Analysis of a genetic region affecting mouse body weight

ABSTRACT Genetic factors affect an individual’s risk of developing obesity, but in most cases each genetic variant has a small effect. Discovery of genes that regulate obesity may provide clues about its underlying biological processes and point to new ways the disease can be treated. Pre-clinical animal models facilitate genetic discovery in obesity because environmental factors can be better controlled compared to the human population. We studied inbred mouse strains to identify novel genes affecting obesity and glucose metabolism. BTBR T+ Itpr3tf/J (BTBR) mice are fatter and more glucose intolerant than C57BL/6J (B6) mice. Prior genetic studies of these strains identified an obesity locus on chromosome 2. Using congenic mice, we found that obesity was affected by a ~316 kb region, with only two known genes, pyruvate dehydrogenase kinase 1 (Pdk1) and integrin alpha 6 (Itga6). Both genes had mutations affecting their amino acid sequence and reducing mRNA levels. Both genes have known functions that could modulate obesity, lipid metabolism, insulin secretion and/or glucose homeostasis. We hypothesized that genetic variation in or near Pdk1 or Itga6 causing reduced Pdk1 and Itga6 expression would promote obesity and impaired glucose tolerance. We used knockout mice lacking Pdk1 or Itga6 fed an obesigenic diet to test this hypothesis. Under the conditions we studied, we were unable to detect an individual contribution of either Pdk1 or Itga6 to body weight. However, we identified a previously unknown role for Pdk1 in cardiac lipid metabolism providing the basis for future investigations in that area.