Melanin-concentrating hormone is a cyclic nonadecapeptide that is produced almost exclusively in neurons of the lateral hypothalamus and sub zona incerta areas while fibers are widespread in the rat brain. Such a localization strongly suggests that this peptide might participate as neurotransmitter/neuromodulator in the control of feeding behavior. In this study we examined first the influence of rat melanin-concentrating hormone on feeding behavior at different times either in the light or in the dark period (light off at 18.00 h) of the day in fed Wistar rats. Intracerebroventricular injection of rat melanin-concentrating hormone (1-100 ng per rat) at 18.00 h reduced food consumption as early as 2 h after injection and for the next 24 h. In addition, similar anorectic effect was noted after bilateral administration of 1 ng melanin-concentrating hormone into the lateral hypothalamic area at 11.30 h but not at 16.30 h. These findings strongly suggest that rat melanin-concentrating hormone may exert inhibitory control over food intake behavior depending on the circadian rhythm. Second, we investigated the modifications induced by food deprivation/refeeding on melanin-concentrating hormone messenger RNA levels in Wistar rats. Total RNA was isolated from whole hypothalamic dissections and the contents of melanin-concentrating hormone messenger RNA, beta-actin messenger RNA (taken as sample control) and neuropeptide Y messenger RNA (taken as control of food-deprivation paradigms) were assessed by using northern blotting. The time-course of messenger RNA expression was determined in groups of rats deprived for 24, 48 and 72 h and revealed a three-fold induction of melanin-concentrating hormone messenger RNA by 24 and 48 h, with reduced increase at 72 h. As expected, the same treatment led to a three-fold increase in neuropeptide Y messenger RNA content by 48 and 72 h. Refeeding groups of animals for up to 72 h after 24 h of food deprivation resulted in full restoration of melanin-concentrating hormone messenger RNA levels by 24 h. Strikingly, a large range of variations in melanin-concentrating hormone messenger RNA content between individuals was observed in food-deprived versus controls or refed rats suggesting that genetic or environmental factors may alter response in melanin-concentrating hormone gene activity after food deprivation. Finally, we investigated the effects of short-term glucoprivation induced by intraperitoneal administration of either 2-deoxy-D-glucose or insulin on melanin-concentrating hormone messenger RNA expression. A transitory increase in melanin-concentrating hormone messenger RNA content was noted 1 h after 2-deoxy-D-glucose injection while melanin-concentrating hormone messenger RNA levels rose two-fold only 5 h after insulin treatment. These results indicate that 2-deoxy-D-glucose and insulin activate melanin-concentrating hormone gene expression through likely distinct regulatory pathways.