Appetite and Obesity: leveraging the power of dog genetics for biomedical insight.

Epidemic obesity threatens global health and has been attributed to changes in diet and lifestyle. However, not everyone gains weight in an obesogenic environment. Heritable variation in appetite renders some individuals susceptible to weight gain, but which genes are responsible and why, and what overlap is there between appetite and obesity genes? I study pet dogs to identify genes and molecular mechanisms underlying obesity, with the overarching aim of reducing the impact of obesity on human (and animal) health. Fat mass and appetite vary widely between individual and breeds of dog and their genetic architecture simplifies trait mapping. This makes dogs a compelling animal model in which to study the genetics of appetite and obesity. My past work shows studying dogs can transform our understanding of how genes affect obesity and appetite. In my senior author paper recently accepted at Science a canine GWAS identified a new dog and human obesity gene, DENND1B, which we showed regulates melanocortin signalling, a critical nexus in the hypothalamic control of energy homeostasis. This project will adopt a similar dog-to-human approach, capitalising on extant populations of well phenotyped dogs and my large collaborative network providing access to pertinent human data. Aim 1: To map genes associated with appetite and obesity in genetically diverse dog populations. Aim 2: To establish if those genes also affect comparable human phenotypes by studying large, well-characterised human data sets. Aim 3: Genes which are important in both species will be prioritised for mechanistic studies: 3.1: In vitro and in silico, initially focussing on the role of DENND1B in regulating signalling by melanocortin and other receptors involved in energy homeostasis. Later, dissecting mechanistic links for newly identified genes. 3.2: In vivo, physiological studies in pet dogs to identify how prioritised genes and mutations affect eating behaviour and energy expenditure.