David S. Ludwig, Kathleen G. Mountjoy, Jeffrey B. Tatro, Jennifer A. Gillette, Robert C. Frederich, Jeffrey S. Flier, and Eleftheria Maratos-Flier
Melanin-concentrating hormone: a functional melanocortin antagonist in the hypothalamus
Am J Physiol Endocrinol Metab 274: E627-E633, 1998.
"Melanin-concentrating hormone (MCH) and alpha-melanocyte-stimulating hormone (alpha-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 alpha-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, alpha-MSH decreased food intake and increased glucocorticoid levels. MCH, at a twofold molar excess, antagonized both actions of alpha-MSH. alpha-MSH, at a threefold molar excess, blocked the orexigenic properties of MCH. MCH did not block alpha-MSH binding or the ability of alpha-MSH to induce cAMP in cells expressing either the MC3 or MC4 receptor, the principal brain alpha-MSH receptor subtypes. These data suggest that MCH and alpha-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." [Full Text]

Nahon JL.
The melanin-concentrating hormone: from the peptide to the gene.
Crit Rev Neurobiol 1994;8(4):221-62
"Melanin-concentrating hormone (MCH) is a cyclic peptide originally isolated from chum salmon pituitaries, then structurally characterized from rat hypothalami. In the fish, MCH induces melanin concentration within the melanophores and may inhibit ACTH secretion in vitro and under stressful conditions in vivo. In the rat, MCH modulates ACTH release in vivo and oxytocin secretion in vitro. However, on the basis of neuroanatomical features, that is, cell bodies almost exclusively confined to the lateral area of the hypothalamus and the zona incerta, while fibers are observed throughout whole rat or human brains, this peptide appears to participate as a neurotransmitter/neuromodulator in the control of goal-oriented behaviors and/or general arousal in mammals. The knowledge of structural and regulatory features of the MCH precursor, mRNA, and genes at the cellular and molecular levels has recently made great progress. (1) The cells expressing MCH and associated peptides have been defined conjointly using radioimmunoassay, immunocytochemistry, and in vitro and in vivo molecular hybridization techniques. (2) The organization of the precursor deduced from cDNA cloning has been established and led to the discovery of two novel putative peptides named NEI and NGE. (3) The regulation of MCH mRNA and peptide production has been explored during the course of development in rodent and human and under a variety of paradigms (neurogenic or osmotic stress, hormonal stimuli, etc.). (4) The structure of the MCH genes has been determined in salmon, rat, mouse, and human and revealed striking exon-intron organization differences between fish and mammals. Strong homology, with a likely functional implication, was found between salmon MCH mRNA and 7SL RNA, a structural RNA involved in protein translocation. Furthermore, a variant gene that may encode slightly different MCH was found exclusively in primates. (5) Chromosomal assignment of the authentic and variant MCH genes in rat and human indicates that these genes may be good candidates involved in neurodegenerative or psychiatric disorders. Based on the framework of these studies, a working model of MCH regulation/function in mammalian brain is finally proposed." [Abstract]

Laetitia Borsu, Françoise Presse, and Jean-Louis Nahon
The AROM Gene, Spliced mRNAs Encoding New DNA/RNA-binding Proteins Are Transcribed from the Opposite Strand of the Melanin-concentrating Hormone Gene in Mammals
J. Biol. Chem. 275: 40576-40587, December 2000.
"Functional relationship between the MCH and the AROM genes is strengthened by the time course studies of the NGF/lithium treatment in PC12 cells which demonstrated a reciprocal relationship between MCH/AROM mRNA (and protein) expressions at the time of MCH mRNA induction (Fig. 8). Interestingly, the largest AROM gene transcripts were totally absent at the time of induction and maximum expression of the MCH mRNA, i.e. 3 and 12 h, respectively, after NGF/lithium stimulation of PC12 cells (Figs. 1B and 8B). Therefore, it is tempting to speculate that transcriptional shut down of antisense MCH RNA synthesis may lead to an increase in MCH mRNA stability. Alternatively, the ratio of sense to antisense RNA may be the "sensing indicator," and transcriptional activation of the MCH gene upon NGF/lithium stimulation would overcome the inhibitory effects of antisense RNAs.
...
Recently, MCH-deficient (MCH-/-) mice were produced by homologous recombination and exhibited striking reduction of body weight due to hypophagia and increased metabolic rate (11). The phenotypes of MCH-/- mice were attributed to the absence of the orexigenic MCH peptide. However, these mice carried a PGK-neor cassette instead of the region encompassing the exons I-III of the MCH gene. It is now of obvious interest to determine whether the presence of the PGK-neor and/or deletion in the putative 3' end-untranslated region of the AROM mRNAs results in any changes of AROM gene expression associated with modifications of feeding behavior (and other functions) in the MCH-/- mice." [Full Text]

Cvetkovic V, Brischoux F, Griffond B, Bernard G, Jacquemard C, Fellmann D, Risold PY.
Evidence of melanin-concentrating hormone-containing neurons supplying both cortical and neuroendocrine projections.
Neuroscience 2003;116(1):31-5
"In the rat, melanin-concentrating hormone-containing projections are detected in the median eminence and in the neural lobe of the pituitary. After vascular injections of the retrograde tracers fluorogold or fastblue, melanin-concentrating hormone neurons are retrogradely labeled in the rostromedial zona incerta and adjacent perifornical region. These neurons may be the source of the melanin-concentrating hormone projections toward the median eminence and posterior pituitary, and may release their secretory products into the bloodstream. After fastblue injections in the cerebral cortex and vascular fluorogold injections, some melaninconcentrating hormone neurons contain both tracers, indicating that they send collaterals in the cerebral cortex and in the median eminence/posterior pituitary. No such collaterals have been described for the classical neuroendocrine systems. The melanin-concentrating hormone system is thought to play a role in arousal in correlation with specific goal oriented behaviors such as feeding or reproduction. Some MCH neurons may be involved in such functions by modulating directly cortical activity as well as being neuroendocrine." [Abstract]

(11) Shimada M, Tritos NA, Lowell BB, Flier JS, Maratos-Flier E.
Mice lacking melanin-concentrating hormone are hypophagic and lean.
Nature 1998 Dec 17;396(6712):670-4 [Abstract]

Donald J. Marsh, Drew T. Weingarth, Dawn E. Novi, Howard Y. Chen, Myrna E. Trumbauer, Airu S. Chen, Xiao-Ming Guan, Michael M. Jiang, Yue Feng, Ramon E. Camacho, Zhu Shen, Easter G. Frazier, Hong Yu, Joseph M. Metzger, Stephanie J. Kuca, Lauren P. Shearman, Shobhna Gopal-Truter, Douglas J. MacNeil, Alison M. Strack, D. Euan MacIntyre, Lex H. T. Van der Ploeg, and Su Qian
Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism
PNAS 99: 3240-3245; published online before print as 10.1073/pnas.052706899 [Full Text]

Christine L. Chaffer, and Margaret J. Morris
The Feeding Response to Melanin-Concentrating Hormone Is Attenuated by Antagonism of the NPY Y1-Receptor in the Rat
Endocrinology 143: 191-197, 2002.
"Inhibition of MCH-induced feeding by two structurally different NPY Y1-receptor antagonists provides strong evidence that the orexigenic action of MCH involves the Y1-receptor." [Abstract]

