Insights into obesity and diabetes at the intersection of mouse and human genetics

• Many critically important physiological pathways related to energy metabolism and diabetes were discovered through mouse genetics.
• Mouse strains and outbred stocks provide a repertoire of genetic diversity comparable to that of the entire human population.
• Technological improvements, largely in -omics methods, together with robust physiological phenotyping will lead to the identification of new genes using newly available resources in mouse and rat genetics.

Many of our insights into obesity and diabetes come from studies in mice carrying natural or induced mutations. In parallel, genome-wide association studies (GWAS) in humans have identified numerous genes that are causally associated with obesity and diabetes, but discovering the underlying mechanisms required in-depth studies in mice. We discuss the advantages of studying natural variation in mice and summarize several examples where the combination of human and mouse genetics opened windows into fundamental physiological pathways. A noteworthy example is the melanocortin-4 receptor (MC4R) and its role in energy balance. The pathway was delineated by discovering the gene responsible for the Agouti mutation in mice. With more targeted phenotyping, we predict that additional pathways relevant to human pathophysiology will be discovered.