Peptides (v.30, #11)

Editorial by Hubert Vaudry; Jean-Louis Nahon (1965-1966).
Keywords: Melanin-concentrating hormone; Neuropeptide; Feeding behavior;

The development of the MCH system by P.Y. Risold; S. Croizier; K. Legagneux; F. Brischoux; D. Fellmann; B. Griffond (1969-1972).
Although a great deal is published on the MCH neurons, very few works were devoted to the study of their development. However, existing literature points out two important traits: first, these neurons differentiate a MCH phenotype very early in all species studied so far, which might suggest a role for the MCH peptide during development; second, in the rat, birth date greatly influence the phenotype of MCH neurons. At least two sub-populations were described on the basis of their chemical phenotype, projection pattern and birth date. The understanding of processes involved in the differentiation of these sub-populations may help understand the medio-lateral differentiation of the tuberal hypothalamus.
Keywords: Hypothalamus; Neurogenesis;

Neuroanatomical distribution of MCH in the brain and pituitary of submammalian vertebrates by Mauro Vallarino; Federica Bruzzone; Hubert Vaudry (1973-1978).
Melanin-concentrating hormone (MCH) is a cyclic neuropeptide that has been initially characterized from a salmon pituitary extract and subsequently identified in various species from all classes of vertebrates. The present review summarizes the current knowledge regarding the neuroanatomical distribution of MCH-immunoreactive neurons in submammalian vertebrates. In all species examined, MCH-immunoreactive perikarya are confined to the hypothalamus, with the exception of the cyclostome Lampetra fluvialis and the lungfish Protopterus annectens, in which additional populations of MCH-immunoreactive cell bodies occur in the telencephalon, and the frogs Rana ridibunda and Rana esculenta which exhibit MCH-positive perikarya in thalamic nuclei. In teleosts, in the frog R. ridibunda and in the L. fluvialis, MCH is present in the classical hypothalamic-neurohypophysial system indicating that the peptide may play the role of a neurohormone. In other groups, MCH-immunoreactive nerve fibers are widely distributed in various brain regions suggesting that, in these species, MCH in the central nervous system may act as a neurotransmitter or/and a neuromodulator rather than a neurohormone.
Keywords: Melanin-concentrating hormone; Neuroanatomy; Submammalian vertebrates;

Melanin-concentrating hormone (MCH) was first discovered in the pituitary gland of the chum salmon for its role in the regulation of skin pallor. Currently, MCH is known to be present in the brains of organisms ranging from fish to mammals. MCH has been suggested to be conserved principally as a central neuromodulator or neurotransmitter in the brain. Indeed, MCH is considered to regulate food intake in mammals. In this review, profiles of MCH in the brain and pituitary gland of teleost fishes are described, focusing on the involvement of MCH in background color adaptation and in food intake regulation.
Keywords: Melanin-concentrating hormone; Fish; Brain; Pituitary gland; Neuron; Receptor; Gene expression; Background color; Food intake;

MCH receptors/gene structure-in vivo expression by Shinjae Chung; Yumiko Saito; Olivier Civelli (1985-1989).
Melanin-concentrating hormone (MCH) is a cyclic peptide which was originally discovered in fish to lighten skin color by affecting melanosomes aggregation. This peptide is highly conserved and also found in rodents whose gene is overexpressed upon fasting. However, the site of MCH action remained obscure until its receptor was discovered in 1999 as a G protein-coupled receptor. After this receptor structure was identified, the functional domains important for MCH-MCHR interaction were revealed. Moreover, the cloning of the MCH receptor led us to identify the in vivo sites of MCH action which suggested potential physiological functions of the MCH system. Furthermore, the MCH receptor identification allow for designing surrogate molecules which can block MCH activity. Studies using these molecules revealed various physiological functions of the MCH system not only in feeding but also in other physiological responses such as stress and emotion. This review will discuss how the MCH receptor was discovered and its impact on many studies investigating the MCH receptor's structure, signaling pathways, and expression pattern.
Keywords: Melanin-concentrating hormone; G protein-coupled receptor; Orphan receptor strategy; Reverse pharmacology;

