A. C. Heijboer,
A. M. van den Hoek,
H. Pijl,
P. J. Voshol,
L. M. Havekes,
J. A. Romijn and
E. P. M. Corssmit
Abstract
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
mol·min–1·kg–1, p<0.01). during="" hyperinsulinaemia,="" glucose="" disposal="" was="" significantly="" higher="" in="" mtii-treated="" mice="" (151±20="" vs="">
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<>
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.