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

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Author: Heijboer, A.C. · Hoek, A.M. van den · Pijl, H. · Voshol, P.J. · Havekes, L.M. · Romijn, J.A. · Corssmit, E.P.M.
Type:article
Date:2005
Institution: TNO Kwaliteit van Leven
Source:Diabetologia, 8, 48, 1621-1626
Identifier: 238642
doi: doi:10.1007/s00125-005-1838-8
Keywords: Biology · Biomedical Research · Brain · Diabetes · Glut4 · Insulin resistance · Metabolism · Neuropeptides · Glucose transporter 4 · Hormone receptor stimulating agent · Insulin · Melanocortin 3 receptor · Melanocortin 4 receptor · Melanotan II · Messenger RNA · Placebo · Tritium · Unclassified drug · Water · Animal experiment · Animal tissue · Body weight · Brain lateral ventricle · Controlled study · Distillation · Drug effect · Food intake · Gluconeogenesis · Glucose blood level · Glucose clamp technique · Glucose metabolism · Hyperinsulinemia · Insulin sensitivity · Isotope labeling · Mouse · Mouse strain · Nonhuman · Skeletal muscle · Alpha-MSH · Animals · Blood Glucose · Corticosterone · Fatty Acids, Nonesterified · Glucose · Glucose Clamp Technique · Glucose Transporter Type 4 · Injections, Intraventricular · Insulin · Insulin Resistance · Kinetics · Liver · Male · Mice · Mice, Inbred C57BL · Monosaccharide Transport Proteins · Muscle Proteins · Peptides, Cyclic · Receptor, Melanocortin, Type 3 · Receptor, Melanocortin, Type 4 · RNA, Messenger

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 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. © Springer-Verlag 2005. Chemicals / CAS: glucose transporter 4, 188071-24-1; glucose, 50-99-7, 84778-64-3; insulin, 9004-10-8; melanocortin 3 receptor, 189235-81-2; melanocortin 4 receptor, 201099-18-5; tritium, 10028-17-8; water, 7732-18-5; alpha-MSH, 581-05-5; Blood Glucose; Corticosterone, 50-22-6; Fatty Acids, Nonesterified; Glucose Transporter Type 4; Glucose, 50-99-7; Insulin, 11061-68-0; melanotan-II, 121062-08-6; Monosaccharide Transport Proteins; Muscle Proteins; Peptides, Cyclic; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; RNA, Messenger; Slc2a4 protein, mouse