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.
Genetics of 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, 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.
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
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, 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.
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 have recently started two clinical trials administering Setmelanotide (a melanocortin 4 receptor agonist) in patients with genetic obesity syndromes.
Our overall aim is to make a major contribution to the design of pharmacological, nutritional and behavioural interventions to benefit patients with severe obesity.
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