melanin-concentrating hormone


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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."
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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."
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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."
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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."

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."

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."

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 brain extracts indicated a t(1/2) of 34.8 min for MCH and 78.5 min for NEI-MCH with a specific pattern of cleavage of MCH but not NEI-MCH by exo- and endo-proteases. Furthermore, MCH was found highly susceptible to degradation by aminopeptidase M and endopeptidase 24.11, whereas NEI-MCH was fully resistant to proteolysis by these enzymes. Therefore, our results strongly suggest that reduced susceptibility to proteases of NEI-MCH compared with MCH account for its enhanced activity in feeding behavior. NEI-MCH represents therefore the first MCH natural functional "superagonist" so far described."

M. Rossi, S. J. Choi, D. O’Shea, T. Miyoshi, M. A. Ghatei, and S. R. Bloom
Melanin-Concentrating Hormone Acutely Stimulates Feeding, But Chronic Administration Has No Effect on Body Weight
Endocrinology 138: 351-355, 1997
"At no dose did MCH inhibit feeding. Twice daily icv injections of MCH (5 µg) caused an average 197 ± 9% increase in 2-h food intake for the first 5 days. Injections from days 6–8 did not stimulate feeding. Food intake and body weight at 24 h remained unchanged. Intracerbroventricular neuropeptide E-I had no effect on food intake alone and did not alter MCH-induced feeding. These studies show a dose-dependent stimulation of feeding by acute central administration of MCH. Tolerance is seen with chronic administration. These findings support a role for MCH in the immediate regulation of food intake, but not in body weight control." [Full Text]

Satya P. Kalra, Michael G. Dube, Shuye Pu, Bin Xu, Tamas L. Horvath, and Pushpa S. Kalra
Interacting Appetite-Regulating Pathways in the Hypothalamic Regulation of Body Weight
Endocr. Rev. 20: 68-100, 1999. [Full Text]

Kemp, E. Helen, Waterman, Elizabeth A., Hawes, Brian E., O'Neill, Kim, Gottumukkala, Raju V.S.R.K., Gawkrodger, David J., Weetman, Anthony P., Watson, Philip F.
The melanin-concentrating hormone receptor 1, a novel target of autoantibody responses in vitiligo
J. Clin. Invest. 2002 109: 923-930 [Full Text]

Valérie Audinot, Philippe Beauverger, Chantal Lahaye, Thomas Suply, Marianne Rodriguez, Christine Ouvry, Véronique Lamamy, Jérôme Imbert, Hervé Rique, Jean-Louis Nahon, Jean-Pierre Galizzi, Emmanuel Canet, Nigel Levens, Jean-Luc Fauchère, and Jean A. Boutin
Structure-Activity Relationship Studies of Melanin-concentrating Hormone (MCH)-related Peptide Ligands at SLC-1, the Human MCH Receptor
J. Biol. Chem. 276: 13554-13562, April 2001. [Full Text]

Miller CL, Burmeister M, Thompson RC.
Antisense expression of the human pro-melanin-concentrating hormone genes.
Brain Res 1998 Aug 24;803(1-2):86-94 [Abstract]

Bachner D, Kreienkamp H, Richter D.
MIZIP, a highly conserved, vertebrate specific melanin-concentrating hormone receptor 1 interacting zinc-finger protein(1).
FEBS Lett 2002 Aug 28;526(1-3):124
"Using the yeast-two-hybrid system a novel protein was identified from human brain that interacts with the C-terminus of melanin-concentrating hormone receptor 1 (MCH-R1). This protein, characterized by a Myeloid translocation protein 8, Nervy, DEAF1 proteins (MYND) zinc-finger domain, is termed MCH-R1-interacting zinc-finger protein, MIZIP. It is fully conserved in man, rat, mouse and highly conserved in Xenopus and zebrafish, but not detectable in invertebrates. MIZIP gene organization in human (six exons on chromosome 9q34.3) and mouse is highly conserved, yet in rodents an additional exon is generated giving rise to alternatively spliced mRNAs. MIZIP is expressed in brain, testis and stomach, where expression of MCH and MCH-R1 was previously reported. MIZIP interaction with MCH-R1 was verified by overlay and pull-down assays as well as by co-transfection experiments in human embryonic kidney-293 cells. MIZIP is cytoplasmically localized but gets recruted to the plasma membrane when cells are co-transfected with MCH-R1 supporting the notion that MIZIP is involved in the function of MCH-R1." [Abstract]

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]

Elias CF, Lee CE, Kelly JF, Ahima RS, Kuhar M, Saper CB, Elmquist JK.
Characterization of CART neurons in the rat and human hypothalamus.
J Comp Neurol 2001 Mar 26;432(1):1-19
"We also found that CART neurons in the parvicellular PVH [periventricular nucleus], in the DMH [hypothalamus] and in the posterior Pe [periventricular nucleus] coexpress thyrotropin-releasing hormone (TRH) mRNA. CART neurons in the magnocellular PVH and in the SON [supraoptic nucleus] coexpress dynorphin (DYN), and CART cell bodies in the LHA [lateral hypothalamic area] and in the posterior Pe coexpress melanin-concentrating hormone (MCH) and glutamic acid decarboxylase (GAD-67) mRNA." [Abstract]

Sergeyev V, Broberger C, Hokfelt T.
Effect of LPS administration on the expression of POMC, NPY, galanin, CART and MCH mRNAs in the rat hypothalamus.
Brain Res Mol Brain Res 2001 Jun 20;90(2):93-100 [Abstract]

Murray JF, Mercer JG, Adan RA, Datta JJ, Aldairy C, Moar KM, Baker BI, Stock MJ, Wilson CA.
The effect of leptin on luteinizing hormone release is exerted in the zona incerta and mediated by melanin-concentrating hormone.
J Neuroendocrinol 2000 Nov;12(11):1133-9 [Abstract]