Ludwig, David S., Tritos, Nicholas A., Mastaitis, Jason W., Kulkarni, Rohit, Kokkotou, Efi, Elmquist, Joel, Lowell, Bradford, Flier, Jeffrey S., Maratos-Flier, Eleftheria
Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance
J. Clin. Invest. 2001 107: 379-386
"Several lines of investigation suggest that the hypothalamic neuropeptide melanin-concentrating hormone (MCH) regulates body weight in mammals. Obese mice lacking functional leptin overexpress the MCH message in the fed or fasted state. Acute intracerebroventricular injection of MCH increases energy intake in rats. Mice lacking the MCH gene are lean. To test the hypothesis that chronic overexpression of MCH in mice causes obesity, we produced transgenic mice that overexpress MCH (MCH-OE) in the lateral hypothalamus at approximately twofold higher levels than normal mice. On the FVB genetic background, homozygous transgenic animals fed a high-fat diet ate 10% more and were 12% heavier at 13 weeks of age than wild-type animals, and they had higher systemic leptin levels. Blood glucose levels were higher both preprandially and after an intraperitoneal glucose injection. MCH-OE animals were insulin-resistant, as demonstrated by markedly higher plasma insulin levels and a blunted response to insulin; MCH-OE animals had only a 5% decrease in blood glucose after insulin administration, compared with a 31% decrease in wild-type animals. MCH-OE animals also exhibited a twofold increase in islet size. To evaluate the contribution of genetic background to the predisposition to obesity seen in MCH-OE mice, the transgene was bred onto the C57BL/6J background. Heterozygote C57BL/6J mice expressing the transgene showed increased body weight on a standard diet, confirming that MCH overexpression can lead to obesity." [Full Text]

Sergeev VG, Akmaev IG.
Effects of blockers of carbohydrate and lipid metabolism on expression of mRNA of some hypothalamic neuropeptides.
Bull Exp Biol Med 2000 Aug;130(8):766-8
"The effects of single injections of 2-deoxyglucose or 2-mercaptoacetate on the expression of mRNA of neuropeptide Y, pro-opiomelanocortin, and melanin-concentrating hormone in rat hypothalamus were studied by in situ hybridization in order to elucidate the role of these neuropeptides in the mechanisms of alimentary behavior caused by decreased levels of available fatty acids and glucose. The levels of neuropeptide Y mRNA in arcuate nuclei neurons are significantly increased under conditions of glucose deficiency, while the synthesis of melanin-concentrating hormone in the lateral hypothalamic neurons is increased in fatty acid deficiency. These data indicate that glyco- and lipodeprivation are different metabolic signals activating various neuropeptide systems responsible for alimentary behavior." [Abstract]

Gonzalez MI, Kalia V, Hole DR, Wilson CA.
alpha-Melanocyte-stimulating hormone (alpha-MSH) and melanin-concentrating hormone (MCH) modify monoaminergic levels in the preoptic area of the rat.
Peptides 1997;18(3):387-92
"The effect of perfusion of melanin-concentrating hormone (MCH) or alpha-melanocyte-stimulating hormone (alpha-MSH) (100 ng/microliter) in the ventromedial nucleus (VMN) or medial preoptic area (MPOA) on monoaminergic levels of female rats was measured using microdialysis and HPLC-electrochemical detection. In the MPOA, alpha-MSH raised 5-HIAA concentration, whereas MCH reduced both 5-HT and 5-HIAA. Neither peptide had any effect in the VMN. The opposite effects of the peptides on the serotonergic system might be responsible for their antagonistic or opposite actions previously reported on several CNS functions. Dopamine may mediate the similar effects of the two peptides, because alpha-MSH inhibits dopaminergic release in the MPOA (but not VMN) and MCH tends to follow the same pattern." [Abstract]

Songzhu An, Gene Cutler, Jack Jiagang Zhao, Shu-Gui Huang, Hui Tian, Wanbo Li, Lingming Liang, Miki Rich, Amy Bakleh, Juan Du, Jin-Long Chen, and Kang Dai
Identification and characterization of a melanin-concentrating hormone receptor
PNAS 98: 7576-7581, June 2001.
"Melanin-concentrating hormone (MCH), a neuropeptide expressed in central and peripheral nervous systems, plays an important role in the control of feeding behaviors and energy metabolism. An orphan G protein-coupled receptor (SLC-1/GPR24) has recently been identified as a receptor for MCH (MCHR1). We report here the identification and characterization of a G protein-coupled receptor as the MCH receptor subtype 2 (MCHR2). MCHR2 has higher protein sequence homology to MCHR1 than any other G protein-coupled receptor. The expression of MCHR2 has been detected in many regions of the brain. In contrast to MCHR1, which is intronless in the coding region and is located at the chromosomal locus 22q13.3, the MCHR2 gene has multiple exons and is mapped to locus 6q21. MCHR2 is specifically activated by nanomolar concentrations of MCH, binds to MCH with high affinity, and signals through Gq protein." [Full Text]

Rodriguez, M., Beauverger, P., Naime, I., Rique, H., Ouvry, C., Souchaud, S., Dromaint, S., Nagel, N., Suply, T., Audinot, V., Boutin, J. A., Galizzi, J. P.
Cloning and Molecular Characterization of the Novel Human Melanin-Concentrating Hormone Receptor MCH2
Mol Pharmacol 2001 60: 632-639
"Using a genomics-based approach for screening orphan G-protein-coupled receptors, we have identified and cloned a novel high-affinity, melanin-concentrating hormone (MCH) receptor. This receptor, named S643b, displays the greatest overall identity (32%) with the previously reported human SLC-1 receptor (MCH1) and to a lesser extent with the somatostatin receptor subtypes. The gene encoding the S643b receptor spans more than 23 kilobase pairs (kb) and was mapped, by radiation hybrid experiments, on chromosome 6q14.3-q15. Comparison of the S643b cDNA with human genomic sequence reveals that the 340-amino-acid receptor is encoded by five exons. Its tissue distribution, as determined by Northern blot and reverse transcription-polymerase chain reaction analysis, indicates that a 4-kb transcript is predominantly expressed in the brain. When expressed in Chinese hamster ovary (CHO) cells, the S643b receptor displays a strong, dose-dependent, transient elevation of intracellular calcium in response to MCH (EC50 = 9.5 nM). During the present study, we isolated a splice variant, designated S643a, encoding for a receptor that was not activated by MCH in a cellular calcium mobilization assay. Comparative pharmacological studies using CHO cells stably expressing either SLC-1 or S643b receptors demonstrated that similar structural features of MCH are required to stimulate intracellular Ca2+ mobilization at both receptors. The identification and localization of this new MCH receptor (MCH2) provides further insight into the physiological implication of MCH in modulating behavioral responses, including food intake." [Abstract]

Mori M, Harada M, Terao Y, Sugo T, Watanabe T, Shimomura Y, Abe M, Shintani Y, Onda H, Nishimura O, Fujino M.
Cloning of a novel G protein-coupled receptor, SLT, a subtype of the melanin-concentrating hormone receptor.
Biochem Biophys Res Commun 2001 May 25;283(5):1013-8
"A DNA fragment encoding an amino acid sequence possessing common features to the G protein-coupled receptor (GPCR) superfamily was found in the human genomic sequence, and from this information, the full-length cDNA of a novel GPCR, designated SLT, was cloned from the human hippocampus cDNA library. SLT showed the highest homology to the melanin-concentrating hormone (MCH) receptor, SLC-1 (31.5% identity), and to a lesser extent, to the somatostatin (SST) receptor subtypes. MCH exhibited agonistic behavior when applied to the SLT-expressing CHO cells at subnanomolar doses whereas more than 200 known peptides, including SST and cortistatin, did not. These results indicated that MCH is the cognate ligand of the SLT receptor and that this newly cloned GPCR is the second subtype of the MCH receptor. Quantitative polymerase chain reaction analysis of the SLT gene expression in human tissues showed that the SLT receptor is expressed mainly in brain areas including the cerebral cortex, amygdala, hippocampus, and corpus callosum, as well as in a limited number of peripheral tissues. The distribution of the SLT nearly overlapped that of SLC-1, suggesting that some of the neural functions of MCH may be mediated by both of these receptor subtypes. Copyright 2001 Academic Press." [Abstract]