Molecular cloning and expression of two melanin-concentrating hormone receptors in goldfish by Kanta Mizusawa; Yumiko Saito; Zhiwei Wang; Yuki Kobayashi; Kouhei Matsuda; Akiyoshi Takahashi (1990-1996).
Melanin-concentrating hormone (MCH) is a neurohypophysial hormone and induces melanin aggregation in the skin in teleosts. MCH also has multiple roles in the central regulation of food intake in teleosts and mammals. MCH receptors (MCH-R) are among type I G-protein-coupled receptors. Here, we cloned two MCH receptors from goldfish, Carassius auratus. The amino acid sequence of goldfish MCH-R1 had 57–88% homology with fish MCH-R1 and 49–50% homology with mammalian MCH-R1, while the amino acid sequence of goldfish MCH-R2 had 72–92% homology with fish MCH-R2 and 32% homology with human MCH-R2. Phylogenetic analysis showed that these two MCH-Rs are orthologous to the respective mammalian MCH-Rs. The common amino acid residues for ligand binding, signal transduction, and receptor conformation were well conserved in these receptors, although some intracellular basic-amino-acid-rich domains, which have been shown to exist in human MCH-R1 and MCH-R2, were absent in goldfish MCH-R2. When stably expressed in HEK293 cells, both goldfish MCH-R1 and MCH-R2 displayed a strong, dose-dependent, transient elevation of intracellular calcium in response to salmon MCH (EC50  = 0.8 nM and 31.8 nM, respectively). In contrast to goldfish MCH-R2, goldfish MCH-R1 signaling is not sensitive to pertussis toxin, suggesting an exclusive Gαq coupling of goldfish MCH-R1 in the mammalian cell-based assay. Reverse transcriptase PCR revealed that both MCH-R1 and MCH-R2 mRNA are distributed in various tissues in goldfish. The various tissues including the brain and skin express both MCH-R1 and MCH-R2. These results suggest that these functional receptors mediate multiple effects of MCH in goldfish.
Keywords: Melanin-concentrating hormone; G-protein-coupled receptor; Pertussis toxin; Calcium influx; Goldfish;

S38151 [p-guanidinobenzoyl-[Des-Gly10]-MCH(7-17)] is a potent and selective antagonist at the MCH1 receptor and has anti-feeding properties in vivo by Valérie Audinot; Odile Della Zuana; Nelly Fabry; Christine Ouvry; Olivier Nosjean; Jean-Michel Henlin; Jean-Luc Fauchère; Jean A. Boutin (1997-2007).
Structure–activity relationships studies have established the minimal sequence of melanin-concentrating hormone (MCH) that retains full agonist potency at the MCH1, to be the dodecapeptide MCH(6-17). The α-amino function is not required for activity since arginine6 can be replaced by p-guanidinobenzoyl, further improving activity. We report that the deletion of glycine in this short potent agonist (EC50 3.4 nM) turns it into a potent and new MCH1 antagonist (S38151, K B 4.3 nM in the [35S]-GTPγS binding assay), which is selective versus MCH2. A compared Ala-scan of the agonist and antagonist sequences reveals major differences in the residues that are mandatory for affinity, including arginine11 and tyrosine13 for the agonist and leucine9 for the antagonist, whereas methionine8 was necessary for both agonist and antagonist activities. A complete molecular study of the antagonist behavior is described in the present report, with a particular focus on the description of several analogues, attempting to find structure–activity relationships. Finally, S38151 antagonizes food intake when injected intra-cerebroventricularly in the rat. This is in agreement with the in vitro data and with our previous demonstration of a good correlation between in vitro and in vivo data on MCH1 agonists.
Keywords: Melanin-concentrating hormone; Receptors; Peptide antagonists; Feeding behavior; Rat;

MCH receptor peptide agonists and antagonists by Douglas J. MacNeil; Maria A. Bednarek (2008-2013).
Melanin-concentrating hormone (MCH) is an important neuropeptide hormone involved in multiple physiological processes. Peptide derivatives of MCH have been developed as tools to aid research including potent radioligands, receptor selective agonists, and potent antagonists. These tools have been used to further understand the role of MCH in physiology, primarily in rodents. However, the tools could also help elucidate the role for MCHR1 and MCHR2 in mediating MCH signaling in higher species.
Keywords: Melanin-concentrating hormone; Peptide agonist; Peptide antagonist; MCH; MCHR1; MCHR2;

