Obesity is one of the most serious threats to human health today. Although there is general agreement that environmental factors such as diet have largely caused the current obesity pandemic, the environmental changes have not affected all individuals equally. To model gene-by-environment interactions in a mouse model system, our group has generated an F(16) advanced intercross line (AIL) from the SM/J and LG/J inbred strains. Half of our sample was fed a low-fat (15% energy from fat) diet while the other half was fed a high-fat (43% energy from fat) diet. The sample was assayed for a variety of obesity- and diabetes-related phenotypes such as growth rate, response to glucose challenge, organ and fat pad weights, and serum lipids and insulin. An examination in the F(16) sample of eight adiposity quantitative trait loci previously identified in an F(2) intercross of SM/J and LG/J mouse strains reveals locus-by-diet interactions for all previously mapped loci. Adip7, located on proximal chromosome 13, demonstrated the most interactions and therefore was selected for fine mapping with microsatellite markers. Three phenotypic traits, liver weight in male animals, serum insulin in male animals, and reproductive fat pad weight, show locus-by-diet interactions in the 127-kb region between markers D13Mit1 and D13Mit302. The phosphofructokinase (PFK) C (Pfkp) and the pitrilysin metalloprotease 1 (Pitrm1) genes are compelling positional candidate genes in this region that show coding sequence differences between the parental strains in functional domains.