Andreas W. Sailer, Hideki Sano, Zhizhen Zeng, Terrence P. McDonald, Jie Pan, Sheng-Shung Pong, Scott D. Feighner, Carina P. Tan, Takehiro Fukami, Hisashi Iwaasa, Donna L. Hreniuk, Nancy R. Morin, Sharon J. Sadowski, Makoto Ito, Masahiko Ito, Alka Bansal, Betty Ky, David J. Figueroa, Qingping Jiang, Christopher P. Austin, Douglas J. MacNeil, Akane Ishihara, Masaki Ihara, Akio Kanatani, Lex H. T. Van der Ploeg, Andrew D. Howard, and Qingyun Liu
Identification and characterization of a second melanin-concentrating hormone receptor, MCH-2R
PNAS 98: 7564-7569; published online before print as 10.1073/pnas.121170598
"Recently, several groups reported the identification of an orphan G protein-coupled receptor as a receptor for MCH (MCH-1R). We hereby report the identification of a second human MCH receptor termed MCH-2R, which shares about 38% amino acid identity with MCH-1R. MCH-2R displayed high-affinity MCH binding, resulting in inositol phosphate turnover and release of intracellular calcium in mammalian cells. In contrast to MCH-1R, MCH-2R signaling is not sensitive to pertussis toxin and MCH-2R cannot reduce forskolin-stimulated cAMP production, suggesting an exclusive G{alpha}q coupling of the MCH-2R in cell-based systems. Northern blot and in situ hybridization analysis of human and monkey tissue shows that expression of MCH-2R mRNA is restricted to several regions of the brain, including the arcuate nucleus and the ventral medial hypothalamus, areas implicated in regulation of body weight. In addition, the human MCH-2R gene was mapped to the long arm of chromosome 6 at band 6q16.2-16.3, a region reported to be associated with cytogenetic abnormalities of obese patients. The characterization of a second mammalian G protein-coupled receptor for MCH potentially indicates that the control of energy homeostasis in mammals by the MCH neuropeptide system may be more complex than initially anticipated.
...
Expression Analysis of MCH-2R. Northern blot analysis of multiple human tissues using radio-labeled MCH-2R cDNA as a probe detected a 4.4-kb mRNA transcript for MCH-2R specifically expressed in brain (Fig. 3A). To increase spatial resolution we continued our expression analysis by in situ hybridization of rhesus monkey brain tissue using radio-labeled human MCH-2R riboprobes (Fig. 3B). The antisense probe demonstrated high levels of MCH-2R mRNA expression in cerebral cortex, hippocampus, and hypothalamus, with lower levels of expression in the caudate nucleus, putamen, and thalamus. Sense control probe showed no signal. To compare expression of the two MCH receptors in the hypothalamus, adjacent coronal sections of African green monkey brain were hybridized with riboprobes complementary to one or the other MCH receptor (Fig. 3 C and D). In the dorsomedial hypothalamus, there was strong MCH-1R expression but little or no MCH-2R expression. Conversely, in the anterior and lateral hypothalamic areas, MCH-2R expression was abundant, whereas MCH-1R signal was barely detectable. The ventromedial hypothalamic nuclei displayed abundant signal for both MCH-1R and MCH-2R." [Full Text]

Jeffrey Hill, Malcolm Duckworth, Paul Murdock, Gillian Rennie, Cibele Sabido-David, Robert S. Ames, Philip Szekeres, Shelagh Wilson, Derk J. Bergsma, Israel S. Gloger, Dana S. Levy, Jon K. Chambers, and Alison I. Muir
Molecular Cloning and Functional Characterization of MCH2, a Novel Human MCH Receptor
J. Biol. Chem. 276: 20125-20129, June 2001.
"This report describes the cloning and functional characterization of a novel second human MCH receptor, which we designate MCH2, initially identified in a genomic survey sequence as being homologous to MCH1 receptors. Using this sequence, a full-length cDNA was generated with an open reading frame of 1023 base pairs, encoding a polypeptide of 340 amino acids, with 38% identity to MCH1 and with many of the structural features conserved in G protein-coupled receptors. This newly discovered receptor belongs to class 1 (rhodopsin-like) of the G protein-coupled receptor superfamily. HEK293 cells transfected with MCH2 receptors responded to nanomolar concentrations of MCH with an increase in intracellular Ca2+ levels and increased cellular extrusion of protons. In addition, fluorescently labeled MCH bound with nanomolar affinity to these cells. The tissue localization of MCH2 receptor mRNA, as determined by quantitative reverse transcription-polymerase chain reaction, was similar to that of MCH1 in that both receptors are expressed predominantly in the brain." [Full Text]

Suke Wang, Jiang Behan, Kim O'Neill, Blair Weig, Steven Fried, Thomas Laz, Marvin Bayne, Eric Gustafson, and Brian E. Hawes
Identification and Pharmacological Characterization of a Novel Human Melanin-concentrating Hormone Receptor, MCH-R2
J. Biol. Chem. 276: 34664-34670, July 2001.
"Herein we identify and characterize a novel receptor for human MCH (MCH-R2). The receptor is composed of 340 amino acids encoded by a 1023-base pair cDNA and is 35% homologous to SLC-1. 125I-MCH specifically bound to Chinese hamster ovary cells stably expressing MCH-R2. MCH stimulated dose-dependent increases in intracellular free Ca2+ and inositol phosphate production in these cells but did not affect cAMP production.
...
In contrast, the MCH-R2 mRNA is expressed almost exclusively in cortical regions of human brain (Fig. 6). Major areas of overlap between the two subtypes appear to be the nucleus accumbens, amygdala, and hippocampus. MCH-R2 also appears to be neuronal in nature because there is no signal in the corpus callosum RNA." [Full Text]

Audinot V, Lahaye C, Suply T, Rovere-Jovene C, Rodriguez M, Nicolas JP, Beauverger P, Cardinaud B, Galizzi JP, Fauchere JL, Nahon JL, Boutin JA.
SVK14 cells express an MCH binding site different from the MCH1 or MCH2 receptor.
Biochem Biophys Res Commun 2002 Jul 26;295(4):841-8
"Melanin-concentrating hormone (MCH) is a cyclic peptide, mainly involved in the regulation of skin pigmentation in teleosts and feeding behavior in mammals. The human keratinocyte SVK14 cell line has been previously shown to express binding sites for the MCH analog [125I]-[Phe13,3-iodo-Tyr19]MCH. We report here that: (1) this binding site similarly recognized [125I]-[3-iodo-Tyr13]MCH; (2) its pharmacological profile clearly differed from those observed at the two human MCH receptor subtypes, MCH1-R and MCH2-R; (3) MCH did not induce any effect on second messenger systems (including cAMP, calcium, and MAP kinase signaling pathways), and (4) no mRNAs corresponding to the MCH receptors were found. In conclusion, the binding site characterized in the SVK14 cell line is distinct from the MCH1 and MCH2 receptors and deserves therefore further investigation." [Abstract]

Brian E. Hawes, Erin Kil, Beverly Green, Kim O’Neill, Steve Fried, and Michael P. Graziano
The Melanin-Concentrating Hormone Receptor Couples to Multiple G Proteins to Activate Diverse Intracellular Signaling Pathways
Endocrinology 141: 4524-4532, 2000.
"The receptor for melanin-concentrating hormone (MCH) was recently identified as the orphan G protein-coupled receptor SLC-1. In this study, a CHO cell line expressing the MCH receptor (Kd = 1.3 nM; binding capacity, 3.6 pmol/mg protein) is used to assess the ability of the MCH receptor to couple to Gi, Go, and Gq proteins. The results demonstrate that MCH inhibits forskolin-stimulated cAMP production in a pertussis toxin- (PTX)-sensitive manner in CHO-MCHR cells (EC50 = 100 pM), indicating that the MCH receptor couples to one or more members of the Gi subfamily of G proteins. In addition, MCH stimulates increases in phosphoinositide metabolism (EC50 = 50 nM) and in intracellular free Ca2+ levels (EC50 = 10 nM). MCH-stimulated inositol phosphate production and increases in intracellular free Ca2+ are partially inhibited (60% and 40%, respectively) by PTX pretreatment, demonstrating that there are at least two components of each of these signaling pathways. One component is PTX sensitive and therefore mediated through a Gi/Go protein. A distinct G protein-coupled (probably Gq type) mediates the PTX-insensitive component. To distinguish Gi vs. Go coupling, MCH-stimulated mitogen-activated protein (MAP) kinase activity was examined. Gi and Go use separate signaling pathways to mediate MAP kinase activation in CHO cells. Protein kinase C (PKC) activity is essential in the Go-dependent MAP kinase signaling pathway, but is not required in the Gi-dependent MAP kinase signaling pathway. MCH stimulated MAP kinase activity is decreased (50%), but not abolished, by inhibition of PKC activity or depletion of cellular PKC, indicating that MCH-stimulated MAP kinase activity is mediated through both Gi- and Go-dependent signaling mechanisms. The results of this study are the first to clearly demonstrate that the MCH receptor couples to multiple G proteins to mediate several diverse intracellular signaling pathways." [Full Text]

