Melanin-concentrating hormone: a functional melanocortin antagonist in the hypothalamus

Abstract

Melanin-concentrating hormone (MCH) and α-melanocyte-stimulating hormone (α-MSH) demonstrate opposite actions on skin coloration in teleost fish. Both peptides are present in the mammalian brain, although their specific physiological roles remain largely unknown. In this study, we examined the interactions between MCH and α-MSH after intracerebroventricular administration in rats. MCH increased food intake in a dose-dependent manner and lowered plasma glucocorticoid levels through a mechanism involving ACTH. In contrast, α-MSH decreased food intake and increased glucocorticoid levels. MCH, at a twofold molar excess, antagonized both actions of α-MSH. α-MSH, at a threefold molar excess, blocked the orexigenic properties of MCH. MCH did not block α-MSH binding or the ability of α-MSH to induce cAMP in cells expressing either the MC3 or MC4 receptor, the principal brain α-MSH receptor subtypes. These data suggest that MCH and α-MSH exert opposing and antagonistic influences on feeding behavior and the stress response and may function in a coordinate manner to regulate metabolism through a novel mechanism mediated in part by an MCH receptor.

Microinjections of melanin concentrating hormone into the nucleus tractus solitarius of the rat elicit depressor and bradycardic responses

“…Intracerebroventricular (i.c.v.) injection of MCH elicits an increase (Ludwig et al, 1998;Rossi et al, 1997) while pharmacological antagonism of MCH-1 receptor elicits a decrease in food intake in rats (Kowalski et al, 2004).…”

Central blockade of melanocortin receptors attenuates the metabolic and locomotor responses to peripheral interleukin-1β administration

“…These two neuropeptides are expressed in separate neuronal populations within the arcuate nucleus and both cell types express MC3R, suggesting either auto-regulation and/or cross talk between these two neuronal populations (Bagnol et al, 1999). One of the more intensely studied aspects of melanocortin biology is their involvement in the regulation of both food intake and energy metabolism (Forbes et al, 2001); α-MSH inhibits food intake (Ludwig et al, 1998), while AgRP is a potent stimulator of food intake (Rossi et al, 1998). With regard to receptors, MC3R knockout mice demonstrate increased adiposity and enhanced feed efficiency (Chen et al, 2000), while MC4R knockout mice are hyperphagic and obese (Huszar et al, 1997).…”

Synthesis and Biological Evaluation in Vitro of a Selective, High Potency Peptide Agonist of Human Melanin-concentrating Hormone Action at Human Melanin-concentrating Hormone Receptor 1

“…In the last couple of years, melanin-concentrating hormone (MCH) 1 emerged as an important regulator of feeding behavior in rodents (1)(2)(3)(4)(5)(6)(7). Similarly to neuropeptide Y, this hormone stimulates appetite in rats when injected intracerebroventricularly, and this orexigenic effect is inhibited by anorectic peptides such as ␣-melanocyte stimulating hormone, glucagon-like peptide 1, and neurotensin (1)(2)(3)(4)(5)(6)(7).…”

“…Similarly to neuropeptide Y, this hormone stimulates appetite in rats when injected intracerebroventricularly, and this orexigenic effect is inhibited by anorectic peptides such as ␣-melanocyte stimulating hormone, glucagon-like peptide 1, and neurotensin (1)(2)(3)(4)(5)(6)(7). Additionally, in the hypothalamus of genetically obese (ob/ob) and fasting mice, the level of MCH messenger RNA is elevated, and the metabolic rate of mice lacking MCH is increased.…”