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Expanding the Scales: The Multiple Roles of MCH in Regulating Energy Balance and Other Biological Functions

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

Correspondence: Address all correspondence and requests for reprints to: Eleftheria Maratos-Flier, Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215. E-mail: emaratos{at}bidmc.harvard.edu

	Abstract

Top Abstract I. Historical Perspective II. MCH Genes and... III. MCH and Energy... IV. MCH Receptor and... V. Neuronal Responses VI. Central Effects Not... VII. Peripheral Effects of... VIII. Summary and Conclusion References

 
Melanin-concentrating hormone (MCH) is a cyclic peptide originally identified as a 17-amino-acid circulating hormone in teleost fish, where it is secreted by the pituitary in response to stress and environmental stimuli. In fish, MCH lightens skin color by stimulating aggregation of melanosomes, pigment-containing granules in melanophores, cells of neuroectodermal origin found in fish scales. Although the peptide structure between fish and mammals is highly conserved, in mammals, MCH has no demonstrable effects on pigmentation; instead, based on a series of pharmacological and genetic experiments, MCH has emerged as a critical hypothalamic regulator of energy homeostasis, having effects on both feeding behavior and energy expenditure.

I. Historical Perspective

II. MCH Genes and Pro-MCH Peptides

III. MCH and Energy Balance

A. Effects of MCH administration

B. Genetic studies

C. MCH and energy balance in fish

D. Interactions with other systems

IV. MCH Receptor and Receptor Signaling

A. Characterization of the receptor

B. MCH receptor polymorphisms

C. MCH receptor antagonists

V. Neuronal Responses

A. Responses of MCH neurons to neurotransmitters and neuropeptides

B. Electrophysiological responses of neurons to MCH

VI. Central Effects Not Related to Energy Balance

A. Effects of MCH on hypothalamic-pituitary axis

B. Other behavioral effects

VII. Peripheral Effects of MCH

VIII. Summary and Conclusion

	I. Historical Perspective

Top Abstract I. Historical Perspective II. MCH Genes and... III. MCH and Energy... IV. MCH Receptor and... V. Neuronal Responses VI. Central Effects Not... VII. Peripheral Effects of... VIII. Summary and Conclusion References

 
FISH AND AMPHIBIANS are known to change skin color acutely in response to environment and stress. This change is mediated within minutes by the migration of the melanosomes. When the melanosomes are dispersed, the skin or scale is dark; when the melanosomes "concentrate" in the perinuclear area, the refractory index of the fish changes, and the skin becomes light (1). The possibility that these changes were mediated through a "dual control" mechanism involving a hormone-mediating melanosome dispersion that makes fish scales darker and another hormone causing skin lightening was considered as early as 1931 (2). The nature of the skin-lightening activity was debated until 1958, when an activity (3) that produced melanosome concentration was separated from melanocyte-stimulating hormone (MSH), which had already been identified as an inducer of skin-darkening activity using an absorption technique. Additional studies confirmed that MCH was the peptide responsible for skin lightening (4, 5). However, the primary sequence was not identified until 1983, when MCH was isolated from pituitaries and chemically characterized as a 17-amino-acid peptide (1) with a dicysteine bridge at positions 5 and 14 forming a ring structure. This ring is essential for biological function (6).

In fish, MCH is expressed in two groups of neurons (recently reviewed by Kawauchi and Baker in Ref. 7). One population of large MCH neurons is located in the nucleus tuberis, the fish homolog of the arcuate nucleus (8), and sends projections mainly to the neurohypophysis (posterior pituitary), although some projections are also sent to the pars distalis (anterior pituitary) as well as to the forebrain. Another group of MCH-positive neurons is found in the dorsal hypothalamus. This dorsal population is more abundant in primitive fish and is less prominent in teleost fish; these neurons are smaller and project to brain and not to pituitary. It is believed that projections to the pars distalis may play a role in regulating pituitary function, whereas the projections to the neurohypophysis are important in the regulation of skin color.

Subsequent to its discovery in fish, MCH was identified in the mammalian hypothalamus as part of a peptide discovery effort aimed at characterizing constituents of rat hypothalamus (9). The mammalian form of MCH is a cyclic 19-amino- acid neuropeptide that is highly homologous to salmon MCH. The N terminus contains two additional amino acids and two amino acid substitutions; there are two additional conserved amino acid substitutions, one in the ring structure and one near the C terminus (Fig. 1).