Monzon ME, Varas MM, De Barioglio SR.
Anxiogenesis induced by nitric oxide synthase inhibition and anxiolytic effect of melanin-concentrating hormone (MCH) in rat brain.
Peptides 2001 Jul;22(7):1043-7
"In this study, the involvement of nitric oxide (NO) in the mechanism of anxiety was investigated. The rats received an intraamygdaline or intrahippocampal injection of the nitric oxide synthase inhibitor, N(G)-nitro-l-arginine (L-NOARG), and were then tested in the plus-maze test. L-NOARG induced a decrease in the time spent by rats in the open arms. Conversely, the administration of the melanin-concentrating hormone (MCH) into these structures increased the number of entries into the open arms as well as the time spent on them. MCH injected in rats pretreated with L-NOARG also was able to revert the anxiogenic effects of L-NOARG in amygdala." [Abstract]

Gao, Xiao-Bing, van den Pol, Anthony N.
Melanin concentrating hormone depresses synaptic activity of glutamate and GABA neurons from rat lateral hypothalamus
J Physiol (Lond) 2001 533: 237-252
"In conclusion, we find that MCH exerts a strong inhibition of synaptic activity in LH neurons. The mechanism appears to be based on a pertussis toxin-sensitive Gi/Go protein coupling that may reduce calcium currents at VDCCs, decrease cation currents at glutamate receptors and reduce transmitter release. The inhibition of both excitatory and inhibitory synaptic activity by MCH underlines the importance of elucidating the precise synaptic relations of MCH, GABA, and glutamatergic cells to fully understand the role of MCH within the brain. This is further underscored by the opposing excitatory actions of hypocretin. Complex behaviours such as feeding that involve neurons of the LH may not be amenable to simple explanations coupling single neuropeptides with a monotonic function." [Full Text]

Gao, Xiao-Bing, van den Pol, Anthony N.
Melanin-concentrating hormone depresses L-, N-, and P/Q-type voltage-dependent calcium channels in rat lateral hypothalamic neurons
J Physiol (Lond) 2002 542: 273-286
"Melanin-concentrating hormone (MCH), a cyclic 19-amino-acid peptide, is synthesized exclusively by neurons in the lateral hypothalamic (LH) area. It is involved in a number of brain functions and recently has raised interest because of its role in energy homeostasis. MCH axons and receptors are found throughout the brain. Previous reports set the foundation for understanding the cellular actions of MCH by using non-neuronal cells transfected with the MCH receptor gene; these cells exhibited an increase in cytoplasmic calcium in response to MCH, suggesting an excitatory action for the peptide. In the study presented here, we have used whole-cell recording in 117 neurons from LH cultures and brain slices to examine the actions of MCH. MCH decreased the amplitude of voltage-dependent calcium currents in almost all tested neurons. The inhibition desensitized rapidly (18 s to half maximum at 100 nM concentration) and was dose-dependent (IC50 = 7.8 nM) when activated with a pulse from -80 mV to 0 mV. A priori activation of G-proteins with GTPS completely eliminated the MCH-induced effect at low MCH concentrations and reduced the MCH-induced effect at high MCH concentrations. Inhibition of G-proteins with pertussis toxin (PTX) blocked the MCH-induced inhibitory effect at high MCH concentrations. Pre-pulse depolarization resulted in an attenuation of the MCH-induced inhibition of calcium currents in most neurons. These data suggest that MCH exerts an inhibitory effect on calcium currents via PTX-sensitive G-protein pathways, probably the Gi/Go pathway, in LH neurons. L-, N- and P/Q-type calcium channels were identified in LH neurons, with L- and N-type channels accounting for most of the voltage-activated current (about 40 % each); MCH attenuated each of the three types (mean 50 % depression), with the greatest inhibition found for N-type currents. In contrast to previous data on non-neuronal cells showing an MHC-evoked increase in calcium, our data suggest that the reverse occurs in LH neurons. The attenuation of calcium currents is consistent with an inhibitory action for the peptide in neurons." [Abstract]

F Presse, B Cardona, L Borsu, and JL Nahon
Lithium increases melanin-concentrating hormone mRNA stability and inhibits tyrosine hydroxylase gene expression in PC12 cells.
Brain Res Mol Brain Res, Dec 1997; 52(2): 270-83.
"Here, we analysed the actions of nerve growth factor (NGF), dexamethasone, forskolin and lithium on MCH mRNA levels in the PC12 pheochromocytoma cell line. We compared them with those observed on tyrosine hydroxylase (TH) mRNA, constitutively expressed in PC12 cells, and neurotensin (NT) mRNA, taken as a control. In untreated cells, MCH RNA species of high molecular weight were found. Exposure of cells at a combination of NGF and lithium resulted in decreased expression of these MCH RNAs and in the transient production of mature MCH mRNA. Strikingly, after short exposure of PC12 cells to NGF, lithium per se elicited a marked increase in MCH mRNA levels whilst it exerted a potent inhibitory action on TH mRNA expression. Detailed investigations revealed that lithium enhanced MCH mRNA expression through post-transcriptional mechanisms whereas it regulated TH gene expression mainly at the level of transcription. These results demonstrate that lithium, an agent widely used for treatment of manic depressive illness, can exert an opposite effect on MCH and TH mRNA production in PC12 cells. The MCH gene system in NGF-treated PC12 cells provides a good opportunity for studying the effect of lithium on gene expression at post-transcriptional levels in a neuron-like cellular model." [Abstract]

Brischoux F, Fellmann D, Risold PY.
Ontogenetic development of the diencephalic MCH neurons: a hypothalamic 'MCH area' hypothesis.
Eur J Neurosci 2001 May;13(9):1733-44
"The ontogeny of rat diencephalic melanin-concentrating hormone (MCH) neurons has been analysed, using the bromodeoxyuridine method to determine the period of birth of these neurons, and using in situ hybridization and immunohistochemistry to study their chemical differentiation. The spatiotemporal pattern of MCH neuron generation is complex, although it is broadly lateromedial with a peak between embryonic days (E) 12 and E13. The first expression of the MCH gene has been detected on E13 in neurons in the presumptive lateral hypothalamic area. But the adult-like pattern was observed from E18. Medial-most MCH neurons express the peptide CART (cocaine-amphetamine-regulated transcript) from E18, and the receptor neurokinin 3 (NK3) from between postnatal day (P) 0 and P5. These results are discussed and compared with data from the literature to better understand the organization of the 'MCH-containing area'." [Abstract]

Efi G. Kokkotou, Nicholas A. Tritos, Jason W. Mastaitis, Lawrence Slieker, and Eleftheria Maratos-Flier
Melanin-Concentrating Hormone Receptor Is a Target of Leptin Action in the Mouse Brain
Endocrinology 142: 680-686, 2001.
"We also studied MCH-R regulation and found that MCH-R expression is increased 7-fold by 48-h fasting or genetic leptin deficiency (ob/ob mice) and is completely blunted by leptin administration. In contrast, MCH-R messenger RNA expression remains unaltered in genetic MCH deficiency. Our findings suggest that MCH-R constitutes a central target of leptin action in the mammalian brain." [Full Text]