Sara R. Chiocchio, María G.P. Gallardo, Patricia Louzan, Viviana Gutnisky, and Juan H. Tramezzani
Melanin-Concentrating Hormone Stimulates the Release of Luteinizing Hormone-Releasing Hormone and Gonadotropins in the Female Rat Acting at Both Median Eminence and Pituitary Levels
Biol Reprod 64: 1466-1472, 2001.
"The purpose of this study was to investigate whether melanin-concentrating hormone (MCH) acts directly on the median eminence and on the anterior pituitary of female rats regulating LHRH and gonadotropin release. In addition, immunohistochemistry was used to examine the density and distribution of MCH-immunoreactive fibers in the median eminence of proestrous rats. MCH-immunoreactive fibers were found in both the internal and external layers of the median eminence and in close association with hypophysial portal vessels. In the first series of in vitro experiments, median eminences and anterior pituitaries were incubated in Krebs-Ringer bicarbonate buffer containing two MCH concentrations (10-10 and 10-8 M). The lowest MCH concentration (10-10 M) increased (P < 0.01) LHRH release only from proestrous median eminences. Anterior pituitaries incubated with both MCH concentrations also showed that 10-10 M MCH increased gonadotropin release only from proestrous pituitaries. In the second series of experiments, median eminences and pituitaries from proestrous rats were incubated with graded concentrations of MCH. MCH (10-10 and 10-9 M) increased (P < 0.01) LHRH release from the median eminence, and only 10-10 M MCH increased (P < 0.01) LH and FSH release from the anterior pituitary. The effect of MCH on the stimulation of both gonadotropins from proestrous pituitaries was similar to the effect produced by LHRH. Simultaneous incubation of pituitaries with MCH and LHRH did not modify LH but increased the FSH release induced by LHRH. The present results suggest that MCH could be involved in the regulation of preovulatory gonadotropin secretion." [Abstract]

Richard L. Bradley, Julia P. R. Mansfield, Eleftheria Maratos-Flier, and Bentley Cheatham
Melanin-concentrating hormone activates signaling pathways in 3T3-L1 adipocytes
Am J Physiol Endocrinol Metab 283: E584-E592, September 2002.
"Energy homeostasis is regulated by peripheral signals, such as leptin, and by several orexigenic and anorectic neuropeptides. Recently, we reported that the orexigenic neuropeptide melanin-concentrating hormone (MCH) stimulates leptin production by rat adipocytes and that the MCH receptor (MCH-R1) is present on these cells. Here, we show that MCH-R1 is present on murine 3T3-L1 adipocytes. Treatment of 3T3-L1 adipocytes with 1 µM MCH for up to 2 h acutely downregulated MCH-R1, indicating a mechanism of ligand-induced receptor downregulation. Potential signaling pathways mediating MCH-R1 action in adipocytes were investigated. Treatment of 3T3-L1 adipocytes with 1 µM MCH rapidly induced a threefold and a fivefold increase in p44/42 MAPK and pp70 S6 kinase activities, respectively. In addition, 3T3-L1 adipocytes transiently transfected with a murine leptin-luciferase promoter construct showed a fourfold and a sixfold increase in leptin promoter-reporter gene expression at 1 h and 4 h, respectively, in response to MCH. Activity decreased to basal levels at 8 h. Furthermore, MCH-stimulated leptin promoter-driven luciferase activity was diminished in the presence of the MAP/ERK kinase inhibitor PD-98059 and in the presence of rapamycin, an inhibitor of pp70 S6 kinase activation. These results provide further evidence for a functional MCH signaling pathway in adipocytes."

G Hervieu, K Volant, O Grishina, M Descroix-Vagne, and JL Nahon
Similarities in cellular expression and functions of melanin- concentrating hormone and atrial natriuretic factor in the rat digestive tract
Endocrinology 137: 561-571, 1996.
"Our data revealed numerous MCH-containing cells located in the lamina propria and submucosa at both duodenal and colonic levels. Second, the localisation of MCH- and arginine vasopressin- or ANF- containing cells appears similar at the duodenal and colonic levels, respectively. Colocalization of MCH/neuropeptide-glutamic acid- isoleucine immunoreactivity (-IR) and catecholamine indicated that MCH- expressing cells are probably antigen-presenting cells forming part of the enterochromaffin cell system. Third, we performed reverse phase HPLC coupled to RIA to characterize MCH-like materials in different portions of the rat gut. Crude acidic extracts of rat intestine contained about 2-3 pmol/g tissue of MCH-IR, close to the values found in brain extracts. Reverse phase HPLC of MCH-IR in the GI tract revealed that only 10-30% of the immunoreactivity corresponded to mature MCH, whereas the rat brain contained 94% mature peptide. Finally, we compared the effect of MCH and ANF on water and electrolyte secretions at different levels of the GI tract by using the in situ ligated loop technique. Similar effects were noted for ANF and MCH; both stimulated water, Na, and K fluxes at the proximal colon level and increased Na and K fluxes in the duodenum. However, only ANF increased water and Cl fluxes in the duodenum and decreased bicarbonate secretion in the ileum, whereas MCH increased bicarbonate absorption in the jejunum. The dose required was 10 nmol/100 g.h for MCH, i.e. 10 times more than for the ANF. These studies strongly suggest that MCH produced by antigen-presenting cells of the lamina propria may have an important role, similar to that of ANF at the colonic level, in the physiology of the GI tract." [Abstract]

Hoogduijn M, Ancans J, Suzuki I, Estdale S, Thody A.
Melanin-concentrating hormone and its receptor are expressed and functional in human skin.
Biochem Biophys Res Commun 2002 Aug 23;296(3):698
"In this study, we have demonstrated the presence of melanin-concentrating hormone (MCH) and melanin-concentrating hormone receptor (MCHR1) transcripts in human skin. Sequence analysis confirmed that the transcripts of both genes were identical to those previously found in human brain. In culture, endothelial cells showed pro-MCH expression whereas no signal was found in keratinocytes, melanocytes, and fibroblasts. MCHR1 expression was restricted to melanocytes and melanoma cells. Stimulation of cultured human melanocytes with MCH reduced the alpha-MSH-induced increase in cAMP production. Furthermore, the melanogenic actions of alpha-MSH were inhibited by MCH. We propose that the MCH/MCHR1 signalling system is present in human skin and may have a role with the melanocortins in regulating the melanocyte."

