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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

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

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 MBL, Coll AP, Reimann F, O’Rahilly S, Gribble FM.

Insulin-like peptide 5 is an orexigenic gastrointestinal hormone.

Proc Natl Acad Sci USA 2014;111:11133-11138.

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.

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.

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.


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.


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.


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.