Jeanrenaud B, Rohner-Jeanrenaud F.
Effects of neuropeptides and leptin on nutrient partitioning: dysregulations in obesity.
Annu Rev Med 2001;52:339-51
"Body weight homeostasis is maintained via a series of complex interactions that occur between the brain (particularly the hypothalamus) and the periphery, notably via the hormone leptin, which is synthesized in and secreted from adipose tissue. Under normal conditions, a dynamic equilibrium exists between anabolic neuropeptides (orexigenic peptides), which favor food intake, decrease energy expenditure, and facilitate fat storage, and catabolic ones (anorexigenic peptides), which decrease food intake, increase energy expenditure, and facilitate the loss of fat stores. Secreted leptin, although it may have some direct peripheral effects, exerts its action principally within the brain. Following its transport through the blood-brain barrier, leptin reaches the hypothalamic area, where it binds to its long receptor isoform. After a specific signaling cascade, leptin inhibits many of the orexigenic neuropeptides while favoring many of the anorexigenic ones. Thus, leptin decreases food intake and body weight, and it increases fat oxidation and energy expenditure, ultimately favoring leanness. Lack of leptin secretion, the inability of leptin to reach the brain, or the inability of leptin to interact with hypothalamic leptin receptors, prevent leptin's effects and lead to obesity." [Abstract]

Viale, A, Ortola, C, Richard, F, Vernier, P, Presse, F, Schilling, S, Dutrillaux, B, Nahon, JL
Emergence of a brain-expressed variant melanin-concentrating hormone gene during higher primate evolution: a gene "in search of a function"
Mol Biol Evol 1998 15: 196-214
"Southern blotting, PCR analyses using several genomic DNAs of Primates, and in situ hybridization on metaphase chromosomes led us to define at least three types of genetic events associated with the emergence of the variant MCH gene: (1) translocation of an exon II-exon III copy of the authentic MCH gene onto the equivalent of the human chromosome 5p arm of Anthropoidea ancestors (between 25 and 55 MYA); (2) exon II truncation and mutations before divergence of the Hylobatidae (about 15 MYA); and (3) duplication of the variant gene on the equivalent of the human chromosome 5p and 5q arms in the Hominidae, i.e., 5-10 MYA. Taken together, these results support the hypothesis that transposition/gene rearrangement processes could underlie the evolutionary emergence of new MCH-related genes expressed differentially in the brains of higher Primates, illustrating the concept of genes "in search of function" instead of true "pseudogenes." "
[Abstract/Full Text]

Viale A, Zhixing Y, Breton C, Pedeutour F, Coquerel A, Jordan D, Nahon JL.
The melanin-concentrating hormone gene in human: flanking region analysis, fine chromosome mapping, and tissue-specific expression.
Brain Res Mol Brain Res 1997 Jun;46(1-2):243-55
"Genomic sequences encoding the human melanin-concentrating hormone (MCH) were isolated from a YAC library and subcloned in pUC vector using a novel E. coli transformation method. A 4.1-kb fragment encompassing approximately 1.0 kb of the 5'-end-flanking region, the three exons-two introns of the coding region and approximately 1.7 kb of the 3'-end-flanking region, was sequenced. Comparison with the rat MCH gene indicated strong conservation in the 5'-flanking region, in particular over the putative TATA box, CAAT box, GRE and AP-1 elements that could potentially regulate MCH gene expression. FISH with a fluorescent MCH genomic probe on human chromosomes and PCR analysis of a YAC panel mapped MCH to chromosome 12q23.1 in a region flanked by D12S1074 and D12S1030 markers. Expression of the MCH RNA species and pro-MCH-derived peptides (MCH and NEI) was investigated in human tissues by combining Northern blotting, RT-PCR, in situ hybridization, immunohistochemistry and RIA. In the human brain, MCH mRNA and MCH/NEI peptides were predominantely expressed in the lateral hypothalamus in agreement with the known distribution of MCH expression in rat. In addition, MCH gene products were detected in extra-hypothalamic sites, such as the pallidum, neocortex and cerebellum. In peripheral tissues, MCH mRNA was identified in several organs, including the thymus, brown adipose tissue, duodenum and testis. An additional shorter MCH gene transcript, likely the result of alternate splicing, was revealed in several brain areas and peripheral tissues. While only fully processed MCH and NEI were found in hypothalamus, a different peptide form, bearing MCH and NEI epitopes, was detected in peripheral organs. This represents the first evidence for differential processing of pro-MCH in mammals." [Abstract]

Breton C, Schorpp M, Nahon JL.
Isolation and characterization of the human melanin-concentrating hormone gene and a variant gene.
Brain Res Mol Brain Res 1993 Jun;18(4):297-310 [Abstract]

Yamada M, Miyakawa T, Duttaroy A, Yamanaka A, Moriguchi T, Makita R, Ogawa M, Chou CJ, Xia B, Crawley JN, Felder CC, Deng CX, Wess J.
Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean.
Nature 2001 Mar 8;410(6825):207-12
"Here we show that mice deficient in the M3 muscarinic receptor (M3R-/- mice) display a significant decrease in food intake, reduced body weight and peripheral fat deposits, and very low levels of serum leptin and insulin. Paradoxically, hypothalamic messenger RNA levels of melanin-concentrating hormone (MCH), which are normally upregulated in fasted animals leading to an increase in food intake, are significantly reduced in M3R-/- mice. Intra-cerebroventricular injection studies show that an agouti-related peptide analogue lacked orexigenic (appetite-stimulating) activity in M3R-/- mice. However, M3R-/- mice remained responsive to the orexigenic effects of MCH. Our data indicate that there may be a cholinergic pathway that involves M3-receptor-mediated facilitation of food intake at a site downstream of the hypothalamic leptin/melanocortin system and upstream of the MCH system." [Abstract]

Gonzalez MI, Baker BI, Hole DR, Wilson CA.
Behavioral effects of neuropeptide E-I (NEI) in the female rat: interactions with alpha-MSH, MCH and dopamine.
Peptides 1998;19(6):1007-16
"The behavioral and neurochemical effects of NEI, and its interaction with alpha-MSH or MCH were investigated in the ventromedial nucleus (VMN) and medial preoptic area (MPOA) in female rats (bilateral administration, 100 ng in 0.5 microliter/side). NEI in the VMN (but not in the MPOA) stimulated exploratory behavior, increased anxiety and reduced dopamine and DOPAC release. The behavioral effects were antagonized by alpha-MSH. NEI stimulated female sexual receptivity in the MPOA. In the VMN, NEI did not have any effect on sexual activity, but partially antagonized the stimulatory effect of MCH. These results show that NEI in the hypothalamus participates in the regulation of behavior, possibly through dopaminergic mediation." [Abstract]

Sanchez M, Baker BI, Celis M.
Melanin-concentrating hormone (MCH) antagonizes the effects of alpha-MSH and neuropeptide E-I on grooming and locomotor activities in the rat.
Peptides 1997;18(3):393-6
"The intraventricular (i.c.v.) administration of the neuropeptide melanocyte stimulating hormone (alpha-MSH) is known to elicit a series of behaviors in the rat which include excessive grooming and other motor activities. In bony fish, the pigmentary effects of alpha-MSH can be antagonized by the neuropeptide melanin-concentrating hormone (MCH). We therefore examined whether MCH or its sister peptide neuro-peptide E-I (NEI), derived from the same precursor molecule, would modulate the effect of alpha-MSH on grooming and motor activity in the rat, or perhaps elicit some responses of their own. Rats were injected i.c.v. with either artificial cerebrospinal fluid, alpha-MSH, MCH, NEI, or with two peptides together, and behavioral responses were monitored over the next 65 min. The i.c.v. injection of 1 microgram MSH significantly enhanced grooming behavior. NEI at the same dose increased grooming, rearing, and locomotor activities. MCH alone had no behavioral effects but it annulled the behavioral responses induced by either alpha-MSH or NEI. alpha-MSH also antagonized the locomotor and rearing behavior induced by NEI. The physiological significance of these observations is discussed." [Abstract]