Evans NA, Groarke DA, Warrack J, Greenwood CJ, Dodgson K, Milligan G, Wilson S.
Visualizing differences in ligand-induced beta-arrestin-GFP interactions and trafficking between three recently characterized G protein-coupled receptors.
J Neurochem 2001 Apr;77(2):476-85
"beta-Arrestin 1-GFP or beta-arrestin 2-GFP were coexpressed transiently with G protein-coupled receptor kinase 2 within cells stably expressing the orexin-1, apelin or melanin-concentrating hormone (MCH), receptors. In response to agonist ligands both the orexin-1 and apelin receptors were able to rapidly translocate both beta-arrestin 1-GFP and beta-arrestin 2-GFP from cytoplasm to the plasma membrane. For the MCH receptor this was only observed for beta-arrestin 2-GFP." [Abstract]

Courseaux, Anouk, Nahon, Jean-Louis
Birth of Two Chimeric Genes in the Hominidae Lineage
Science 2001 291: 1293-1297
"How genes with newly characterized functions originate remains a fundamental question. PMCHL1 and PMCHL2, two chimeric genes derived from the melanin-concentrating hormone (MCH) gene, offer an opportunity to examine such an issue in the human lineage. Detailed structural, expression, and phylogenetic analysis showed that the PMCHL1 gene was created near 25 million years ago (Ma) by a complex mechanism of exon shuffling through retrotransposition of an antisense MCH messenger RNA coupled to de novo creation of splice sites. PMCHL2 arose 5 to 10 Ma by an event of duplication involving a large chromosomal region encompassing the PMCHL1 locus. The RNA expression patterns of those chimeric genes suggest that they have been submitted to strong regulatory constraints during primate evolution."
[Full Text]

Monzon ME, de Souza MM, Izquierdo LA, Izquierdo I, Barros DM, de Barioglio SR.
Melanin-concentrating hormone (MCH) modifies memory retention in rats.
Peptides 1999 Dec;20(12):1517-9
"The purpose of the present study was to evaluate the possible effect of melanin-concentrating hormone (MCH) on learning and memory by using the one-trial step-down inhibitory avoidance test in rats. The peptide was infused into hippocampus, amygdala, and entorhinal cortex. MCH caused retrograde facilitation when given at 0 or 4 h post-training into hippocampus, but only at 0 h into amygdala. From these results, it seems that MCH modulates memory early after training by acting on both the amygdala and hippocampus and, 4 h after training, on the hippocampus." [Abstract]

Varas M, Perez M, Monzon ME, de Barioglio SR.
Melanin-concentrating hormone, hippocampal nitric oxide levels and memory retention.
Peptides 2002 Dec;23(12):2213-21
"The present study attempts to determine, if the effect of melanin-concentrating hormone (MCH) upon memory retention is correlated with changes in nitric oxide synthase (NOS) activity and tissue levels of nitric oxide (NO) and cGMP. We used a behavioral experiment using a step-down inhibitory avoidance test, the biochemical determinations of NO and cGMP, and electrophysiological model. Results of behavioral studies (step-down test) showed that MCH administration reverts the amnesic effects induced by N(G)-nitro-L-arginine (L-NOArg). Moreover, electrophysiological studies demonstrated that L-NOArg did not block the potentiation induced by the peptide. Hippocampal NO and cGMP levels increased after MCH injection."

Sanchez MS, Cremer MC, Celis ME.
Effects and interactions between alpha-MSH and MCH/NEI upon striatal cAMP levels.
Peptides 1999;20(5):611-4
"It is known that alpha-MSH augments cAMP levels in rat brain slices containing accumbens and caudate-putamen nuclei. In this study we examined: a) the effect of other neuropeptides: MCH and NEI, on this cyclic nucleotide; b) if the effects of alpha-MSH on cAMP production can be modulated by addition of MCH or NEI to the incubation medium. Both MCH and NEI (3.6 microM) increased the production of cAMP, whereas at doses of 0.6 microM exerted no effects. When alpha-MSH 0.6 microM was added with NEI or MCH (0.6 microM), only MCH blocked the increase in the cAMP induced by alpha-MSH. Neither MCH nor NEI at the highest dose used (3.6 microM) had any additive effect on AMPc when added together with alpha-MSH. We conclude that, at a high concentration, (MCH/NEI)-like peptides can use the intracellular signal transduction linked to cyclic nucleotides in the CNS." [Abstract]

Bluet-Pajot MT, Presse F, Voko Z, Hoeger C, Mounier F, Epelbaum J, Nahon JL.
Neuropeptide-E-I antagonizes the action of melanin-concentrating hormone on stress-induced release of adrenocorticotropin in the rat.
J Neuroendocrinol 1995 Apr;7(4):297-303
"The physiological role of melanin-concentrating hormone (MCH) in mammals is still very elusive, but this peptide might participate in the central control of the hypothalamopituitary adrenal (HPA) axis during adaptation to stress. Cloning and sequencing of the rat MCH (rMCH) cDNA revealed the existence of additional peptides encoded into the MCH precursor. Among these peptides, neuropeptide (N) glutamic acid (E) isoleucine (I) amide (NEI) is co-processed and secreted with MCH in rat hypothalamus. In the present work we examined: (1) The pattern of rMCH mRNA expression during the light and dark conditions in the rat hypothalamus and (2) The effect of intracerebroventricular (ICV) injections of rMCH and NEI in the control of basal or ether stress-modified release of corticotropin (ACTH), prolactin (PRL) and growth hormone (GH) secretion in vivo in light-on and light-off conditions. Our data indicate that rMCH mRNA levels do not change during the light-on period, but increase after the onset of darkness. Either alone or co-administered, rMCH and NEI do not modify basal secretion of GH and PRL at any time tested nor do they alter ether stress-induced changes in these two hormonal secretions. At the end of the light on period corresponding to the peak of the circadian rhythm in ACTH, administration of rMCH but not NEI leads to a decrease in ACTH levels while MCH is not effective during the light off period of the cycle (i.e. when basal ACTH levels are already low). Using a moderate ether induced stress, ACTH levels are only stimulated during the dark phase of the cycle." [Abstract]