View larger version (39K): [in this window] [in a new window]   FIG. 1. Amino acid sequence of the mature mammalian MCH peptide. Amino acid residues in green are conserved between mammals and salmon. Amino acid residues in red are different in salmon.

View larger version (83K): [in this window] [in a new window]   FIG. 2. A, In situ hybridization showing wide distribution of MCH mRNA-expressing neurons in the lateral hypothalamus and ZI of the mouse. B, Immunohistochemical detection of MCH-expressing neurons reveals a similar distribution pattern throughout the lateral hypothalamus and the ZI. LHA, Lateral hypothalamic area; 3v, third ventricle.

More recently, accumulating evidence from physiological, genetic, and pharmacological studies indicates that MCH plays a critical role in energy homeostasis and is involved in the regulation of both feeding behavior and energy expenditure.

	II. MCH Genes and Pro-MCH Peptides

Top Abstract I. Historical Perspective II. MCH Genes and... III. MCH and Energy... IV. MCH Receptor and... V. Neuronal Responses VI. Central Effects Not... VII. Peripheral Effects of... VIII. Summary and Conclusion References

 
In chum salmon, identification of two homologous but not identical mRNAs encoding MCH was reported in 1988 (18), and identification of the two corresponding genes, officially designated pMCH1 and pMCH2, was reported in 1989 (19). Two genes also exist in trout, which is in the salmonid family (20). The reduplication of the gene likely relates to the tetraploid nature of the salmonid genome. In fish, the MCH gene is intronless and encodes for a preprohormone 132 amino acids in length.

In addition to several species of trout (20) and salmon (21), MCH cDNA has been cloned from several genera of fish, including flounder (22) and tilapia (23). As shown in Fig. 3, homology between salmon and other fish is not particularly high. At the peptide sequence of the preprohormone, homology between chinook and coho salmon is 90%, and homology between chinook salmon and trout is also 90%. In contrast, homology between chinook and tilapia is only 61%. Similarly, homology between chinook and flounder is 59%. However, the peptide sequence of MCH is identical among these species.

View larger version (21K): [in this window] [in a new window]   FIG. 3. Amino acid sequence alignment of prepro-MCH among different species of fish. A high degree of homology is seen in the salmonid family. Chinook and coho prepro-MCH are 80% identical and 90% homologous. Similarly, there is 81% identity and 90% homology between chinook and trout. In contrast, homology between chinook and tilapia is only 61%, and homology between chinook and flounder is only 59%. This is similar to the 54% homology between salmon and human MCH. However, the sequence of the mature MCH peptide is identical in all fish species compared. Blue, Polar positive; red, polar negative; green, polar neutral; white, nonpolar aliphatic; purple, nonpolar aromatic; brown, proline, glycine; yellow, cysteine.

Identification of the MCH gene in fish made it possible to clone MCH in mammals. Thus, rat and human mRNAs were identified within 1 or 2 yr (25, 26, 27), followed by the mouse mRNA (28). Furthermore, mRNA analysis revealed that the transcript encodes for two other potential products, neuropeptide E-I (NEI) and neuropeptide G-E (NGE) (25). In humans, rats, and mice, the gene contains three exons and two introns (Fig. 4). It is localized on the long arm of the human chromosome 12, the long arm of chromosome 7 in the rat, and on chromosome 10 in the mouse. There are untranslated regions at both the 5' end and the 3' end.

View larger version (19K): [in this window] [in a new window]   FIG. 4. Schematic representation of the genomic structure of the MCH gene. The human MCH gene is located on the long arm of chromosome 12 (12q23–24). The MCH gene contains three exons and two introns. The peptides NGE, NEI, and MCH are all encoded in the second and third exons.

View larger version (28K): [in this window] [in a new window]   FIG. 5. Amino acid sequence alignment of prepro-MCH among different species of mammals. A high degree of homology is observed among all species examined. The sequence of the mature MCH peptide is identical in all species. See Fig. 3 for color scheme.

