Genetic, molecular and physiological mechanisms involved in human obesity
We use a number of complementary genetic strategies including whole exome sequencing to study a cohort of over 5000 patients with severe early onset obesity in collaboration with colleagues at the Wellcome Trust Sanger Institute. Through these approaches we are discovering mutations in novel obesity genes whose function is studied using a number of molecular and cellular approaches. We work on mammalian and iPSC-derived neural lines and model organisms to explore how these molecules modulate the hypothalamic neural circuits involved in the regulation of energy balance. As part of our parallel programme of translational research, we undertake physiological studies in patients with genetic obesity syndromes to examine the role of the relevant molecules in eating behaviour, energy expenditure and peripheral metabolism. Our overall aim is to make a major contribution to the design of pharmacological, nutritional and behavioural interventions to benefit patients with severe obesity.
Asai, M. et al. Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity. Science 341, 275–278 (2013).
Pearce, L. et al. KSR2 mutations are associated with obesity, insulin resistance and impaired cellular fuel oxidation. Cell 155, 767–777 (2013).