Member Listing


Stephen O'Rahilly


Department of Clinical Biochemistry, Metabolic Research Laboratories


Professor Sir


Principal Investigator

Research Summary

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).


Biochemistry and Molecular Biology, Cell Biology, Clinical Trials, Endocrinology, Genetics, Medical Devices and Therapeutics, Translational Medicine

Selected 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. PubMed PMID: 25480301; PubMed Central PMCID: PMC4259491.

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. PubMed PMID: 25105364; PubMed Central PMCID: PMC4151221.

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. PubMed PMID: 25028498; PubMed Central PMCID: PMC4121845.

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. PubMed PMID: 24889630; PubMed Central PMCID: PMC4066527.

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. PubMed PMID: 24209692; PubMed Central PMCID: PMC3898740.

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. PubMed PMID: 23778139; PubMed Central PMCID: PMC3696558.

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. PubMed PMID: 23770608; PubMed Central PMCID: PMC3785143.

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. PubMed PMID: 23563609; PubMed Central PMCID: PMC4106235.

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. PubMed PMID: 23359686; PubMed Central PMCID: PMC3574930.

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. PubMed PMID: 23160192; PubMed Central PMCID: PMC3533535.

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. PubMed PMID: 22729222; PubMed Central PMCID: PMC3461408.

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. PubMed PMID: 21555852; PubMed Central PMCID: PMC3104774.

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. PubMed PMID: 21345103; PubMed Central PMCID: PMC3773916.