The role of the two other peptides encoded by pro-MCH remains somewhat obscure. Limited experiments suggest that NEI is present in the same nerve terminals as MCH and injections of this neuropeptide produce behavioral changes in rats (see Section VI.B). There is no experimental evidence that NGE is a functional peptide in the central nervous system. Injections of synthetic NEI and NGE into the rat lateral ventricle, alone or combined with MCH, did not produce any effects on feeding behavior (29). Recently, two additional products of the MCH gene have been described. Translation of an alternative frame produces two peptides named MCH gene overprinted polypeptide (MGOP)-14 and MGOP-27 (30). The second product is transcribed from the antisense strand partially overlapping with the MCH gene and is named antisense RNA overlapping MCH (AROM) gene. This gene produces multiple products through alternative splicing, but the coding sequence of the AROM peptide does not overlap with MCH cDNA (31). The function of these novel transcripts from the MCH gene locus is unknown at the present time.

In humans, the authentic pMCH gene is reduplicated into two additional MCH-like genes on chromosome 5, pMCHL1 at 5p14 and pMCHL2 at 5q13. These genes have 92–95% homology with the authentic gene, but lack exon I. pMCHL1 produces several sense and antisense RNAs that are expressed in developing human brain (32, 33). pMCHL2 does not appear to yield any transcripts. Although at this time, the precise functional nature of these MCH-like genes is unknown, the genes have been useful in tracing primate brain evolution (34).

	III. MCH and Energy Balance

Top Abstract I. Historical Perspective II. MCH Genes and... III. MCH and Energy... IV. MCH Receptor and... V. Neuronal Responses VI. Central Effects Not... VII. Peripheral Effects of... VIII. Summary and Conclusion References

 
A. Effects of MCH administration
The potential role of MCH in energy balance emerged from studies aimed at evaluating differential expression of RNA in the hypothalamus of the genetically obese, leptin-deficient ob/ob mouse (35). MCH mRNA expression was found to be substantially increased in these mice compared with their thin littermates. Furthermore, an additional increase in expression was seen with fasting in both control and ob/ob animals. This suggested that MCH might be an orexigenic peptide; this hypothesis was confirmed when a rapid induction of increased feeding behavior was observed when MCH was injected intracerebroventricularly (ICV) in the lateral ventricle of rats (36, 37). The relative increment in food intake seen is 2- to 3-fold, usually occurs within the first hour after injection, and persists for at least 6 h. Furthermore, the effect is dose-dependent and requires injection of at least 1–1.5 µg into the ventricle. Five micrograms produces a maximal effect; higher doses do not increase the amplitude of the response, but increase its duration. Although injections into the paraventricular nucleus (PVN), dorsomedial hypothalamic nucleus, and arcuate nucleus all induce feeding (38), the actual sites critical for MCH action on feeding remain unknown.

In another study, MCH was injected into the fourth ventricle of rats to target the nucleus tractus solitarius in the hindbrain. No effect on feeding was seen. However, there was a significant decrease in core body temperature and a trend toward decreased physical activity, suggesting that MCH acts on the hindbrain in a manner consistent with energy conservation (39).

In rats, MCH also increases water intake independent of food intake (40). ICV injections may also increase both alcohol intake (41) and sucrose intake (41, 42). These effects of MCH may be related, at least in part, to its effects on reward systems.

B. Genetic studies
Additional data about the role of MCH are derived from genetic studies. Knockout of the MCH gene produces a lean mouse that has both decreased feeding and increased resting energy expenditure (43). Mice lacking MCH weigh 25–30% less than control littermates, secondary to a reduction in body fat, and have low circulating leptin levels. Because leptin acts to suppress expression of orexigenic peptides such as neuropeptide Y (NPY) and agouti-related polypeptide (AgRP) and to increase expression of proopiomelanocortin (POMC; the precursor of -MSH) (12, 44, 45, 46, 47), one might predict altered expression of these neuropeptides in the hypothalamus of MCH-knockout mice, in a direction consistent with lowered leptin levels. However, although expression of POMC is reduced, expression of both AgRP and NPY is similar to that seen in normal animals.