Melanin-concentrating hormone induces neurite outgrowth in human neuroblastoma SH-SY5Y cells through p53 and MAPKinase signaling pathways by Natacha Cotta-Grand; Carole Rovère; Alice Guyon; Alexandra Cervantes; Frédéric Brau; Jean-Louis Nahon (2014-2024).
Melanin-concentrating hormone (MCH) peptide plays a major role in energy homeostasis regulation. Little is known about cellular functions engaged by endogenous MCH receptor (MCH-R1). Here, MCH-R1 mRNA and cognate protein were found expressed in human neuroblastoma SH-SY5Y cells. Electrophysiological experiments demonstrated that MCH modulated K+ currents, an effect depending upon the time of cellular growth. MCH treatments induced a transient phosphorylation of MAPKinases, abolished by PD98059, and partially blocked by PTX, suggesting a Gαi/Gαo protein contribution. MCH stimulated expression and likely nuclear localization of phosphorylated p53 proteins, an effect fully dependent upon MAPKinase activities. MCH treatment also increased phosphorylation of Elk-1 and up-regulated Egr-1, two transcriptional factors targeted by the MAPKinase pathway. Finally, MCH provoked neurite outgrowth after 24 h-treatment of neuroblastoma cells. This effect and transcriptional factors activation were partly prevented by PD98059. Collectively, our results provide the first evidence for a role of MCH in neuronal differentiation of endogenously MCH-R1-expressing cells via non-exclusive MAPKinase and p53 signaling pathways.
Keywords: MCH; MCH-R1; Neuroblastoma; MAPKinase; p53; Neurite outgrowth;

Melanin concentrating hormone (MCH) has been implicated in many brain functions and behaviors essential to the survival of animals. The hypothalamus is one of the primary targets where MCH-containing nerve fibers and MCH receptors are extensively expressed and its actions in the brain are exerted. Since the identification of MCH receptors as orphan G protein coupled receptors, the cellular effects of MCH have been revealed in many non-neuronal expression systems (including Xenopus oocytes and cell lines), however, the mechanism by which MCH modulates the activity in the neuronal circuitry of the brain is still under investigation. This review summarizes our current knowledge of electrophysiological effects of MCH on neurons in the hypothalamus, particularly in the lateral hypothalamus. Generally, MCH exerts inhibitory effects on neurons in this structure and may serve as a homeostatic regulator in the lateral hypothalamic area. Given the contrast between the limited data on cellular functions of MCH in the hypothalamus versus a fast growing body of evidence on the vital role of MCH in animal behavior, further investigations of the former are warranted.
Keywords: Synaptic transmission; Ion channel; Action potential; Hypocretin/orexin;

Melanin-concentrating hormone producing neurons: Activities and modulations by Alice Guyon; Gregory Conductier; Carole Rovere; Antoine Enfissi; Jean-Louis Nahon (2031-2039).
Regulation of energy homeostasis in animals involves adaptation of energy intake to its loss, through a perfect regulation of feeding behavior and energy storage/expenditure. Factors from the periphery modulate brain activity in order to adjust food intake as needed. Particularly, “first order” neurons from arcuate nucleus are able to detect modifications in homeostatic parameters and to transmit information to “second order” neurons, partly located in the lateral hypothalamic area. These “second order” neurons have widespread projections throughout the brain and their proper activation leads them to a coordinated response associated to an adapted behavior. Among these neurons, melanin-concentrating hormone (MCH) expressing neurons play an integrative role of the various factors arising from periphery, first order neurons and extra-hypothalamic arousal systems neurons and modulate regulation of feeding, drinking and seeking behaviors. As regulation of MCH release is correlated to regulation of MCH neuronal activity, we focused this review on the electrophysiological properties of MCH neurons from the lateral hypothalamic area. We first reviewed the knowledge on the endogenous electrical properties of MCH neurons identified according to various criteria which are described. Then, we dealt with the modulations of the electrical activity of MCH neurons by different factors such as glucose, glutamate and GABA, peptides and hormones regulating feeding and transmitters of extra-hypothalamic arousal systems. Finally, we described the current knowledge on the modulation of MCH neuronal activity by cytokines and chemokines. Because of such regulation, MCH neurons are some of the best candidate to account for infection-induced anorexia, but also obesity.
Keywords: Melanin-concentrating hormone; Electrophysiology; Patch-clamp; Hypothalamus; Brain slices; Feeding behavior;