Sanchez MS, Barontini M, Armando I, Celis ME.
Correlation of increased grooming behavior and motor activity with alterations in nigrostriatal and mesolimbic catecholamines after alpha-melanotropin and neuropeptide glutamine-isoleucine injection in the rat ventral tegmental area.
Cell Mol Neurobiol 2001 Oct;21(5):523-33
"1. We wished to further study the behavioral effects of alpha-melanotropin (alpha-MSH), melanin-concentrating hormone (MCH), and neuropeptide glutamine-isoleucine (NEI). 2. To this effect we administered alpha-MSH, MCH, and NEI in the ventral tegmental area of the rat, a structure where these neuropeptides are highly concentrated. To further elucidate the biochemical mechanisms of the behavioral effect of these neuropeptides, we determined the degree of grooming behavior and the levels of catecholamines. after neuropeptide administration. 3. We preselected those animals responding to the central injection of alpha-MSH with excessive grooming behavior. We administered the neuropeptides at the dose of 1 microg/0.5 microL, in each side of the ventral tegmental area, bilaterally. We studied grooming behavior, locomotor activity, and total behavior scores, 30 and 65 min after administration of the peptides. 4. Three groups of animals were decapitated immediately after the injection of the neuropeptides, and 30 or 65 min after injection. We measured dopamine (DA), noradrenaline (NA), and the dopac/dopamine ratio (DOPAC/DA) to determine steady state levels of catecholamines and an indirect measure of DA release and metabolism, respectively. 5. Injections of alpha-MSH produced significant elevations in grooming behavior, locomotor activity, and total behavior scores, both 30 and 65 min after peptide administration. This was correlated with significant decreases in DA content, increases in DOPAC content, and increases in the DOPAC/DA ratio. In the caudate putamen, changes in catecholamines occurred both at 30 and 65 min after injection. In the nucleus accumbens, changes were present at 65 min after injection. Conversely, there were no alterations in NA content, either in the caudate putamen or in the nucleus accumbens, at any time after the injection. 6. Injections of NEI resulted in significant elevations in grooming behavior, locomotor activity, and total behavior scores, both 30 and 65 min after peptide administration. This was correlated with increased DOPAC/DA ratio in the nucleus caudatus but not in the nucleus accumbens. Conversely, NEI produced increased NA concentrations in the nucleus accumbens, but not in the nucleus caudatus. 7. Injections of MCH did not produce significant changes in behavior or significant changes in nucleus caudatus or nucleus accumbens catecholamines. 8. Our results indicate (a) There is a correlation with alterations in behavior as induced for the neuropeptides injected here, and changes in extrapyramidal catecholamines. (b) There is a correlation between alterations in behavior and increases in DOPAC/DA ratio in the nucleus caudatus. (c) There is a correlation between alterations in behavior and alterations in catecholamines in the nucleus accumbens. In the nucleus accumbens, DOPAC/DA ratio is changed after alpha-MSH, and NA ratio is changed after NEI injection. (d) Absence of alterations in extrapyramidal catecholamines, and in particular in catecholamines in the nucleus accumbens, correlates with absence of behavioral alterations after neuropeptide administration to the ventral tegmental area. 9. In conclusion, the behavioral effect of exogenous administration of neuropeptides in the ventral tegmental area is peptide-specific, and is probably associated with alterations in catecholamine metabolism and release in the nucleus caudatus and the nucleus accumbens. Both alpha-MSH and NEI seem to stimulate the nigrostriatal DA system. While alpha-MSH appears to stimulate the mesolimbic DA system as well, NEI may exert its actions not through the DA, but through the NA mesolimbic system. The precise contribution of DA and NA, and the relative role of the nucleus caudatus and nucleus accumbens in these behaviors remain to be elucidated." [Abstract]

Compagnone N, Fellmann D.
Implication of NMDA receptors in glutamate-induced MCH secretion.
Neuroreport 1993 Dec 13;5(3):231-2
"The action of glutamate and N-methyl-D-aspartate (NMDA) on melanin-concentrating hormone (MCH) release was examined in primary cultures of rat hypothalamic neurons. Increasing concentrations of both glutamate and NMDA stimulated MCH release in a dose-dependent manner. We report here a specific toxic effect of 10(-4) M glutamate not observed after NMDA-induced MCH release. The involvement of the NMDA receptor in the MCH-evoked secretion was confirmed using MK-801 a specific NMDA non-competitive inhibitor. MK-801 inhibited NMDA-induced MCH release in a dose dependent manner. At 10(-6) M, this drug significantly inhibited MCH release suggesting an endogenous glutamatergic stimulation of MCH secretion. This study established that MCH neurons are sensitive to glutamate stimulation and that the evoked MCH secretion is mediated via NMDA receptor activation." [Abstract]

McBride RB, Beckwith BE, Swenson RR, Sawyer TK, Hadley ME, Matsunaga TO, Hruby VJ.
The actions of melanin-concentrating hormone (MCH) on passive avoidance in rats: a preliminary study.
Peptides 1994;15(4):757-9
"Melanin-concentrating hormone (MCH) is a hepadecapeptide hormone that is synthesized in the CNS and is responsible for melanosome aggregation in the teleost fish. Recent evidence suggests that this peptide hormone has a unique distribution in the mammalian brain, which leads to the speculation that it may serve as a neuromodulator. The present study was undertaken to explore the comparative effects of MCH to those of alpha-melanocyte-stimulating Hormone (MSH) (a neuropeptide that is known to influence learning) on the rate of extinction of a passive avoidance response in rats. Both MCH and MSH were administered SC at 10 micrograms per animal. Treatment with MCH appeared to hasten, whereas treatment with MSH appeared to delay, extinction of the passive avoidance response." [Abstract]







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Recent Melanin-Concentrating Hormone Research

1) Nagel JM, Geiger BM, Karagiannis AK, Gras-Miralles B, Horst D, Najarian RM, Ziogas DC, Chen X, Kokkotou E
Reduced Intestinal Tumorigenesis in APCmin Mice Lacking Melanin-Concentrating Hormone.
PLoS One. 2012;7(7):e41914.
[PubMed Citation] [Order full text from Infotrieve]

2) Guerrero M, Urbano M, Wang Z, Zhao J, Velaparthi S, Schaeffer MT, Brown SJ, Saldanha SA, Chase P, Ferguson J, Civelli O, Roberts E, Hodder P, Rosen H, Kang DY, Kim HC
Influence of density and background color to stress response, appetite, growth, and blind-side hypermelanosis of flounder, Paralichthys olivaceus.
Fish Physiol Biochem. 2010;
Heterotrimeric G-protein coupled receptors (GPCRs), the largest family of membrane-bound receptors, are major targets for therapeutic applications due to their broad tissue distribution, structural diversity, varied modes of action, and disease-associated mutations. The recently de-orphanized GPCR, GPR7, is distributed predominantly in the central nervous system. Neuropeptides W (NPW) and B (NPB) have been identified as endogenous ligands of GPR7. GPR7 represents a new and expanding target for drug development as it has been demonstrated to modulate the release of pituitary-derived hormones, and implicated in feeding behavior, the development of obesity, and mediating the inflammatory pain response. There is a significant medical need for novel compounds for treating chronic pain that are effective, long lasting and safe. To date, no small molecules that bind to the GPR7 receptor have been reported in the literature. The Scripps Research Institute Molecular Screening Center (SRIMSC), part of the Molecular Libraries Probe Production Centers Network (MLPCN), identified a potent and selective GPR7 antagonist probe, ML181, by high-throughput screening using a cell-based fluorescence assay. ML181 inhibited human GPR7 expression in the presence of a GPR7 agonist NPW with an IC50 of 272 nM. In a counterscreen for melanin-concentrating hormone receptor 1 (MCH1) antagonism in the presence of an agonist, ML181 has an IC50 of 3.9 ?M, for a 14-fold selectivity for GPR7. ML181 is nontoxic to human colon adenocarcinoma (HT29) cells, with a CC50 of > 20 ?M. As the first reported small molecule to modulate GPR7 activity, ML181 represents a significant milestone that will allow experiments aimed at elucidating the diverse roles of this receptor in physiological and pathological processes. ML181 also represents a potential therapeutic option in treating chronic pain. [PubMed Citation] [Order full text from Infotrieve]

