Mutations in the melanocortin-4 receptor (MC4R) are associated with obesity. The obesity syndrome observed in humans with MC4R haploinsufficiency is similar to that observed in MC4R knockout mice: increased longitudinal growth, hyperphagia, and fasting hyperinsulinemia. For comparison with other commonly investigated models of obesity and insulin resistance, we have backcrossed Mc4r- mice into the C57BL/6J (B6) background. Female obese Mc4r- mice exhibit reduced energy expenditure and an attenuated increase in fatty acid oxidation following exposure to high fat diets compared with obese Lep^ob/ Lep^ob mice. The reduced energy expenditure and fatty acid oxidation correlates with changes in hepatic gene expression. The expression of genes involved in fatty acid oxidation increased in obese Lep^ob/ Lep^ob mice compared with wild-type and obese Mc4r- mice. In contrast, a key lipogenic enzyme (fatty acid synthase) is increased in obese Mc4r- mice compared with obese Lep^ob/ Lep^ob mice. Hyperinsulinemia, increased FAS mRNA expression and hepatic steatosis appear to be secondary to obesity in B6 Mc4r- mice. However, Mc4r- mice in a mixed genetic background develop severe hepatic steatosis at an early age. This might suggest an important role of the MC4R in regulating liver fatty acid metabolism this is masked on the B6 background. Interestingly, the 10- to 20-fold increase in liver triglyceride in this strain of Mc4r- mice is not always associated with fasting hyperinsulinemia or increased FAS mRNA expression. This observation suggests changes in liver secondary to triglyceride accumulation lead to hyperinsulinemia and increased hepatic FAS expression in Mc4r- mice.