Melanin-concentrating hormone (MCH) has attracted considerable attention because of its effects on food intake and body weight and the MCH receptor (MCHR1) remains one of the viable targets for obesity therapy. This review summarizes the literature examining the effects of MCH on body weight, food intake and energy expenditure in rodent models, and the central sites where MCH acts in regulating energy homeostasis. Emphasis is given on the discrepancies between the genetic and pharmacologic models of MCHR1 inactivation. We propose some solutions to resolve these discrepancies and discuss some future directions in MCH research.
Keywords: Melanin-concentrating hormone; MCHR1; Appetite; Obesity;

MCH and feeding behavior-interaction with peptidic network by B. Griffond; P.Y. Risold (2045-2051).
Numerous works associate the MCH peptide, and the hypothalamic neurons that produce it, to the feeding behavior and energy homeostasis. It is commonly admitted that MCH is an orexigenic peptide, and MCH neurons could be under the control of arcuate NPY and POMC neurons. However, the literature data is not always concordant. In particular questions about the intrahypothalamic circuit involving other neuropeptides and about the mechanisms through which MCH could act are not yet clearly answered. For example, which receptors mediate a MCH response to NPY or alpha-MSH, does MCH act alone, is there any local anatomical organization within the tuberal LHA? A review of the current literature is then needed to help focus attention on these unresolved and often neglected issues.
Keywords: MCH; NPY; POMC; Hypocretin; Hypothalamus;

Role of the melanin-concentrating hormone neuropeptide in sleep regulation by Christelle Peyron; Emilie Sapin; Lucienne Leger; Pierre-Hervé Luppi; Patrice Fort (2052-2059).
Melanin-concentrating hormone (MCH), a neuropeptide secreted by a limited number of neurons within the tuberal hypothalamus, has been drawn in the field of sleep only fairly recently in 2003. Since then, growing experimental evidence indicates that MCH may play a crucial role in the homeostatic regulation of paradoxical sleep (PS). MCH-expressing neurons fire specifically during PS. When injected icv MCH induces a 200% increase in PS quantities in rats and the lack of MCH induces a decrease in sleep quantities in transgenic mice. Here, we review recent studies suggesting a role for MCH in the regulation of the sleep–wake cycle, in particular PS, including insights on (1) the specific activity of MCH neurons during PS; (2) how they might be controlled across the sleep–wake cycle; (3) how they might modulate PS; (4) and finally whether MCH might take part in the expression of some symptoms observed in primary sleep disorders.
Keywords: Rapid eye movement sleep; Narcolepsy; Memory; Hypocretin; Orexin; MCH; Hypothalamus;

Regulation of food intake by melanin-concentrating hormone in goldfish by Kouhei Matsuda; Kenji Kojima; Sei-Ichi Shimakura; Akiyoshi Takahashi (2060-2065).
Melanin-concentrating hormone (MCH), originally discovered in the teleost pituitary, is a hypothalamic neuropeptide involved in the regulation of body color in fish. Although MCH is also present in the mammalian brain, it has no evident function in providing pigmentation. Instead, this peptide is now recognized to be one of the key neuropeptides that act as appetite enhancers in mammals such as rodents and primates. Although there has been little information about the central action of MCH on appetite in fish, recent studies have indicated that, in goldfish, MCH acts as an anorexigenic neuropeptide, modulating the α-melanocyte-stimulating hormone signaling pathway through neuronal interaction. These observations indicate that there may be major differences in the mode of action of MCH between fish and mammals. This paper reviews what is currently known about the regulation of food intake by MCH in fish, especially the goldfish.
Keywords: MCH; Feeding regulation; Fish; Goldfish; Neuropeptides; Hypothalamus; Neuronal interaction; Anorexigenic action;

