Administration Of Melanin-concentrating Hormone Research Articles

Interactions of neuropeptide Y, hypocretin-I (orexin A) and melanin-concentrating hormone on feeding in rats

Amongst various neuropeptidergic systems, neuropeptide Y (NPY), hypocretin-1 and melanin-concentrating hormone (MCH) producing neurons have been shown to play an important role in the regulation of food intake and body weight. All of these neuropeptides are orexigenic signals and recent evidence suggests the existence of morphological connections between these neuronal systems in the hypothalamus. However, the functional interactions between these neuronal systems are not clearly understood. Therefore, in the present study, we examined whether there is a cooperative action on food intake between these neuropeptides after third intracerebroventricular (icv) injection in the rat. The icv administration of NPY (0.118, 0.588, 1.176 nmol), hypocretin-1 (1, 3 nmol) and MCH (0.42, 1.048, 2.096 nmol) stimulated food intake in a dose dependent manner. Coinjection with 0.118 nmol of NPY and hypocretin-1 (1, 3 nmol) or MCH (0.42, 1.048, 2.096 nmol) had no additive effect on food intake as compared to that of NPY alone. However, coinjection with lower dose of NPY (0.023 nmol) and hypocretin-1 (0.25 nmol), that did not have any effect alone, significantly induced food intake. In contrast, combination of a lower dose of NPY (0.023 nmol) or hypocretin-1 (0.25 nmol) with lower stimulatory dose (0.21, 0.42 nmol) of MCH did not result in further increase in food intake as compared to that of MCH alone. Also, combination of 0.25 nmol hypocretin-1 and a non-stimulatory dose of MCH (0.105 nmol) was ineffective in stimulating food intake. Finally, coinjection with of 0.023 nmol NPY and 0.105 nmol MCH significantly induced food intake as compared to saline control group but not as compared to NPY or MCH treated groups. In total, these results show (1) a synergistic action between NPY and hypocretin-1, (2) no interaction between hypocretin-1 and MCH and (3) very little interaction, if any, between NPY and MCH in inducing food intake. In conclusion, these results provide a physiological concomitant to the previous demonstration of morphological contacts between NPY and hypocretin producing neurons by suggesting an interaction between these two orexigenic signals in control of food intake, and further suggest that MCH’s action on feeding may be independent of NPY and hypocretin-1 action.

Role of hypothalamic neuropeptide Y and orexigenic peptides in anorexia associated with experimental colitis in the rat

Neuropeptide Y (NPY) is thought to play a crucial role in the normal hypothalamic response to starvation. After a period of food restriction, increased release of NPY induces hunger and hyperphagia, and helps to restore body weight to its set point. Persistent anorexia in rats with experimental colitis implies failure of this adaptive feeding response. In vivo NPY release and regional hypothalamic NPY concentrations were measured in rats with trinitrobenzenesulphonic acid (TNBS)-induced colitis, healthy controls and animals pair-fed to match the food intake of the colitic group. Food intake in the colitic group was assessed after administration of NPY and two other potent orexigenic peptides: melanin-concentrating hormone (MCH) and hypocretin (orexin-A). Food intake was decreased by 30-80% below control values for 5 days in the colitic rats. In both the pair-fed and colitic groups, release of NPY in the paraventricular nucleus was significantly increased compared with free-feeding controls. Intraventricular or intrahypothalamic administration of NPY, MCH or hypocretin elicited a feeding response in healthy controls, but not in the colitic group. In summary, animals with TNBS-colitis and anorexia show an appropriate increase in hypothalamic NPYergic activity. However, the failure of NPY and other orexigenic peptides to increase feeding in the colitic group indicates suppression of feeding, either by inhibition of a common downstream hypothalamic neuronal pathway or by induction of one or more potent anorexigenic agents.

Intracerebroventricular administration of melanin-concentrating hormone suppresses pulsatile luteinizing hormone release in the female rat.

Melanin-concentrating hormone (MCH) has been reported to be involved in the regulation of feeding behaviour in rats and mice. Because many neuropeptides that influence ingestive behaviour also regulate reproductive function, the present study was designed to determine if central administration of MCH changes pulsatile secretion of luteinizing hormone (LH) in the rats. Wistar-Imamichi strain female rats were ovariectomized and implanted with oestradiol to produce a moderate inhibitory feedback effect on LH release. The effects of i. c.v. injections of MCH on LH release were examined in freely moving animals. Blood samples were collected every 6 min for 3 h through an indwelling cannula. After 1 h of sampling, MCH (0.1, 1 or 10 microg/animal) or vehicle (saline) was injected into the third cerebroventricle. Because MCH is also reported to affect the hypothalamo-pituitary-adrenal (HPA) axis, which in turn, can influence reproductive function, plasma corticosterone concentrations were determined in the same animals at 30-min intervals during the first and last hours and every 12 min during the second hour of the 3-h sampling period. When expressed as per cent changes, mean plasma LH concentrations after MCH administration were significantly lower in the animals injected with all doses of the peptide compared with vehicle-treated animals; LH pulse frequency was significantly lowered by 1 microg of MCH. Per cent changes in mean plasma corticosterone levels were not significantly affected by MCH administration. These results in oestradiol-treated ovariectomized rats indicate that central MCH is capable of inhibiting pulsatile LH secretion. We have previously shown that 48-h fasting suppresses pulsatile LH release in the presence of oestrogen. Take together, these results raise the possibility that MCH could play a role in mediating the suppression of LH secretion during periods of reduced nutrition.

