Aims/hypothesis: The present study was conducted to evaluate the effects of central administration of melanotan II (MTII), a melanocortin-3/4 receptor agonist, on hepatic and whole-body insulin sensitivity, independent of food intake and body weight. Methods: Over a period of 24 h, 225 ng of MTII was injected in three aliquots into the left lateral ventricle of male C57Bl/6 mice. The animals had no access to food. The control group received three injections of distilled water. Whole-body and hepatic insulin sensitivity were measured by hyperinsulinaemic-euglycaemic clamp in combination with [3H]glucose infusion. Glut4 mRNA expression was measured in skeletal muscle. Results: Plasma glucose and insulin concentrations under basal and hyperinsulinaemic conditions were similar in MTII- and placebo-treated mice. Endogenous glucose production (EGP) and glucose disposal in the basal state were significantly higher in MTII-treated mice than in the control group (71±22 vs 43±12 μmol·min-1·kg-1, p<0.01). During hyperinsulinaemia, glucose disposal was significantly higher in MTII-treated mice (151±20 vs 108±20 μmol·min -1·kg-1, p<0.01). In contrast, the inhibitory effect of insulin on EGP was not affected by MTII (relative decrease in EGP: 45±27 vs 50±20%). Glut4 mRNA expression in skeletal muscle was significantly increased in MTII-treated mice (307±94 vs 100±56%, p<0.01). Conclusions/interpretation: Intracerebroventricular administration of MTII acutely increases insulin-mediated glucose disposal but does not affect the capacity of insulin to suppress EGP in C57Bl/6 mice. These data indicate that central stimulation of melanocortin-3/4 receptors modulates insulin sensitivity in a tissue-specific manner, independent of its well-known impact on feeding and body weight.