The objective of this study was to investigate the effect of a long-term chronic intracerebroventricular (ICV) infusion of the non-selective MC3/MC4 receptor agonist MT-II and the selective MC4 receptor antagonist HS024 on food intake, metabolic rate (MR) and body weight (BW) homeostasis.

Male Wistar rats (300-400g) were randomly assigned into three groups, one received ICV infusion of MT-II (n = 9), another received HS024 (n = 10) and the third received artificial cerebrospinal fluid (ACSF; n = 11) delivered by osmotic minipumps.

HS024 infusion caused hyperphagia and development of obesity during a 4-week infusion period. Large accumulation of fat and a 6-fold increase in leptin levels were observed in the HS024-group, while the rats in the MT-II group lost fat and their leptin level was less than half the level of the ACSF-group. The MT-II caused a transient reduction in BW during the first week of infusion. The effect was not as striking during the following two weeks and had reached the level of ACSF-group by the fourth week of infusion. A similar non-significant trend was observed in food intake during the treatment period. Further investigation showed an increase in MR in the MT-II group two days after the onset of treatment, which returned to the same level as in the other groups by day four.

Long-term blocking of MC4 receptors causes hyperphagia and development of obesity. Stimulation of MC3 and MC4 receptors results in a transient reduction in BW, which partly may be explained by a temporal increase in MR.