3) Chen YW, Barson JR, Chen A, Hoebel BG, Leibowitz SF
Glutamatergic Input to the Lateral Hypothalamus Stimulates Ethanol Intake: Role of Orexin and Melanin-Concentrating Hormone.
Alcohol Clin Exp Res. 2012 Jul 25;
BACKGROUND: Glutamate (GLUT) in the lateral hypothalamus (LH) has been suggested to mediate reward behaviors and may promote the ingestion of drugs of abuse. This study tested the hypothesis that GLUT in the LH stimulates consumption of ethanol ( EtOH ) and that this effect occurs, in part, via its interaction with local peptides, hypocretin/orexin (OX), and melanin-concentrating hormone (MCH). METHODS: In Experiments 1 and 2, male Sprague-Dawley rats, after being trained to drink 9% EtOH , were microinjected in the LH with N-methyl-d-aspartate (NMDA) or its antagonist, D-AP5, or with alpha-amino-5-methyl-3-hydroxy-4-isoxazole propionic acid (AMPA) or its antagonist, CNQX-ds. Consumption of EtOH , chow, and water was then measured. To provide an anatomical control, a separate set of rats was injected 2mm dorsal to the LH. In Experiment 3, the effect of LH injection of NMDA and AMPA on the expression of OX and MCH was measured using radiolabeled in situ hybridization (ISH) and also using digoxigenin-labeled ISH, to distinguish effects on OX and MCH cells in the LH and the nearby perifornical area (PF) and zona incerta (ZI). RESULTS: When injected into the LH, NMDA and AMPA both significantly increased EtOH intake while having no effect on chow or water intake. The GLUT receptor antagonists had the opposite effect, significantly reducing EtOH consumption. No effects were observed with injections 2mm dorsal to the LH. In addition to these behavioral effects, LH injection of NMDA significantly stimulated expression of OX in both the LH and PF while reducing MCH in the ZI, whereas AMPA increased OX only in the LH and had no effect on MCH. CONCLUSIONS: Glutamatergic inputs to the LH, acting through NMDA and AMPA receptors, appear to have a stimulatory effect on EtOH consumption, mediated in part by increased OX in LH and PF and reduced MCH in ZI. [PubMed Citation] [Order full text from Infotrieve]

4) Egwuenu EJ, Fong AY, Pilowsky PM
Intrathecal melanin concentrating hormone reduces sympathetic tone and blocks cardiovascular reflexes.
Am J Physiol Regul Integr Comp Physiol. 2012 Jul 23;
Melanin concentrating hormone (MCH) is a neuropeptide that acts to increase feeding behaviour and decrease energy expenditure. The role of MCH in central cardiorespiratory regulation is still poorly understood. Experiments were conducted on urethane-anaesthetised, vagotomised and artificially ventilated male Sprague-Dawley rats (n= 22) to ascertain if MCH modulates sympathetic vasomotor tone as well as baro-, chemo- and somato-sympathetic reflexes at the level of the spinal cord. Intrathecal injection of 10l MCH produced a dose-dependent hypotension, bradycardia, and sympatho-inhibition. Peak response was observed following administration of 1mM MCH, causing a decrease in mean arterial pressure of 39 2 mmHg (P < 0.001), splanchnic sympathetic nerve activity of 78 11 % (P < 0.001) and heart rate of 87 11 beats/min (P < 0.01). The two peaks of the somatosympathetic reflex were decreased by intrathecal MCH, 7 3 % (P < 0.01), and 31 6 % (P < 0.01) respectively, and the spinal component of the reflex was accentuated 96 23 % (P < 0.05), with respect to the baseline for MCH, compared to the two peaks and spinal component of the somatosympathetic reflex elicited following saline injection with respect to the baseline for saline. MCH decreased the sympathetic gain to 120s of hyperoxic hypercapnea (10% CO(2) in 90% O(2)) and to 10-12s poikilocapneic anoxia (100% N(2)) from 0.74 0.14%/s to 0.23 0.04 %/s (P < 0.05) and 16.47 3.2 % to 4.35 1.56 % (P < 0.05) respectively. There was a 34% decrease in gain and a 62% decrease in range of the sympathetic baroreflex with intrathecal MCH. This data demonstrates that spinal MCH blunts the central regulation of sympathetic tone and adaptive sympathetic reflexes. [PubMed Citation] [Order full text from Infotrieve]

5) Luppi PH
[Progress in our understanding of the architecture of parae doxical sleep since William Dement and Michel Jouvet].
Bull Acad Natl Med. 2012 Jul 18;195(7):1517-24; discussion 1524-5.
Paradoxical or REM sleep, characterized by cortical activation combined with muscle atonia and rapid eye movements, was discovered at the end of the 1950s by Michel Jouvet and William C. Dement. Studies over the next twenty years suggested that the onset and maintenance of paradoxical sleep was due to a reciprocal inhibitory interaction between monoaminergic neurons inhibiting PS and cholinergic neurons generating PS located in a small part of the pontine reticular formation called the sublaterodorsal tegmental nucleus. Our recent studies rather indicate that these neurons are respectively GABAergic and glutamatergic. Further, they suggest that three populations of GABAergic neurons and population of hypothalamic neurons expressing melanin concentrating hormone, a peptide, play a important role in PS control. [PubMed Citation] [Order full text from Infotrieve]