Griffond B, Ciofi P, Bayer L, Jacquemard C, Fellmann D.
Immunocytochemical detection of the neurokinin B receptor (NK3) on melanin-concentrating hormone (MCH) neurons in rat brain.
J Chem Neuroanat 1997 Mar;12(3):183-9
"The presence of the neurokinin B receptor (NK3 receptor) in the rat lateral hypothalamus and the zona incerta was previously reported. The aim of the present study was to define its cellular localization in these areas. Investigations, coupling immunocytochemical and in situ hybridization techniques, focussed on two neuron populations: the melanin-concentrating hormone (MCH) neurons and a population of neurons recognized by an ovine prolactin antiserum (PRL-ir neurons). While PRL-ir neurons did not exhibit NK3 immunoreactivity, 57% +/- 6% of MCH neurons were strongly stained by the NK3 antiserum. These results suggest that neurokinin B is involved in the regulation of MCH neuron activity via the NK3 receptor; they provide new bases for further investigations on MCH role in the control of food and water intake." [Abstract]

Bahjaoui-Bouhaddi M, Fellmann D, Griffond B, Bugnon C.
Insulin treatment stimulates the rat melanin-concentrating hormone-producing neurons.
Neuropeptides 1994 Oct;27(4):251-8
"Melanin-concentrating hormone (MCH) is involved in the regulation of body colour in teleost fish. A peptide highly homologous to salmon MCH has been found in the rat brain, but its physiological functions have not yet been precisely defined. The location of MCH neurons in the lateral hypothalamus (LHT) of the rat suggests possible implication in feeding behaviour. In the present study, immunohistochemical and in situ hybridization methods were used to investigate MCH gene expression following insulin injections. Five hours after insulin injection, a significant increase in the abundance and staining intensity of MCH immunoreactive perikarya and fibres was observed. Concurrently the level of MCH mRNA significantly increased (50%). Insulin-treatment also induced a marked and progressive increase in the number and staining intensity of nuclei detected by a Fos antiserum in LHT and other brain areas. Double labelling technique demonstrated that very few if any MCH neurons exhibited Fos-like immunoreactivity. These results demonstrate that an insulin-treatment stimulates MCH neuron activity without the mediation of the proto-oncogene c-fos. The mechanisms triggering this activation remain to be elucidated." [Abstract]

Presse F, Hervieu G, Imaki T, Sawchenko PE, Vale W, Nahon JL.
Rat melanin-concentrating hormone messenger ribonucleic acid expression: marked changes during development and after stress and glucocorticoid stimuli.
Endocrinology 1992 Sep;131(3):1241-50
"Melanin-concentrating hormone (MCH) is a cyclic neuropeptide first isolated from fish and rats. MCH may be involved in the control of the hypothalamic-pituitary-adrenocortical axis and, more generally, of specific goal-oriented behaviors and homeostatic functions in mammals. In this paper we examine 1) the cellular distribution of MCH gene transcripts in the rat central nervous system, 2) the changes in neuronal expression of MCH mRNA during rat development, and 3) the effects of stress and hormonal stimuli on rat MCH (rMCH) gene activity. Northern blot analysis and in situ hybridization histochemistry show that mature rMCH mRNA (1.0 kilobase) is very abundant in the zona incerta and the dorsolateral hypothalamus. While this is in agreement with previous peptide mapping by immunohistochemical techniques, a surprising new result is that a few clusters of rMCH mRNA-containing cells are found outside the hypothalamus, in the olfactory tubercle and the pontine tegmentum. Developmentally, rMCH mRNA is detected on embryonic day 18; its level increases gradually during early postnatal life and rises abruptly at weaning to reach a constant value in adult rats. In addition, striking variations in rMCH mRNA length occur during postnatal development and are found to be variations in the polyadenylate tail. Interestingly, this structural modification appears to be independent of the increase in rMCH mRNA levels. The regulation of rMCH mRNA expression by glucocorticoids and chronic stress is examined by Northern blot analysis. Chronic intermittent footshock stress causes a 58% or 29% decrease in rMCH mRNA content in the whole hypothalamus after a 1- or 3-day regimen, respectively. In contrast, the rMCH mRNA level returns to normal after a 7-day regimen. Two weeks after adrenalectomy (ADX) the whole hypothalamus rMCH mRNA content decreases 2.5-fold, but rises close to the control value 3 weeks after ADX. Dexamethasone administration 2 weeks after ADX not only reverses the fall in rMCH mRNA, it even provokes a slight increase (123% of control). No change in rMCH mRNA length is observed after chronic stress or ADX and dexamethasone injection. These results provide evidence for a negative regulation of rMCH gene expression by stress and suggest a major role for glucocorticoids in a positive feedback control of rMCH gene activity." [Abstract]

Hervieu GJ, Cluderay JE, Harrison D, Meakin J, Maycox P, Nasir S, Leslie RA.
The distribution of the mRNA and protein products of the melanin-concentrating hormone (MCH) receptor gene, slc-1, in the central nervous system of the rat.
Eur J Neurosci 2000 Apr;12(4):1194-216
"Melanin-concentrating hormone (MCH), a 19 amino acid cyclic peptide, is largely expressed in the hypothalamus. It is implicated in the control of general arousal and goal-orientated behaviours in mammals, and appears to be a key messenger in the regulation of food intake. An understanding of the biological actions of MCH has been so far hampered by the lack of information about its receptor(s) and their location in the brain. We recently identified the orphan G-protein-coupled receptor SLC-1 as a receptor for the neuropeptide MCH. We used in situ hybridization histochemistry and immunohistochemistry to determine the distribution of SLC-1 mRNA and its protein product in the rat brain and spinal cord. SLC-1 mRNA and protein were found to be widely and strongly expressed throughout the brain. Immunoreactivity was observed in areas that largely overlapped with regions mapping positive for mRNA. SLC-1 signals were observed in the cerebral cortex, caudate-putamen, hippocampal formation, amygdala, hypothalamus and thalamus, as well as in various nuclei of the mesencephalon and rhombencephalon. The distribution of the receptor mRNA and immunolabelling was in good general agreement with the previously reported distribution of MCH itself. Our data are consistent with the known biological effects of MCH in the brain, e.g. modulation of the stress response, sexual behaviour, anxiety, learning, seizure production, grooming and sensory gating, and with a role for SLC-1 in mediating these physiological actions." [Abstract]

A. R. Kennedy, J. F. Todd, S. A. Stanley, C. R. Abbott, C. J. Small, M. A. Ghatei, and S. R. Bloom
Melanin-Concentrating Hormone (MCH) Suppresses Thyroid Stimulating Hormone (TSH) release, in Vivo and in Vitro, via the Hypothalamus and the Pituitary
Endocrinology 142: 3265, 2001.
"MCH significantly reduces plasma TSH in vivo at 10 min (0.5 ± 0.07 ng/ml, p < 0.05, n = 8) and 60 min (0.33 ± 0.04 ng/ml, p < 0.01, n = 10) compared to saline (0.7 ± 0.07 ng/ml and 0.69 ± 0.07 ng/ml respectively) when administered intracerebroventricularly. Release of TRH form hypothalamic explants was significantly reduced in the presence of MCH production (7.1 ± 0.99 fmol/explant to 2.3 ± 0.4 fmol/explant p < 0.01, n = 18) and Neuropeptide EI (NEI) (8.47 ± 1.28 fmol/explant to 4.6 ± 1.13 p < 0.05, n = 16), a peptide, also encoded in the pre-pro-MCH gene. MCH was also shown to significantly reduce TRH stimulated TSH release from dispersed pituitary cell cultures (basal = 0.5 ± 0.06 ng/ml, 100 nM TRH = 0.9 ± 0.2 ng/ml, p < 0.05 0.1 nM MCH = 0.5 ± 0.1 ng/ml, p < 0.05, 1 nM MCH = 0.3 ± 0.03 ng/ml, p < 0.01, 10 nM MCH = 0.4 ± 0.02 ng/ml, p < 0.01, 1000 nM MCH = 0.4 ± 0.05 ng/ml, P < 0.01, n = 4), although basal release of TSH from these cultures was unaffected.

