Genetic approaches in the GOOS cohort are leading to the discovery of new obesity genes. We study the function of these genes using a number of molecular and cellular approaches depending on the nature of the molecule that is disrupted. These molecular studies play a critical role in laying the foundation for the development and validation of new drug targets for obesity.
For example, we have identified a gene called Kinase Suppressor of Ras 2 (KSR2). This gene is involved in coordinating intracellular signals via the ERK and AMPK signalling pathways, which are responsible for cell growth and energy utilization, respectively. Mutations in KSR2 can disrupt signalling through these pathways leading to hyperphagia, insulin resistance and reduced basal metabolic rate in individuals. In fact, mutations in KSR2 are the first to be discovered that decrease the basal metabolic rate in some people. In a cell model, treatment with the often-prescribed anti-diabetic drug metformin rescues the defects in fatty acid oxidation seen in cells, suggesting a possible treatment for individuals with KSR2 mutations.
We use a range of state-of-the-art cell biology/molecular biology techniques to study the functional effects of mutations at the protein and cellular level. We are currently looking at mutations in G-Protein Coupled Receptors (GPCRs), transcription factors and signalling molecules, several of which are potential drug targets for obesity and metabolic disease.
One example of a potential target informed by genetic studies, is MC4R (melanocortin 4 receptor), a GPCR which acts in the brain to suppress appetite. People who have variants that disrupt MC4R, gain weight easily (link to paper).
Different variants in MC4R that increase its activity by signalling through the beta-arrestin pathway are associated with protection from obesity and its metabolic complications (link to paper). We are keen to see if we can design drugs that mimic the protective variants of these variants which could provide new, safer weight loss therapies.