6) Sherwood A, Wosiski-Kuhn M, Nguyen T, Holland PC, Lakaye B, Adamantidis A, Johnson AW
The role of melanin-concentrating hormone in conditioned reward learning.
Eur J Neurosci. 2011 Oct;
The orexigenic neuropeptide melanin-concentrating hormone (MCH) is well positioned to play a key role in connecting brain reward and homeostatic systems due to its synthesis in hypothalamic circuitry and receptor expression throughout the cortico-striatal reward circuit. Here we examined whether targeted-deletion of the MCH receptor (MCH-1R) in gene-targeted heterozygote and knockout mice (KO), or systemic treatment with pharmacological agents designed to antagonise MCH-1R in C57BL/6J mice would disrupt two putative consequences of reward learning that rely on different neural circuitries: conditioned reinforcement (CRf) and Pavlovian-instrumental transfer (PIT). Mice were trained to discriminate between presentations of a reward-paired cue (CS+) and an unpaired CS-. Following normal acquisition of the Pavlovian discrimination in all mice, we assessed the capacity for the CS+ to act as a reinforcer for new nose-poke learning (CRf). Pharmacological disruption in control mice and genetic deletion in KO mice impaired CRf test performance, suggesting MCH-1R is necessary for initiating and maintaining behaviors that are under the control of conditioned reinforcers. To examine a dissociable form of reward learning (PIT), a nave group of mice were trained in separate Pavlovian and instrumental lever training sessions followed by the PIT test. For all mice the CS+ was capable of augmenting ongoing lever responding relative to CS- periods. These results suggest a role for MCH in guiding behavior based on the conditioned reinforcing value of a cue, but not on its incentive motivational value. [PubMed Citation] [Order full text from Infotrieve]

7) Song Z, Liu L, Yue Y, Jiao H, Lin H, Sheikhahmadi A, Everaert N, Decuypere E, Buyse J
Fasting alters protein expression of AMP-activated protein kinase in the hypothalamus of broiler chicks (Gallus gallus domesticus).
Gen Comp Endocrinol. 2012 Jul 9;
An experiment was conducted to investigate the effects of fasting and re-feeding on hypothalamic 5'-AMP-activated protein kinase (AMPK) levels and (an)orexigenic neuropeptides. Male Arbor Acres chicks (7-day-old, n=160) were allocated to four equal treatment groups: control chicks (fed ad libitum for 48h, C48), chicks that were fasted for 48h (F48), chicks that were first fasted for 48h and then re-fed for 24h (F48C24), and chicks that were fed ad libitum for 72h (C72). Fasting for 48h significantly (P<0.05) increased the ratio of phosphorylated AMPK? to total AMPK? and phosphorylated LKB1 to total LKB1, whereas re-feeding for 24h reduced these ratios to that of the ad libitum fed C72 chicks. The gene expressions of agouti-related peptide (AgRP), neuropeptide Y (NPY), melanocortin receptor 4, melanin-concentrating hormone, prepro-orexins and carnitine palmitoyltransferase-1 were significantly (P<0.05) increased in the fasted chicks relative to the ad libitum fed C48 group. The gene expression of pro-opiomelanocortin (POMC), as well as cocaine- and amphetamine-regulated transcript (CART) was not affected by the nutritional status. Fasting significantly (P<0.05) decreased the mRNA levels of fatty acid synthase (FAS) and sterol regulatory element binding protein-1 (SREBP-1). The results suggest that the LKB1/AMPK signal pathway is involved in the energy homeostasis of fasted chicks, and its possible role in feed intake regulation might be mediated by the AgRP/NPY rather than the POMC/CART pathway. [PubMed Citation] [Order full text from Infotrieve]

8) Azuma M, Suzuki T, Mochida H, Tanaka S, Uchiyama M, Takahashi A, Matsuda K
Polymorphism of somatolactin-producing cells in the goldfish pituitary: immunohistochemical investigation for somatolactin-α and -β
Cell Tissue Res. 2012 Jul 5;
Somatolactin (SL) is a pituitary hormone belonging to the growth hormone/prolactin family of adenohypophyseal hormones. In teleost fish, SL is encoded by one or two paralogous genes, namely SL-? and -?. Our previous studies have revealed that pituitary adenylate-cyclase-activating polypeptide stimulates SL release from cultured goldfish pituitary cells, whereas melanin-concentrating hormone suppresses this release. As in other fish, the goldfish possesses SL-? and -?. So far, however, no useful means of detecting the respective SLs immunologically in this species has been possible. In order to achieve this aim, we raised rabbit antisera against synthetic peptide fragments deduced from the goldfish SL-? and -? cDNA sequences. Using these antisera, we observed adenohypophyseal cells showing SL-?- and -?-like immunoreactivities in the goldfish pituitary, especially the pars intermedia (PI). Several cells in the PI showed the colocalization of SL-?- and -?-like immunoreactivities. Then, using single-cell polymerase chain reaction with laser microdissection, we examined SL-? and -? gene expression in adenohypophyseal cells showing SL-?- or -?-like immunoreactivity. Among cultured pituitary cells, we observed three types of cell: those that possess transcripts of SL-?, -?, or both. These results suggest a polymorphism of SL-producing cells in the goldfish pituitary. [PubMed Citation] [Order full text from Infotrieve]

9) Barson JR, Fagan SE, Chang GQ, Leibowitz SF
Neurochemical Heterogeneity of Rats Predicted by Different Measures to be High Ethanol Consumers.
Alcohol Clin Exp Res. 2012 May 22;
BACKGROUND: Alcoholism is a heterogeneous disease, with subjects possibly differing both in the best measure that predicts their excess consumption and in their most effective pharmacotherapy. Two different measures, high novelty-induced activity and high-fat-induced triglycerides (TGs), are known to identify subgroups of animals prone to consuming higher amounts of ethanol (EtOH). The question investigated here is whether these subgroups are, in fact, similar in their neurochemical phenotype that may contribute to their overconsumption. METHODS: EtOH-nave, Sprague-Dawley rats were subgrouped based on the 2 predictor measures of activity or TG levels, and then quantitative real-time polymerase chain reaction and digoxigenin-labeled in situ hybridization were used to measure their expression of hypothalamic peptides that affect EtOH intake. In additional subgroups subsequently trained to drink 9% EtOH, the opioid antagonist and alcoholism medication, naltrexone, was tested at a low dose (0.02mg/kg, s.c.) to determine the rats' sensitivity to its effects. RESULTS: The 2 measures, while both effective in predicting amount of EtOH intake, were found to identify distinctive subgroups. Rats with high compared to low activity exhibited significantly greater expression of galanin and enkephalin in the paraventricular nucleus (PVN) and of orexin in the perifornical lateral hypothalamus (PFLH), but no difference in melanin-concentrating hormone in PFLH or neuropeptide Y in arcuate nucleus. This contrasts with rats having high TG, which exhibited greater expression only of PVN galanin, along with reduced PFLH orexin. The high-activity rats with elevated enkephalin, but not high-TG rats, were also unusually sensitive to naltrexone, which significantly reduced their alcohol intake. CONCLUSIONS: In addition to revealing differences in endogenous peptides and drug responsiveness in predicted high EtOH drinkers, this study demonstrates that these disturbances differ markedly between the 2 at-risk subgroups. This indicates that simple tests may be effective in identifying subjects most responsive to a specific pharmacotherapy. [PubMed Citation] [Order full text from Infotrieve]

