From gene to function: strategies for unravelling complex traits and their biology to improve metabolic health

Obesity (excess fat tissue) was classified a disease only recently – but its impact on the “epidemic" prevalence of diabetes, heart disease and certain cancers is a global health crisis. Our understanding of the origins of obesity are sketchy. Most people know there is some family link and a large influence from our diet and lifestyle. Fewer know that studies on twins, for example, showed that how much fat we carry can be determined to a surprisingly large extent by our genes (>50%), the DNA blueprint for life we inherit from our biological parents. Moreover, our genes determine where we store our excess fat anatomically – which is important because when stored around our middles (apple shaped) there is a higher risk for disease than when its stored in other places (pear shaped). Our work takes a combined approach, investigating the relationship between DNA sequence variance (genome wide association studies) in large populations (e.g. ~500K participant UKBiobank) and animal modelling of the genetic extremes of obesity and leanness to identify the underlying causal genes that determine our fatness and its disease risks. We aim to understand the biological mechanisms underpinning obesity (and thinness) but also, ultimately, we wish to find new therapeutic targets with which to treat obesity when first line interventions such as diet and exercise fail, or because currently available anti-obesity drugs have limited efficacy (likely because of genetic variance in response to them). I will outline the two major approaches we take to identify fatness genes and how we use cell and and whole animal model systems to test function and mechanisms that contribute to obesity and metabolic disease. I will demonstrate how this information can be used to inform preclinical drug discovery studies and the route to new therapies.