Obesity: Exploiting Genomes for Novel Insights (360G-Wellcome-205187_Z_16_Z)

What are the mechanisms by which genes influence an individual’s propensity to obesity? I study pet dogs to find answers to that question. Dogs are a compelling obesity model. Canine obesity is common, and dogs share genes, risk factors and environments with humans. Breed predispositions implicate genetics, as in humans where <4% of the estimated 40-70% heritability of obesity has been explained. Importantly, selective breeding means dogs have an unusual haplotype structure so mapping complex diseases remarkably tractable compared to humans. I will study the link between genes and obesity in two complementary research streams. Firstly, I will build on my recent discovery of an obesity-associated POMC mutation in Labrador dogs which disrupts hypothalamic leptin-melanocortin signalling. Deep phenotyping of eating behaviour and physiology in the absence and presence of a synthetic MC4R agonist with the goal of defining the contribution of POMC-derived peptides to energy homeostasis. Secondly, I will use genome-wide association studies in multiple breeds to find further genetic determinants of canine obesity. Their relevance to humans will be tested in large patient cohorts with both rare, severe obesity and common obesity, and putative obesity loci studied in relevant cell models. Preliminary data has shown this approach is successful.