A role for Melanin-Concentrating Hormone in learning and memory by Antoine Adamantidis; Luis de Lecea (2066-2070).
The neurobiological substrate of learning process and persistent memory storage involves multiple brain areas. The neocortex and hippocampal formation are known as processing and storage sites for explicit memory, whereas the striatum, amygdala, neocortex and cerebellum support implicit memory. Synaptic plasticity, long-term changes in synaptic transmission efficacy and transient recruitment of intracellular signaling pathways in these brain areas have been proposed as possible mechanisms underlying short- and long-term memory retention. In addition to the classical neurotransmitters (glutamate, GABA), experimental evidence supports a role for neuropeptides in modulating memory processes. This review focuses on the role of the Melanin-Concentrating Hormone (MCH) and receptors on memory formation in animal studies. Possible mechanisms may involve direct MCH modulation of neural circuit activity that support memory storage and cognitive functions, as well as indirect effect on arousal.
Keywords: Melanin-Concentrating Hormone; Learning; Memory; Hypothalamus;

To date, there is a dearth of evidence to support functions for melanin-concentrating hormone (MCH) and melanin-concentrating hormone receptors (MCH-R) in mammalian skin physiology including pigmentation, inflammation and immune responses and skin cell proliferation. Much research is therefore still needed to define the roles of the hormone and its receptors in mammalian skin. This will be a crucial step to identifying pathogenic mechanisms that may involve the MCH/MCH-R system in the context of inflammatory and autoimmune skin diseases as well as skin cancers. The following review summarizes the studies which have been carried out to examine the expression and function of MCH and MCH-R in mammalian skin. Recent findings with regard to humoral immune responses to the MCH-R1 in patients with the skin depigmenting disease vitiligo are also discussed.
Keywords: Melanin-concentrating hormone; Melanin-concentrating hormone receptor; Melanocyte; Pigmentation; Skin; Vitiligo;

Melanin-concentrating hormone and immune function by Bernard Lakaye; Bernard Coumans; Sophie Harray; Thierry Grisar (2076-2080).
To date, melanin-concentrating hormone (MCH) has been generally considered as peptide acting almost exclusively in the central nervous system. In the present paper, we revise the experimental evidence, demonstrating that MCH and its receptors are expressed by cells of the immune system and directly influence the response of these cells in some circumstances. This therefore supports the idea that, as with other peptides, MCH could be considered as a modulator of the immune system. Moreover, we suggest that this could have important implications in several immune-mediated disorders and affirm that there is a clear need for further investigation.
Keywords: Melanin-concentrating hormone; MCHR1; MCHR2; Neuropeptide; Immune system; Lymphocyte; Cytokine; Inflammation;

Neuropeptide glutamic-isoleucine (NEI) specifically stimulates the secretory activity of gonadotrophs in primary cultures of female rat pituitary cells by Ana Lucía De Paul; Andrés Maximiliano Attademo; Ruben Walter Carón; Marta Soaje; Alicia Inés Torres; Graciela Alma Jahn; María Ester Celis (2081-2087).
The neuropeptide EI (NEI) is derived from proMCH. It activates GnRH neurons, and has been shown to stimulate the LH release following intracerebroventricular administration in several experimental models. The aim of the present paper was to evaluate NEI actions on pituitary hormone secretion and cell morphology in vitro. Pituitary cells from female rats were treated with NEI for a wide range of concentrations (1–400 × 10−8  M) and time periods (1–5 h). The media were collected and LH, FSH, PRL, and GH measured by RIA. The interaction between NEI (1, 10 and 100 × 10−8  M) and GnRH (0.1 and 1 × 10−9  M) was also tested. Pituitary cells were harvested for electron microscopy, and the immunogold immunocytochemistry of LH was assayed after 2 and 4 h of NEI incubation. NEI (100 × 10−8  M) induced a significant LH secretion after 2 h of stimulus, reaching a maximum response 4 h later. A rapid and remarkable LH release was induced by NEI (400 × 10−8  M) 1 h after stimulus, attaining its highest level at 2 h. However, PRL, GH and FSH were not affected. NEI provoked ultrastructural changes in the gonadotrophs, which showed accumulations of LH-immunoreactive granules near the plasma membrane and exocytotic images, while the other populations exhibited no changes. Although NEI (10 × 10−8  M), caused no action when used alone, its co-incubation with GnRH (1 × 10−9  M), promoted a slight but significant increase in LH. These results demonstrate that NEI acts at the pituitary level through a direct action on gonadotrophs, as well as through interaction with GnRH.
Keywords: NEI; Gonadotroph; LH; Pituitary cell culture; GnRH; Electron microscopy;