These data suggest a possible role for MCH in the control of energy homeostasis via inhibition of the thyroid axis." [Abstract]

Knigge KM, Baxter-Grillo D, Speciale J, Wagner J.
Melanotropic peptides in the mammalian brain: the melanin-concentrating hormone.
Peptides 1996;17(6):1063-73
"Melanin-concentrating hormone (MCH) has been identified in neurons of the mammalian brain. This review summarizes some current information regarding the cell biology of this neuropeptide and the topography of MCH-immunoreactive (-IR) neurons in several species including mouse, rat, hamster, guinea pig, rabbit, dog and monkey; and atlas of MCH-IR neurons in the hypothalamus and subthalamus of the brain of guinea pig is presented. Based upon the location of this MCH cell group, it is hypothesized that they may be functionally involved in circuits of extrapyramidal motor systems from striatal centers to the thalamus and cerebral cortex and to the midbrain and spinal cord." [Abstract]

Abrahamson EE, Moore RY.
The posterior hypothalamic area: chemoarchitecture and afferent connections.
Brain Res 2001 Jan 19;889(1-2):1-22
"This study provides an analysis of the chemoarchitecture of the posterior hypothalamic area (PHA) and a retrograde transport analysis of inputs to the PHA in the rat. The chemoarchitectural analysis reveals that the majority of PHA neurons contain glutamate. Hypocretin, melanin concentrating hormone, tyrosine hydroxylase, neuropeptide Y and gamma-aminobutyric acid are also found in subsets of PHA neurons, and fibers immunoreactive for these substances as well as for serotonin, dopamine-beta-hydroxylase and met-enkephalin are observed in the area and aid in the delineation of its borders. The retrograde tracing study demonstrates that the PHA receives input from multiple, diverse neuron populations. Descending projections to the PHA arise from the limbic forebrain (cingulate cortex and lateral septum) and both the medial and lateral hypothalamus. Subcortical visual nuclei, including the ventral lateral geniculate nucleus and intergeniculate leaflet, pretectal area, and superior colliculus, and the subthalamus (zona incerta, fields of Forel) also project to the PHA. Ascending projections to the PHA arise from brainstem cholinergic nuclei, the reticular formation, midbrain raphe nuclei, periaqueductal gray and parabrachial nucleus. Retrograde transport studies using the psuedorabies virus (PRV) demonstrate that the PHA receives input indirectly from the hippocampus, amygdala and suprachiasmatic nucleus through circuits including nuclei in the limbic forebrain and hypothalamus. These data suggest that the PHA is important in the neural control of behavioral state, modulating aspects of hippocampal, autonomic and cortical function as they relate to the elaboration of adaptive behavior." [Abstract]

Abrahamson EE, Leak RK, Moore RY.
The suprachiasmatic nucleus projects to posterior hypothalamic arousal systems.
Neuroreport 2001 Feb 12,;12(2):435-40
"The suprachiasmatic nucleus (SCN) temporally organizes behavior in part by sustaining arousal during the wake period of the sleep/wake cycle to consolidate adaptive waking behavior. In this study, we demonstrate direct projections from the SCN, in both the rat and the human brains, to perikarya and proximal dendrites of two groups of posterior hypothalamic neurons with axonal projections that suggest they are important in the regulation of arousal, one producing hypocretins (HCT) and the other melanin-concentrating hormone (MCH). In addition, we demonstrate that both HCT and MCH-producing neurons are immunoreactive for glutamate (GLU). These observations support the hypothesis that direct projections from the SCN to the posterior hypothalamus mediate the arousal function of the circadian timing system." [Abstract]

CL Miller, VJ Hruby, TO Matsunaga, and PC Bickford
Alpha-MSH and MCH are functional antagonists in a CNS auditory gating paradigm.
Peptides, May 1993; 14(3): 431-40.
"The peptides alpha-melanocyte stimulating hormone (alpha-MSH) and melanin concentrating hormone (MCH; rat and salmon sequence) were administered to anesthetized rats by intracerebroventricular infusion. Depth recordings were carried out in the dorsal hippocampus, and auditory gating was assessed. Auditory gating in this paradigm refers to the decrease in amplitude of the second of two tone-evoked CNS potentials that can be measured when pairs of identical tones are presented 500 ms apart. Alpha-MSH increases auditory gating, whereas MCH has the opposite effect. When MCH was administered prior to alpha-MSH, the ability of alpha-MSH to increase auditory gating was blocked. Thus, the two peptides appear to be functional antagonists." [Abstract]

KM Knigge and JE Wagner
Melanin-concentrating hormone (MCH) involvement in pentylenetetrazole (PTZ)-induced seizure in rat and guinea pig.
Peptides, Jan 1997; 18(7): 1095-7.
"Intraperitoneal injection of 60 mg/kg of pentylenetetrazole (PTZ) induced seizure in rats, but was subthreshold and did not result in seizure in guinea pigs. Three days after intracerebroventricular (i.c.v.) injection of 75 micrograms 6-hydroxydopamine (6-OHDA) in guinea pigs, PTZ induced seizures similar to those seen in rats. In both rats and 6-OHDA-treated guinea pigs, i.c.v. injection of melanin-concentrating hormone (MCH) 15 min before PTZ prevented seizure activity. These results suggest that MCH-containing neurons may participate in the neural circuits involved in expression of PTZ-induced seizure." [Abstract]

Viale, Agnes, Courseaux, Anouk, Presse, Francoise, Ortola, Christine, Breton, Christophe, Jordan, Daniel, Nahon, Jean-Louis
Structure and Expression of the Variant Melanin-Concentrating Hormone Genes: Only PMCHL1 Is Transcribed in the Developing Human Brain and Encodes a Putative Protein
Mol Biol Evol 2000 17: 1626-1640
"PMCHL1 was assigned to a 1-Mb region in chromosome 5p14.3." [Full Text]

Borowsky B, Durkin MM, Ogozalek K, Marzabadi MR, DeLeon J, Heurich R, Lichtblau H, Shaposhnik Z, Daniewska I, Blackburn TP, Branchek TA, Gerald C, Vaysse PJ, Forray C.
Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist.
Nat Med 2002 Aug;8(8):825-30
"Melanin concentrating hormone (MCH) is an orexigenic hypothalamic neuropeptide, which plays an important role in the complex regulation of energy balance and body weight. Here we show that SNAP-7941, a selective, high-affinity MCH1 receptor (MCH1-R) antagonist, inhibited food intake stimulated by central administration of MCH, reduced consumption of palatable food, and, after chronic administration to rats with diet-induced obesity, resulted in a marked, sustained decrease in body weight. In addition, after mapping the binding sites for [(3)H]SNAP-7941 in rat brain, we evaluated its effects in a series of behavioral models. SNAP-7941 produced effects similar to clinically used antidepressants and anxiolytics in three animal models of depression/anxiety: the rat forced-swim test, rat social interaction and guinea pig maternal-separation vocalization tests. Given these observations, an MCH1-R antagonist may be useful not only in the management of obesity but also as a treatment for depression and/or anxiety." [Abstract]

