Understanding and disrupting the link between obesity and metabolic disease (360G-Wellcome-219417_Z_19_Z)

Obesity is strongly associated with common metabolic diseases (T2DM, fatty liver and cardiovascular disease) which collectively account for a huge global health burden. Insulin resistance underpins this association and our goal is to understand, and reverse, its molecular pathogenesis. Having worked on rare monogenic lipodystrophies, almost all of which are associated with the metabolic diseases typically seen in obesity, for ~20 years, we have recently convincingly shown that subtle forms of lipodystrophy are a major factor in common insulin resistance/metabolic disease. Specifically we showed that SNPs associated primarily with reduced hip (femorogluteal) fat, are as strongly associated with T2DM and cardiovascular disease risk as variants associated with central adiposity. We will build on this step-change in understanding by: Deepening understanding of the molecular mechanisms by which adipocytes form and then store surplus energy in unilocular lipid droplets Performing an experimental medicine intervention study designed to demonstrate the clinical and molecular impact of alleviating energetic overload using a very low energy diet in patients with partial lipodystrophy. Investigating the source and action of two hormones (GDF15 and FGF21) which we hypothesize to be stress signals released in response to sustained overnutrition. Both of these molecules represent exciting therapeutic opportunities.