10) Karlsson C, Zook M, Ciccocioppo R, Gehlert DR, Thorsell A, Heilig M, Cippitelli A
Melanin-concentrating hormone receptor 1 (MCH1-R) antagonism: Reduced appetite for calories and suppression of addictive-like behaviors.
Pharmacol Biochem Behav. 2012 Jun 22;102(3):400-6.
[PubMed Citation] [Order full text from Infotrieve]

11) Poon K, Barson JR, Fagan SE, Leibowitz SF
Developmental Changes in Embryonic Hypothalamic Neurons during Prenatal Fat Exposure.
Am J Physiol Endocrinol Metab. 2012 Sep;
Maternal consumption of a fat-rich diet during pregnancy, which causes later overeating and weight gain in offspring, has been shown to stimulate neurogenesis and increase hypothalamic expression of orexigenic neuropeptides in these postnatal offspring. The studies here, using an in vitro model that mimics in vivo characteristics after prenatal high-fat diet (HFD) exposure, investigate whether these same peptide changes occur in embryos and if they are specific to neurons. Isolated hypothalamic neurons were compared to whole hypothalamus from E19 embryos that were prenatally exposed to HFD and were both found to show similar increases in mRNA expression of enkephalin (ENK) and neuropeptide Y (NPY) compared to that of chow exposed embryos, with no change in melanin concentrating hormone, orexin or galanin. Further examination using immunofluorescence cytochemistry revealed an increase in the number of cells expressing ENK and NPY. By plotting the fluorescence intensity of each cell as a probability density function, three different populations of neurons with low, medium, or high levels of ENK or NPY were found in both HFD and chow groups. The prenatal HFD shifted the density of neurons from the population containing low peptide levels to the population containing high peptide levels. This study indicates that neuronal culture is a useful in vitro system for studying diet effects on neuronal development and shows that prenatal HFD exposure alters the population of hypothalamic neurons containing ENK and NPY in the embryo. These changes may contribute to the increase in HFD intake and body weight observed in offspring. [PubMed Citation] [Order full text from Infotrieve]

12) Sakurai T
[Hypothalamic neuropeptides implicated in the regulation of sleep/wakefulness states].
Brain Nerve. 2012 Jun 12;64(6):629-37.
Several neuropeptides, including galanin, orexin, melanin-concentrating hormone (MCH), urocortin-2, pituitary adenylate cyclase activating protein, and vasoactive intestinal peptide, have been implicated in the regulation of sleep/wakefulness states. In particular, neuropeptides produced in the hypothalamus, including galanin, orexin, and MCH, have been shown to play crucial roles. Galanin is localized to the prepotic area of the hypothalamus and is likely to be involved in the promotion and maintenance of sleep. MCH, which is expressed by neurons in the lateral hypothalamic area (LHA), seems to be implicated in rapid eye movement sleep regulation. Orexins are also localized in the LHA and have been established as one of the most important factors in the regulation of sleep/wakefulness states. A series of studies have suggested that orexin deficiency causes narcolepsy in humans and other mammalian species, highlighting the roles of this hypothalamic neuropeptide in the regulation of sleep and wakefulness. Studies of efferent and afferent systems of orexin-producing neurons have shown that the orexin neuronal system has close interactions with the systems that regulate emotion, energy homeostasis, reward, and arousal. These observations suggest that orexin neurons are involved in sensing the body's external and internal environments and regulate vigilance states accordingly. [PubMed Citation] [Order full text from Infotrieve]

13) Cui H, Sohn JW, Gautron L, Funahashi H, Williams KW, Elmquist JK, Lutter M
Neuroanatomy of melanocortin-4 receptor pathway in the lateral hypothalamic area.
J Comp Neurol. 2012 Jun;
The central melanocortin system regulates body energy homeostasis including the melanocortin-4 receptor (MC4R). The lateral hypothalamic area (LHA) receives dense melanocortinergic inputs from the arcuate nucleus of hypothalamus and regulates multiple processes including food intake, reward behaviors and autonomic function. Using a mouse line in which green fluorescent protein (GFP) is expressed under control of MC4R gene promoter, we systemically investigated MC4R signaling in the LHA by combining double immunohistochemistry, electrophysiology and retrograde tracing techniques. We found that LHA MC4R-GFP neurons co-express neurotensin as well as the leptin receptor but not with other peptide neurotransmitters found in the LHA including orexin, melanin concentrating hormone and nesfatin-1. Furthermore, electrophysiological recording demonstrated that leptin, but not the MC4R agonist melanotan II, hyperpolarizes the majority of LHA MC4R-GFP neurons in an ATP-sensitive potassium channel-dependent manner. Retrograde tracing revealed that LHA MC4R-GFP neurons do not project to the ventral tegmental area, dorsal raphe nucleus, nucleus accumbens and spinal cord, and only limited number of neurons project to the nucleus of solitary tract and parabrachial nucleus. Our findings provide new insight into MC4R signaling in the LHA and its potential implication in homeostatic regulation of body energy balance. J. Comp. Neurol., 2012. 2012 Wiley-Liss, Inc. [PubMed Citation] [Order full text from Infotrieve]

14) Lagos P, Monti JM, Jantos H, Torterolo P
Microinjection of the melanin-concentrating hormone into the lateral basal forebrain increases REM sleep and reduces wakefulness in the rat.
Life Sci. 2012 May 17;90(23-24):895-9.
[PubMed Citation] [Order full text from Infotrieve]

15) Mihalic JT, Fan P, Chen X, Chen X, Fu Y, Motani A, Liang L, Lindstrom M, Tang L, Chen JL, Jaen J, Dai K, Li L
Discovery of a novel melanin concentrating hormone receptor 1 (MCHR1) antagonist with reduced hERG inhibition.
Bioorg Med Chem Lett. 2012 Jun 14;22(11):3781-5.
An initial SAR study resulted in the identification of the novel, potent MCHR1 antagonist 2. After further profiling, compound 2 was discovered to be a potent inhibitor of the hERG potassium channel, which prevented its further development. Additional optimization of this structure resulted in the discovery of the potent MCHR1 antagonist 11 with a dramatically reduced hERG liability. The decrease in hERG activity was confirmed by several in vivo preclinical cardiovascular studies examining QT prolongation. This compound demonstrated good selectivity for MCHR1 and possessed good pharmacokinetic properties across preclinical species. Compound 11 was also efficacious in reducing body weight in two in vivo mouse models. This compound was selected for clinical evaluation and was given the code AMG 076. [PubMed Citation] [Order full text from Infotrieve]

