Intracerebroventricular administration of melanotan II increases insulin sensitivity of glucose disposal in mice.
OBJECTIVE
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 [(3)H]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 micromol.min(-1).kg(-1), p<0.01). During hyperinsulinaemia, glucose disposal was significantly higher in MTII-treated mice (151+/-20 vs 108+/-20 micromol.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
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.
Heijboer
A C
AC
Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. a.c.heijboer@lumc.nl
van den Hoek
A M
AM
Pijl
H
H
Voshol
P J
PJ
Havekes
L M
LM
Romijn
J A
JA
Corssmit
E P M
EP
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D051275:Glucose Transporter Type 4; D007276:Injections, Intraventricular; D007328:Insulin / Q000097:blood / Q000502:physiology*; D007333:Insulin Resistance / Q000502:physiology; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D044104:Receptor, Melanocortin, Type 3 / Q000819:agonists; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists; D000521:alpha-MSH / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; C495693:Slc2a4 protein, mouse; C079282:melanotan-II; D000521:alpha-MSH; D005947:Glucose; D003345:Corticosterone