Here we report the application of this integrated approach to study the significance of sex on the genetic determinants of obesity and the associated regulation of liver gene expression in an F2 intercross derived from the inbred strains C57BL/6J (B6) and C3H/HeJ (C3H) on an apolipoprotein E null (ApoE−/−) background. The BXH.ApoE−/− population was designed to recapitulate several of the phenotypes associated with the so-called metabolic syndrome. The cross consists of 334 animals of both sexes, allowing us to specifically test for the dependence of QTLs on sex. We detected several thousand gene expression QTLs (eQTLs), a significant proportion of which were sex-biased. We used these analyses to dissect the genetic regulation of the gonadal fat mass trait and to identify genes associated with the trait.