Melanin-concentrating hormone, melanocortin receptors and regulation of luteinizing hormone release.

Melanin-concentrating hormone (MCH) is a neuropeptide, identified by its ability to either mimic or antagonize the melanin-dispersing action of alpha-melanocyte stimulating hormone (alphaMSH) on skin melanophores. MCH and alphaMSH also have antagonistic actions in the brain affecting feeding behaviour, aggression, anxiety, arousal and reproductive function through the release of luteinizing hormone (LH). It is not clear, however, how they exert their opposite effects in the central nervous system (CNS). One possibility is that they act via a common receptor. In this study we have examined the effect of a number of MC receptor antagonists, with relative selectivity for the MC3, 4 and 5 subtypes, on the actions of MCH on LH release. We confirmed that bilateral administration of MCH (100 and 200 ng/side) into the medial preoptic area of oestrogen-primed (oestradiol benzoate 5 microgram) ovariectomized anaesthetized rats, stimulated the release of LH. This effect was blocked by the concomitant administration into the medial preoptic area of the MC4/5 antagonist ([D-Arg8]ACTH(4-10) and the MC3/5 antagonist ([Ala6]ACTH(4-10)-both at 500 ng/side-but not by the MC3/4 antagonist, SHU9119 (200 ng/side). Furthermore, the MC3 agonist [Nle3]-gamma2 MSH failed to affect LH release. These results indicate that the MC3 and MC4 receptors are not involved in mediating the action of MCH but are consistent with an action via the MC5 subtype. Preputial glands, which express MC5 receptors, were also stimulated by MCH which is in keeping with this idea. In HEK293 cells transfected with the MC5 receptor MCH increased the production of IP3. However, it was much less potent than alphaMSH and unlike alphaMSH, had no effect on the production of cAMP. MCH (10-10 to 10-5 M) also failed to displace I125NDP-MSH from cells transfected with MC5 receptors indicating that it was not acting as a competitive antagonist and its binding site was distinct from that of alphaMSH. Thus while MCH may function as an agonist at the MC5 receptor, its stimulation of LH release is more likely to be mediated via a specific MCH receptor that has common properties with the MC5 receptor.

Response to Novelty After i.c.v. Injection of Melanin-Concentrating Hormone (MCH) in Rats

Some behavioral response of rats to spatial novelty after ICV administration of melanin-concentrating hormone (MCH) were evaluated. To this purpose, an open-field test was used, as well as an elevated plus-maze to study the possible anxiolytic effect of this peptide. In the open field, the frequency of exploratory components (locomotion and rearing) increased after MCH administration in comparison to controls. Moreover, in the plus-maze, MCH increased the number of entries into the open arms as well as the time spent on them, whereas no changes in the number of entries onto the closed arms were found. The data indicate that MCH exerts an anxiolytic effect, and suggests a physiological role for this.

Leptin decreases food intake induced by melanin-concentrating hormone (MCH), galanin (GAL) and neuropeptide Y (NPY) in the rat.

Recent evidence suggests that leptin reduces food intake (FI) by acting at the hypothalamic level. Leptin decreases hypothalamic neuropeptide Y (NPY), melanin-concentrating hormone (MCH) and galanin (GAL) gene expression in rats. The purpose of the present study was to test the hypothesis that leptin decreases FI by additionally modulating the action of NPY, MCH or GAL in the hypothalamus. Intracerebroventricular (i.c.v.) administration of NPY, MCH or GAL induced FI in satiated rats. A prior i.c.v. injection of leptin (4 microg) completely prevented the increase of FI either by MCH, GAL or NPY. These results suggest that modulation of post-synaptic actions of MCH, GAL and NPY is one of the mechanisms of leptin signaling in the hypothalamus.

Melanin-concentrating hormone acutely stimulates feeding, but chronic administration has no effect on body weight.

Melanin-concentrating hormone (MCH) has recently been proposed as both a central stimulator and an inhibitor of food intake. To clarify its role, we investigated the effects of MCH and the prepro-MCH-derived peptide neuropeptide E-I injected intracerebroventricularly (icv) in rats. MCH (0.15-15 micrograms) was injected icv at the beginning of the light phase. Food intake at 2 h showed a dose-dependent increase from 325 +/- 7% of the control value (1.5-microgram dose; P < 0.05) to 462 +/- 30% of the control value (15-microgram dose; P < 0.005). When 10 ng, 100 ng, and 5 micrograms MCH were injected icv at the beginning of the dark phase, only 5 micrograms stimulated feeding (166 +/- 16% of the control value; P < 0.05). At no dose did MCH inhibit feeding. Twice daily icv injections of MCH (5 micrograms) caused an average 197 +/- 9% increase in 2-h food intake for the first 5 days. Injections from days 6-8 did not stimulate feeding. Food intake and body weight at 24 h remained unchanged. Intracerebroventricular neuropeptide E-I had no effect on food intake alone and did not alter MCH-induced feeding. These studies show a dose-dependent stimulation of feeding by acute central administration of MCH. Tolerance is seen with chronic administration. These findings support a role for MCH in the immediate regulation of food intake, but not in body weight control.