Circulating levels of leptin correlate with food intake and adiposity. A decline in serum leptin associated with calorie restriction instigates behavioral and metabolic adaptation, increasing appetite and conserving energy. Brain melanocortin-4 receptors (Mc4r) are important mediators of leptin's effects on appetite and energy expenditure. Since subtle changes in function associated with heterozygous null mutations for either the Leptin (Lep-HET) or Mc4r genes (Mc4r-HET) increase adiposity, we tested the hypothesis that combined heterozygous mutations (Dbl-HET) would severely exacerbate diet-induced obesity (DIO) and insulin resistance in C57BL/6J mice. Serum leptin levels were lower as a function of adiposity in heterozygous Leptin mutants (Lep-HET, Dbl-HET) matched with mice homozygous for the wild type Lep gene (WT, Mc4r-HET). Evidence for an additive interaction on adiposity in Dbl-HET mice maintained on low fat diet was observed at 10 weeks of age. Male but not female mice developed DIO and insulin resistance on high fat diet. Compared to WT, DIO was more severe in Mc4r-HET but not Lep-HET mice, irrespective of sex. However, the response of male and female Dbl-HET mice was different, with males being less and females more responsive relative to Mc4r-HET. Glucose tolerance of Dbl-HET mice was not significantly different from WT in either sex. These results show a complex interaction between the Leptin and Mc4r genes that is influenced by age, gender and diet. Remarkably, while heterozygous Lep mutations initially exacerbate obesity, in situations of severe obesity reduced leptin levels may act oppositely and have beneficial effects on energy homeostasis.