Intracerebroventricular administration of melanotan II increases insulin sensitivity of glucose disposal in mice

Aims/hypothesis: The present study was conducted to evaluate the effects of central administration of melanotan II ( MTII), amelanocortin-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 C57B1/6 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 [H-3] 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 mu mol . min(-1) . kg(-1), p < 0.01). During hyperinsulinaemia, glucose disposal was significantly higher in MTII- treated mice (151 +/- 20 vs 108 +/- 20 mu mol . 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 C57B1/ 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.