I. Sadaf Farooqi
The long term goal of our research is to understand the molecular and physiological pathways involved in the regulation of human appetite and body weight. To this end, we use a number of complementary genetic strategies to study over 5,500 patients we have recruited with the help of many international collaborators to the Genetics of Obesity Study (GOOS).
We have shown that mutations that affect the adipocyte-derived hormone leptin and its hypothalamic targets cause severe early onset obesity in 8% of the GOOS cohort. In addition to pursuing new candidate genes, we are using hypothesis free approaches including SNP-arrays and whole exome sequencing to identify novel rare genetic variants. Working closely with Ines Barrose, we play a major role in the UK10K consortium which aims to identify rare variants in health and disease (www.uk10k.org).
These approaches are leading to the discovery of novel obesity genes whose function we study using a number of molecular and cellular approaches. We undertake physiological studies in cohorts of patients and volunteers to examine the role of the relevant molecules in eating behaviour, energy expenditure and peripheral metabolism. Major recent studies include the first description of highly penetrant genetic obesity syndromes involving the disruption of SH2B1 (JCI 2012), SIM1 (JCI 2013), MRAP2 (SCIENCE 2013) and the cellular scaffolding protein, KSR2 (CELL 2013). The characterisation of patients with loss of function mutations in KSR2 provided the first evidence that genes can affect metabolic rate and fuel utilisation. In addition, several novel common variants associated with severe childhood obesity were discovered as part of a genome wide association study (Nature Genetics 2013).
This integrated approach has allowed us to demonstrate the importance of specific molecular pathways in the development of severe obesity which can be considered a neurobehavioural disease. In collaboration with Professor Paul Fletcher, we have a major interest in using functional MRI to study the pattern of brain activation involved in aspects of eating behaviour, such as food reward and motivation. We plan a significant expansion in this area of research with the building of new dedicated facilities for the study of eating behaviour as part of a Wellcome Trust Award to the Institute.
To date, our work has allowed us to provide improved diagnostics for a range of obesity syndromes. We have been able to provide a mechanism based treatment for one of these disorders, congenital leptin deficiency, where we successfully treat patients from around the world. We are working with a number of Industrial partners including AstraZeneca, Pfizer, Rhythym Pharmaceuticals to identify and validate new drug targets. Our overall aim is to make a major contribution to the design of pharmacological, nutritional and behavioural interventions to benefit patients with severe obesity.
Our research is funded by the Wellcome Trust, MRC, NIHR Cambridge Biomedical Research Centre, European Research Council, EU FP7 NEUROFAST and BETAJUDO and the Bernard Wolfe Endowment.
Van der Klaauw AA, von dem Hagen EA, Keogh JM, Henning E, O’Rahilly S, Lawrence AD, Calder AJ, Farooqi IS. Obesity-Associated Melanocortin-4 Receptor Mutations Are Associated With Changes in the Brain Response to Food Cues. J Clin Endocrinol Metab. 2014 Jul 25:jc20141651. PMID: 25062455.
Pearce LR, Joe R, Doche ME, Su HW, Keogh JM, Henning E, Argetsinger LS, Bochukova EG, Cline JM, Garg S, Saeed S, Shoelson S, O’Rahilly S, Barroso I, Rui L, Farooqi IS, Carter-Su C. Functional characterisation of obesity-associated variants involving the alpha and beta isoforms of human SH2B1. Endocrinology. 2014 Jun 27:en20141264. PMID: 24971614.
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 Nov 7;155(4):765-77. PMID: 24209692. PMCID: PMC3898740.
Asai M, Ramachandrappa S, Joachim M, Shen Y, Zhang R, Nuthalapati N, Ramanathan V, Strochlic DE, Ferket P, Linhart K, Ho C, Novoselova TV, Garg S, Ridderstråle M, Marcus C, Hirschhorn JN, Keogh JM, O’Rahilly S, Chan LF, Clark AJ, Farooqi IS (co-corresponding), Majzoub JA. Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity. Science. 2013; Jul 19;341(6143):275-8. PMID: 23869016. PMCID: PMC3788688.
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 Jul; PMID: 23778139. PMCID: PMC3696558.
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. (2013). Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity. Nat Genet, 45(5):513-7. PMID: 23563609.
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 Dec; 3;122(12):4732-6. PMID: 23160192. PMCID: PMC3533535.
Hatoum IJ, Stylopoulos N, Vanhoose AM, Boyd KL, Yin DP, Ellacott KL, Ma LL, Blaszczyk K, Keogh JM, Cone RD, Farooqi IS, Kaplan LM. (2012). Melanocortin-4 receptor signalling is required for weight loss after gastric bypass surgery. J Clin Endocrinol Metab, 97(6):E1023-31. PMID: 22492873. PMCID: PMC3387412.
Fletcher PC, Napolitano A, Skeggs A, Miller SR, Delafont B, Cambridge VC, 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 ventral striatum. J Neurosci, 30(43):14346-55. PMID: 20980590.
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.