Our goal is to develop new treatments for people living with severe obesity by delivering a step-change in our understanding of the control of human energy balance.
Severe Childhood Obesity
Previously, we have demonstrated that mutations disrupting the hormone leptin and its downstream neural targets cause severe childhood obesity. In clinical studies, we have demonstrated the critical role of this pathway in food intake, food reward and fat preference. Our current work builds on this framework to obtain a deeper understanding of the genetic, molecular and physiological mechanisms that control human energy homeostasis.
With the help of many international collaborators, we have recruited over 7000 people with severe childhood onset obesity to the Genetics of Obesity Study (GOOS) (www.goos.org.uk). We use a number of genetic approaches to identify networks of genes and the molecular mechanisms they perturb. We undertake physiological studies in patients and volunteers to examine the role of the relevant molecules in eating behaviour, energy expenditure and peripheral metabolism. In this work, we benefit hugely from the Translational Research Facility (TRF) (www.mrl.ims.cam.ac.uk/research/core-facilities/wellcome-mrc-ims-translational-research-facility-trf/)
We are also interested in understanding how and why some people remain thin in an obesogenic environment. Thinness (BMI<18kg/m2) is as heritable as severe obesity. We have recruited a UK cohort of 4000 thin people (STILTS cohort; www.stilts.org.uk) in whom we are undertaking genetic and physiological studies.
Our aim is to deliver treatments that will benefit people with severe obesity and use new knowledge to reduce weight stigma and discrimination. To that end, we work with a patient advocacy group, Obesity Empowerment Network (https://oen.org.uk/) and other partners. We developed new diagnostics for a range of obesity syndromes and an NHS Obesity Gene Panel is now available for use by Physicians in the UK (https://www.england.nhs.uk/publication/national-genomic-test-directories/). We treat patients with congenital leptin deficiency from around the world. We are running clinical trials administering Setmelanotide (a melanocortin 4 receptor agonist) in patients with several genetic obesity syndromes and work with other companies in drug discovery and trials.
We are working with colleagues at the MRC Toxicology Unit, Dept of Medicine and Babraham Institute to study immune responses to the SARS CoV-2 vaccine in people with severe obesity (https://scorpiostudy.org.uk/).
Agrawal N, Lawler K,Davidson CM, Keogh JM, Legg R, INTERVAL, Barroso I, Farooqi IS, Brand AH. Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila, 8 November 2021, PLOS Biology, 19(11): e3001255.
Mendes de Oliveira E, Keogh JM, Talbot F, Henning E, Ahmed R, Perdikari A, Bounds R, Wasiluk N, Ayinampudi V, Barroso I, Mokrosiński J, Jyothish D, Lim S, Gupta S, Kershaw M, Matei C, Partha P, Randell T, McAculay A, Wilson LC, Cheetham T, Crowne EC, Clayton P, Farooqi IS, Obesity-Associated GNAS Mutations and the Melanocortin Pathway. New England Journal of Medicine, 2021 October; PMID: 34614324
Brouwers B, Mendes de Oliveira E, Marti-Solano M, Monteiro FBF, Laurin SA, Keogh JM, Henning E, Bounds R, Daly CA, Houston S, Ayinampudi V, Wasiluk N, Clarke D, Plouffe B, Bouvier M, Banu MM, Farooqi IS, Mokrosinski J. Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation. Cell Reports, 23 March 2021, 34, 108862
Clément K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, De Waele K, Farooqi IS, Gonneau-Lejeune J, Gordon G, Kohlsdorf K, Poitou C, Puder L, Swain J, Stewart M, Yuan G, Wabitsch M, Kühnen P; Setmelanotide POMC and LEPR Phase 3 Trial Investigators. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol. 2020;8(12):960-970. PMID: 33137293.
Marenne G, Hendricks AE, Perdikari A, Bounds R, Payne F, Keogh JM, Lelliott CJ, Henning E, Pathan S, Ashford S, Bochukova EG, Mistry V, Daly A, Hayward C; INTERVAL, UK10K Consortium, Wareham NJ, O’Rahilly S, Langenberg C, Wheeler E, Zeggini E, Farooqi IS#, Barroso I#. Exome Sequencing Identifies Genes and Gene Sets Contributing to Severe Childhood Obesity, Linking PHIP Variants to Repressed POMC Transcription. Cell Metabolism 2020;31(6):1107-1119.e12. PMID: 32492392.
Lawler K, Huang-Doran I, Sonoyama T, Collet TH, Keogh JM, Henning E, O’Rahilly S, Bottolo L, Farooqi IS. Leptin-Mediated Changes in the Human Metabolome. J Clin Endocrinol Metab. 2020;105(8):2541-52. PMID: 32392278.
Lotta LA, Mokrosiński J, Mendes de Oliveira E, Li C, Sharp SJ, Luan J, Brouwers B, Ayinampudi V, Bowker N, Kerrison N, Kaimakis V, Hoult D, Stewart ID, Wheeler E, Day FR, Perry JRB, Langenberg C, Wareham NJ, Farooqi IS. Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity Cell. 2019 Apr 18;177(3):597-607.e9. doi: 10.1016/j.cell.2019.03.044
Yang Y, van der Klaauw AA, Zhu L, Cacciottolo TM, He Y, Stadler LKJ, Wang C, Xu P, Saito K, Hinton A Jr, Yan X, Keogh JM, Henning E, Banton MC, Hendricks AE, Bochukova EG, Mistry V, Lawler KL, Liao L, Xu J, O’Rahilly S, Tong Q; UK10K Consortium, Inês Barroso, O’Malley BW, Farooqi IS (co-corresponding), Xu Y. Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis. Nature Communications. 2019 Apr 12;10(1):1718. doi: 10.1038/s41467-019-08737-6.
Van der Klaauw AA, Croizier S, Mendes de Oliveira E, Stadler LKJ, Park S, Kong Y, Banton MC, Tandon P, Hendricks AE, Keogh JM, Riley SE, Papadia S, Henning E, Bounds R, Bochukova EG, Mistry V, O’Rahilly S, Simerly RB; INTERVAL; UK10K Consortium, Minchin JEN, Barroso I, Jones EY, Bouret SG, Farooqi IS. Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance. Cell. 2019 Feb 7;176(4):729-742.e18. doi: 10.1016/j.cell.2018.12.009.
Riveros-McKay F, Mistry V, Bounds R, Hendricks A, Keogh JM, Thomas H, Henning E, Corbin LJ; Understanding Society Scientific Group, O’Rahilly S, Zeggini E, Wheeler E, Barroso I, Farooqi IS. Genetic architecture of human thinness compared to severe obesity. PLoS Genet. 2019 Jan 24;15(1):e1007603. doi: 10.1371/journal.pgen.1007603.