genetic Spectrum of Congenital Leptin Receptor Deficiency. New Eng J Med 2007;356(3):237-47. Abstract
Farooqi IS, Drop S, Clements A, Keogh JM, Biernacka J, Lowenbein S, Challis BG and O'Rahilly S. Heterozygosity for a POMC-Null Mutation and Increased Obesity Risk in Humans. Diabetes 2006;55(9):2549-53. Abstract
Yeo GSH, Hung C-C C, Rochford J, Keogh J, Gray J, Sivaramakrishnan S., O’Rahilly S*, Farooqi IS.A de novo mutation affecting human TrkB associated with severe obesity & developmental delay. (* communicating author) Nature Neuroscience 2004; 7:1187 – 1189. Abstract
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, Alban Davies H, Schafer AJ, Stoffel M, O’Rahilly S*,Barroso I. A Family with Severe Insulin Resistance and Diabetes Mellitus due to a Missense Mutation in AKT2. (* communicating author) Science 2004; 304:1325-1328. Abstract
Challis BG, Coll AP, Yeo GSH, 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-YY3-36. PNAS 2004; 101, 13:4695-4700. Abstract
Farooqi IS, Keogh JM, Yeo G, Lank E, Cheetham T, Genetics of Obesity Study Group, O’Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor. New Eng J Med 2003; 348(12):1085-95. Abstract
Farooqi IS, Keogh J, Kamath S, Jones S, Gibson W, Trussell R, Jebb S, Lip G, O’Rahilly S. Partial leptin deficiency increases adiposity in humans. Nature 2001; 414:34-35. Abstract
Barroso I, Gurnell M, Crowley VEF, Agostini M, Schwabe JW, Soos MA, Maslen GLI, Williams TDM, Schafer AJ, Lewis H, Chatterjee VKK, O’Rahilly S. Dominant-negative mutations in human PPARg are associated with severe insulin resistance, diabetes mellitus & hypertension. Nature 1999; 402, 6764:880-883. Abstract
Farooqi S, 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. New Eng J Med 1999, 341, 12: 879-884. Abstract
Yeo G, Farooqi IS, Aminian S, Halsall D, Stanhope R, O’Rahilly S. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nature Genetics 1998; 20:111-112. Abstract
Adams M, Montague C, Prins J, Holder J, Sewter C, Sanders L, Chatterjee VKK, O’Rahilly S. Activators of PPARg have depot-specific effects on human pre-adipocyte differentiation. J Clin Invest 1997; 100:3149-53. Abstract
Jackson RS, Creemers JWM, Ohagi S, Raffin-Sanson M-L, Sanders L, Montague C, Hutton JC, O’Rahilly S. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 (PC1) gene. Nature Genetics 1997; 16,3:303-306. Abstract
Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohamed SN, Hurst JA, Cheatham KH, Earley AR, Barnett AH, Prins JB, O’Rahilly S. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997; 387, 6636:903-908. Abstract