Obesity-associated co-morbidities are greatest in children and adults with severe obesity for whom lifestyle interventions are seldom effective and therapeutic interventions are limited. Our goal is to inform therapeutic strategies for severe obesity by delivering a step-change in our understanding of human energy homeostasis.
Severe Childhood Obesity
Previously, we have demonstrated that mutations disrupting the hormone leptin and its downstream neural targets can 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 seeks to build on this framework to obtain a deeper understanding of the 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). We use exome sequencing to identify rare genetic variants that are enriched in severe obesity and use computational approaches to comprehensively map these 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).
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. Funded by an ERC Consolidator Award, we have recruited a UK cohort of 4000 thin people (STILTS cohort; www.stilts.org.uk) in whom we are undertaking genetic studies.
Our overall aim is to make a major contribution to pharmacological, nutritional and behavioural interventions to benefit patients with severe obesity. 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 running clinical trials administering Setmelanotide (a melanocortin 4 receptor agonist) in patients with genetic obesity syndromes and work with other companies in the areas of drug discovery.
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.