Kisspeptin controls reproduction by stimulating GnRH neurons via Kiss1r, its receptor. Kiss1r is also expressed in other brain areas and peripheral tissues predicating a non-reproductive role. We recently examined the role of kisspeptin in energy balance by characterising the metabolic profile of Kiss1r knockout (KO) mice. These mice develop an obese and diabetic phenotype compared to wild type (WT) littermates. Our aim was to investigate why these Kiss1r KOs develop this obese phenotype. We hypothesised that hypothalamic metabolic gene expression will be altered in Kiss1r KOs. Genes examined were neuropeptide Y (Npy) (orexigenic neuropeptide) and pro-opiomelanocortin (Pomc) (anorexigenic neuropeptide). We also examined leptin receptor (Lepr), ghrelin receptor (Ghsr) and melanocortin receptor 3 and 4 (Mc3r, Mc4r). Body weights and hypothalamic gene expression (both genders) was measured in four groups. These four groups consisted of gonad intact and gonadectomised (GNX) Kiss1r KO and WT mice prior to obesity onset (8 weeks) and at obesity (20 weeks). We observed a significant increase in Pomc mRNA in gonad intact 8 week female Kiss1r KO mice (p<0.05) and 20 week male and female Kiss1r KO mice (p<0.05) compared to WT. These changes appeared to be sex steroid dependent because GNX Kiss1r KO mice exhibit no significant changes in hypothalamic gene expression. In 20 week gonad intact Kiss1r KO mice, we examined plasma leptin, insulin and c-peptide concentrations. Higher leptin, insulin and c-peptide concentrations were seen in female Kiss1r KO mice (p<0.05) compared to WT. Overall, we have identified changes in hypothalamic gene expression in Kiss1r KO mice reflecting a compensatory mechanism to their obese phenotype. Higher leptin, insulin and C-peptide levels were evident in Kiss1r KO obese female mice consistent with their obesity. These changes suggest that kisspeptin signalling influences metabolism with implications to energy balance and obesity.