The long term goal of our research is to understand the mechanisms involved in the regulation of human body weight, investigate how their disruption leads to severe obesity and find ways to target these mechanisms for therapeutic benefit.
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, reward and more recently in fat preference. We also showed that the leptin-melanocortin pathway plays a key role in mediating weight-induced changes in blood pressure. Our current work seeks to build on this framework to obtain a deeper mechanistic understanding of how human energy homeostasis is controlled.
Genetics of Severe Childhood Obesity
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 and genome sequencing to identify novel and 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.
Genetics of Thinness
In a developing area of research, we are interested in understanding how and why some people remain thin in an obesogenic environment. Thinness (BMI<18kg/m2) is as heritable as severe obesity, however, comprehensive genetic studies of thinness have not been conducted to date. Funded by an ERC Consolidator Award, we have recruited a UK cohort of 2000 thin people (STILTS cohort; www.stilts.org.uk) in whom we are undertaking genetic studies.
Molecular and Cellular Studies
Genetic discoveries pave the way for experiments in cells and model organisms to establish whether and how mutations affect specific proteins, their targets and the mechanisms they regulate. One exciting new area of work is conducted in collaboration with Florian Merkle who has pioneered protocols for the differentiation of hypothalamic neurons from human induced pluripotent stem cells. We study how human obesity-associated mutations affect the functioning of stem cell derived POMC neurons and seek to develop cellular assays for drug discovery.
Physiological and Behavioural Studies
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. Recent findings 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.
This integrated approach has allowed us to demonstrate that leptin-melanocortin signalling primarily affects eating behaviour. In collaboration with Paul Fletcher, we have a major interest in using functional MRI and cognitive testing to study the pattern of brain activation involved in aspects of eating behaviour, such as food reward and motivation. Our new Translational Research Facilities will greatly increase our capacity for experimental medicine and translational research.
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 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.
Hendricks AE, Bochukova EG, Marenne G, Keogh JM, Atanassova N, Bounds R, Wheeler E, Mistry V, Henning E, Körner A, Muddyman D, McCarthy S, Hinney A, Hebebrand J, Scott RA, Langenberg C, Wareham NJ, Surendran P, Howson JM, Butterworth AS, Danesh J, Nordestgaard BG, Nielsen SF, Afzal S, Papadia S, Ashford S, Garg S, Millhauser GL, Palomino RI, Kwasniewska A, Tachmazidou I, O’Rahilly S, Zeggini E, Barroso I, Farooqi IS; Understanding Society Scientific Group; EPIC-CVD Consortium; UK10K Consortium. Sci Rep. 2017 Jun 29;7(1):4394. doi: 10.1038/s41598-017-03054-8. PMID: 28663568.
van der Klaauw AA, Ziauddeen H, Keogh JM, Henning E, Dachi S, Fletcher PC, Farooqi IS. Oxytocin administration suppresses hypothalamic activation in response to visual food cues. Sci Rep. 2017 Jun 27;7(1):4266. doi: 10.1038/s41598-017-04600-0. PMID: 28655900.
Divergent effects of central melanocortin signalling on fat and sucrose preference in humans. Agatha A. van der Klaauw, Julia M. Keogh, Elana Henning, Cheryl Stephenson, Sarah Kelway, Victoria M. Trowse, Naresh Subramanian, Stephen O’Rahilly, Paul C. Fletcher, I. Sadaf Farooqi. Nat Comms. 2016 Oct 4;7:13055. doi: 10.1038/ncomms13055. PMID: 27701398.
van der Klaauw AA1, Farooqi IS. The hunger genes: pathways to obesity. Cell. 2015 Mar 26;161(1):119-32. doi: 10.1016/j.cell.2015.03.008. PMID: 25815990
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 Dec; PMID: 25480301. PMCID: PMC4259491.
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.