Saito Y, Cheng M, Leslie FM, Civelli O.
Expression of the melanin-concentrating hormone (MCH) receptor mRNA in the rat brain.
J Comp Neurol 2001 Jun 18;435(1):26-40
"The melanin-concentrating hormone (MCH) system is thought to be an important regulator of food intake. Recently the orphan G protein-coupled receptor SLC-1 was identified as the MCH receptor (MCHR). Preliminary analyses of MCHR mRNA distribution have supported a role for the MCH system in nutritional homeostasis. We report here a complete anatomical distribution of the MCHR mRNA. We have found high levels of expression of MCHR mRNA in most anatomical areas implicated in control of olfaction, with the exception of the main olfactory bulb. Dense labeling was also detected in the hippocampal formation, subiculum, and basolateral amygdala, all of which are important in learning and memory, and in the shell of the nucleus accumbens, a substrate for motivated behavior and feeding. Within the hypothalamus, MCHR mRNA was moderately expressed in the ventromedial nucleus, arcuate nucleus, and zona incerta, all of which serve key roles in the neuronal circuitry of feeding. In the brainstem, strong expression was observed in the locus coeruleus, which is implicated in arousal, as well as in nuclei that contribute to orofacial function and mastication, including the facial, hypoglossal, motor trigeminal, and dorsal motor vagus nuclei. In most regions there was a good correspondence between MCHR mRNA distribution and that of MCH-immunoreactive fibers. Taken together, these data suggest that MCH may act at various levels of the brain to integrate various aspects of feeding behavior. However, the extensive MCHR distribution throughout the brain suggests that this receptor may play a role in other functions, most notably reinforcement, arousal, sensorimotor integration, and autonomic control. Copyright 2001 Wiley-Liss, Inc." [Abstract]

Maria A. Bednarek, Carina Tan, Donna L. Hreniuk, Oksana C. Palyha, Douglas J. MacNeil, Lex H. Y. Van der Ploeg, Andrew D. Howard, and Scott D. Feighner
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
J. Biol. Chem. 277: 13821-13826, April 2002.
"Human melanin-concentrating hormone (hMCH) is a nonselective natural ligand for the human melanin-concentrating hormone receptors: hMCH-1R and hMCH-2R. Similarly, the smaller peptide encompassing the disulfide ring and Arg6 of hMCH, Ac-Arg6-cyclo(S-S)(Cys7-Met8-Leu9-Gly10-Arg11-Val12-Tyr13-Arg14-Pro15-Cys16)-NH2, Ac-hMCH(6-16)-NH2, binds to and activates equally well both human MCH receptors present in the brain. To separate the physiological functions of hMCH-1R from those of hMCH-2R, new potent and hMCH-1R selective agonists are necessary. In the present study, analogs of Ac-hMCH(6-16)-NH2 were prepared and tested in binding and functional assays on cells expressing the MCH receptors. In these peptides, Arg in position 6 was replaced with various D-amino acids and/or Gly in position 10 was substituted with various L-amino acids. Several of the new compounds turned out to be potent agonists at hMCH-1R with improved selectivity over hMCH-2R. For example, peptide 26 with D-Arg in place of L-Arg in position 6 and Asn in place of Gly in position 10, Ac-DArg6-cyclo(S-S)(Cys7-Met8-Leu9-Asn10-Arg11-Val12-Tyr13-Arg14-Pro15-Cys16)-NH2, was a potent hMCH-1R agonist (IC50 = 0.5 nM, EC50 = 47 nM) with more than 200-fold selectivity with respect to hMCH-2R. Apparently, these structural changes in positions 6 and 10 results in peptide conformations that allow for efficient interactions with hMCH-1R but are unfavorable for molecular recognition at hMCH-2R." [Abstract]

Macdonald, Douglas, Murgolo, Nicholas, Zhang, Rumin, Durkin, James P., Yao, Xiaorui, Strader, Catherine D., Graziano, Michael P.
Molecular Characterization of the Melanin-Concentrating Hormone/Receptor Complex: Identification of Critical Residues Involved in Binding and Activation
Mol Pharmacol 2000 58: 217-225
"In summary, the results of the present study are consistent with an interaction between Arg11 of MCH and Asp123(3.32) of the MCH receptor as a key component of agonist-mediated receptor activation. Further biophysical and genetic analysis will be required to completely map the interaction of MCH with its receptor." [Full Text]

Audinot, Valerie, Lahaye, Chantal, Suply, Thomas, Beauverger, Philippe, Rodriguez, Marianne, Galizzi, Jean-Pierre, Fauchere, Jean-Luc, Boutin, Jean A.
[125I]-S36057: a new and highly potent radioligand for the melanin-concentrating hormone receptor
Br. J. Pharmacol. 2001 133: 371-378
"In conclusion, [125I]-S36057 is a more potent and more stable radioligand than [125I]-[3-iodo Tyr13]-MCH that will represent a reliable tool for binding assays in the search of novel MCH ligands. It should also provide great help for autoradiographic studies of the MCH receptor distribution in the central nervous system." [Abstract]

Hintermann, Edith, Erb, Carl, Talke-Messerer, Christiane, Liu, Rong, Tanner, Heidi, Flammer, Josef, Eberle, Alex N.
Expression of the Melanin-Concentrating Hormone Receptor in Porcine and Human Ciliary Epithelial Cells
Invest. Ophthalmol. Vis. Sci. 2001 42: 206-209
"CONCLUSIONS. The presence of MCH-R in ciliary epithelial cells of both human and porcine origin but the absence of MSH-Rs indicates that in these cells, MCH and {alpha}-MSH do not form a functionally antagonistic hormonal pair as they do in several other systems. Although effects of MCH on intestinal water and ion transport have been documented, a direct control of Na,K-ATPase activity was not detected in human NPE cells in vitro." [Abstract]

Suply, Thomas, Della Zuana, Odile, Audinot, Valerie, Rodriguez, Marianne, Beauverger, Philippe, Duhault, Jacques, Canet, Emmanuel, Galizzi, Jean-Pierre, Nahon, Jean-Louis, Levens, Nigel, Boutin, Jean A.
SLC-1 Receptor Mediates Effect of Melanin-Concentrating Hormone on Feeding Behavior in Rat: A Structure-Activity Study
J Pharmacol Exp Ther 2001 299: 137-146
"Several studies have shown that melanin-concentrating hormone (MCH) is an orexigenic peptide in rat. In the present study, a structure-activity relationship with MCH analogs was performed in rat, both in vitro and in vivo. On rat recombinant SLC-1 receptor, both cAMP inhibition and [125I]S36057 binding were measured. In vivo, these analogs were injected intracerebroventricularly in rats and their effects were evaluated upon food intake. First, data obtained with the rat recombinant receptor were highly correlated with those obtained from its human counterpart. Second, agonist potencies in the cAMP assay were also highly correlated with binding affinities. These peptides could be classified into several groups according to their potency at the SLC-1 receptor (from subnanomolar activity to complete inactivity). Indeed, there was a strong correlation between their effects upon food intake and the results obtained at the rat SLC-1 receptor. The present report describes for the first time the rat SLC-1 receptor pharmacology and clearly establishes the relevance of the SLC-1 receptor in feeding behavior." [Abstract]

Maulon-Feraille L, Della Zuana O, Suply T, Rovere-Jovene C, Audinot V, Levens N, Boutin JA, Duhault J, Nahon JL.
Appetite-boosting property of pro-melanin-concentrating hormone(131-165) (neuropeptide-glutamic acid-isoleucine) is associated with proteolytic resistance.
J Pharmacol Exp Ther 2002 Aug;302(2):766-73
"Melanin-concentrating hormone (MCH) is a cyclic neuropeptide, with a major role in stimulation of feeding behavior in mammals. MCH signals in the brain occur via two seven-transmembrane G protein-coupled receptors, namely MCH1 (SLC-1, MCH(1), MCH-R1, or MCH-1R) and MCH2 (SLT, MCH(2), MCH-R2, or MCH-2R). In this study, we demonstrate that the pro-MCH(131-165) peptide neuropeptide-glutamic acid-isoleucine (NEI)-MCH is more potent than MCH in stimulating feeding in the rat. Using rat MCH1-expressed human embryonic kidney 293 cells, we show that NEI-MCH exhibits 5-fold less affinity in a binding assay and 2-fold less potency in a cAMP assay than MCH. A similar 7- to 8-fold shift in potency was observed in a Ca(2+)(i) assay using rat MCH1 or human MCH2-transfected Chinese hamster ovary cell models. This demonstrates that NEI-MCH is not a better agonist than MCH at either of the MCH receptors. Then, we compared the proteolysis resistance of MCH and NEI-MCH to rat brain membrane homogenates and purified proteases. Kinetics of peptide degradation using br