16) Sasmal S, Balasubrahmanyam D, Kanna Reddy HR, Balaji G, Srinivas G, Cheera S, Abbineni C, Sasmal PK, Khanna I, Sebastian VJ, Jadhav VP, Singh MP, Talwar R, Suresh J, Shashikumar D, Harinder Reddy K, Sihorkar V, Frimurer TM, Rist , Elster L, Hgberg T
Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists: part 2.
Bioorg Med Chem Lett. 2012 Jun 1;22(9):3163-7.
Melanin concentrating hormone receptor 1 (MCHR1) antagonists have potential for the treatment of obesity and several CNS disorders. In the preceding article, we have described a novel series of quinazolines as MCHR1 antagonists and demonstrated in vivo proof of principle with an early lead. Herein we describe the detailed SAR and SPR studies to identify an optimized lead candidate having good efficacy in a sub-chronic DIO model with a good cardiovascular safety window. [PubMed Citation] [Order full text from Infotrieve]

17) Kasai S, Kamata M, Masada S, Kunitomo J, Kamaura M, Okawa T, Takami K, Ogino H, Nakano Y, Ashina S, Watanabe K, Kaisho T, Imai YN, Ryu S, Nakayama M, Nagisa Y, Takekawa S, Kato K, Murata T, Suzuki N, Ishihara Y
Synthesis, structure-activity relationship, and pharmacological studies of novel melanin-concentrating hormone receptor 1 antagonists 3-aminomethylquinolines: reducing human ether-a-go-go-related gene (hERG) associated liabilities.
J Med Chem. 2012 May 1;55(9):4336-51.
Recently, we discovered 3-aminomethylquinoline derivative 1, a selective, highly potent, centrally acting, and orally bioavailable human MCH receptor 1 (hMCHR1) antagonist, that inhibited food intake in F344 rats with diet-induced obesity (DIO). Subsequent investigation of 1 was discontinued because 1 showed potent hERG K(+) channel inhibition in a patch-clamp study. To decrease hERG K(+) channel inhibition, experiments with ligand-based drug designs based on 1 and a docking study were conducted. Replacement of the terminal p-fluorophenyl group with a cyclopropylmethoxy group, methyl group introduction on the benzylic carbon at the 3-position of the quinoline core, and employment of a [2-(acetylamino)ethyl]amino group as the amine portion eliminated hERG K(+) channel inhibitory activity in a patch-clamp study, leading to the discovery of N-{3-[(1R)-1-{[2-(acetylamino)ethyl]amino}ethyl]-8-methylquinolin-7-yl}-4-(cyclopropylmethoxy)benzamide (R)-10h. The compound (R)-10h showed potent inhibitory activity against hMCHR1 and dose-dependently suppressed food intake in a 2-day study on DIO-F344 rats. Furthermore, practical chiral synthesis of (R)-10h was performed to determine the molecule's absolute configuration. [PubMed Citation] [Order full text from Infotrieve]

18) Sasmal S, Balaji G, Kanna Reddy HR, Balasubrahmanyam D, Srinivas G, Kyasa S, Sasmal PK, Khanna I, Talwar R, Suresh J, Jadhav VP, Muzeeb S, Shashikumar D, Harinder Reddy K, Sebastian VJ, Frimurer TM, Rist , Elster L, Hgberg T
Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists.
Bioorg Med Chem Lett. 2012 May 10;22(9):3157-62.
Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays a role in metabolic and CNS disorders. The modeling-supported design, synthesis and multi-parameter optimization (biological activity, solubility, metabolic stability, hERG) of novel quinazoline derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified. Clusters of refined hMCHR1 homology models derived from the X-ray structure of the ?2-adrenergic receptor, including extracellular loops, were developed and used to guide the design. [PubMed Citation] [Order full text from Infotrieve]

19) Verty AN, Lockie SH, Stefanidis A, Oldfield BJ
Anti-obesity effects of the combined administration of CB1 receptor antagonist rimonabant and melanin-concentrating hormone antagonist SNAP-94847 in diet-inudced obese mice.
Int J Obes (Lond). 2012 May 1;
OBJECTIVE:Current anti-obesity monotherapies have proven only marginally effective and are often accompanied by adverse side effects. The cannabinoid 1 (CB1) receptor antagonist rimonabant, while effective at producing weight loss, has been discontinued from clinical use owing to increased incidence of depression. This study investigates the interaction between the cannabinoid and melanin-concentrating hormone (MCH) systems in food intake, body weight control, and mood.DESIGN:Lean male C57BL/6 mice were injected i.p. with rimonabant (0.0, 0.03, 0.3 and 3.0?mg?kg(-1)) or the MCH1-R antagonist SNAP-94847 (0.0, 1.0, 5.0 and 10.0?mg?kg(-1)) to establish dose response parameters for each drug. Diet-induced obese (DIO) mice were given either vehicle, sub-threshold dose of rimonabant and SNAP-94847 alone or in combination. Impact on behavioral outcomes, food intake, body weight, plasma metabolites and expression of key metabolic proteins in the brown adipose tissue (BAT) and white adipose tissue (WAT) were measured.RESULTS:The high doses of rimonabant and SNAP-94847 produced a reduction in food intake after 2 and 24?h. Combining sub-threshold doses of rimonabant and SNAP-94847 produced a significantly greater loss of body weight in DIO mice compared with vehicle and monotherapies. In addition, combining sub effective doses of these drugs led to a shift in markers of thermogenesis in BAT and lipid metabolism in WAT consistent with increased energy expenditure and lipolysis. Furthermore, co-administration of rimonabant and SNAP-94847 produced a transient reduction in food intake, and significantly reduced fat mass and adipocyte size. Importantly, SNAP-94847 significantly attenuated the ability of rimonabant to reduced immobility time in the forced swim test.CONCLUSION:These results provide proof of principle that combination of rimonabant and a MCH1 receptor antagonist is highly effective in reducing body weight below that achieved by rimonabant and SNAP-94847 monotherapies. In addition, the combination therapy normalizes the rimonabant-induced behavioral changes seen in the forced swim test.International Journal of Obesity advance online publication, 3 April 2012; doi:10.1038/ijo.2012.35. [PubMed Citation] [Order full text from Infotrieve]