On the basis of the high levels of MCH seen in ob/ob animals, coupled with the pharmacological effect of MCH to increase food intake, one would expect that leptin-deficient ob/ob mice also lacking MCH might be lean and that leanness would result from a decrease in food consumption. This hypothesis was evaluated in a study where mice lacking MCH were backcrossed onto a C57BL/6 background for six generations and then crossed with leptin-deficient mice of the same genetic background. Evaluation of these "double null" animals revealed that while still obese, they were markedly leaner than ob/ob animals (48). However, the attenuation of the obese phenotype that was seen was secondary to increased energy expenditure rather than to decreased feeding. The increase in energy expenditure was a result of both a 3-fold increase in locomotor activity and a 25% increase in metabolic rate (48). In terms of feeding, ob/ob mice also deficient in MCH ate the same amount of food as ob/ob mice with an intact MCH gene.

Additional insights into the role of MCH in regulating energy expenditure are derived from studies of MCH ablation in two different background strains. Mice lacking MCH were crossed for multiple generations onto either a C57BL/6 background or a 129/SvEv background. These two strains were chosen because the C57BL/6 strain is known to be quite susceptible to rodent obesity caused by high-fat/high-sucrose diets, whereas the 129/SvEv strain is relatively resistant to diet-induced obesity (DIO). Both C57BL/6 and 129/SvEv animals lacking MCH are lean relative to control animals with an intact MCH gene. In neither case is hypophagia a feature; in fact, 129/SvEv mice lacking MCH eat more than wild-type littermates. In both strains, increased energy expenditure appears to account for leanness. This difference in energy expenditure becomes more pronounced when animals are placed on a high-fat diet, which results in further increases in activity and metabolic rate in mice lacking MCH compared with control mice. The magnitude of the effect is different in the two strains; 129/SvEv mice lacking MCH resist DIO entirely, whereas C57BL/6 animals show significantly reduced weight gain (125).

The lean phenotype of mice lacking MCH persists out to at least 19 months of age. Aged MCH^–/– male mice are 30% leaner and females are 25% leaner than their wild-type counterparts, an effect due entirely to decreased adipose mass. Furthermore, aged mice lacking MCH have improved glucose tolerance secondary to being more insulin sensitive than control mice (29). Plasma insulin levels during glucose tolerance tests are significantly lower in aged MCH^–/– mice compared with wild-type animals. In addition, aging-associated decreases in locomotor activity and resting energy expenditure are attenuated in MCH^–/– mice compared with wild-type animals. These data suggest that hypothalamic leanness may lead to an amelioration of the processes associated with aging.

Recently, a mouse model in which MCH neurons are ablated was developed using a genetic construct that mediates expression of the toxin, ataxin-3, in target MCH neurons (49). Mice expressing this gene have a time-dependent loss of MCH neurons, which begins at 4 wk of age and leads to loss of about two thirds of all MCH neurons at 15 wk. These mice show a divergence in weight at 7 wk of age, when ataxin-3 MCH mice become leaner than wild-type animals. The phenotype of these mice, lacking most MCH neurons as adults, is remarkably similar to the phenotype of mice lacking only the peptide. Leanness in ataxin-3/MCH mice may be due to a slight reduction in food intake; however, energy expenditure also contributes significantly, because ataxin-3/MCH mice show increased oxygen consumption. Furthermore, crossing the ataxin-3/MCH mouse to ob/ob mice leads to improved obesity and glucose tolerance.

The finding that both ablation of the MCH gene from MCH neurons and loss of MCH neurons themselves lead to a remarkably similar phenotype is of significant interest. This result indicates that the peptide itself is the critical mediator of signals from the MCH neuronal population that regulates energy balance. This is in contrast to comparable experiments performed with two other orexigenic peptides from the arcuate, NPY and AgRP. These peptides are coexpressed in a population of arcuate neurons that is suppressed by leptin. Ablation of either peptide individually, or both peptides, is not associated with a distinct phenotype (50). In contrast, ablation of the neuronal population using a toxin-based approach leads to a profound hypophagia (51, 52). In the case of AgRP/NPY, the peptides do not appear to be as critically important as the neurons in regulating energy balance.

Although MCH ablation leads to leanness, eutopic overexpression of an MCH transgene (MCH-OE) leads to increased susceptibility to obesity (53). On an FVB background, mice homozygous for the transgene overexpressing MCH have enhanced susceptibility to developing obesity when on a high-fat diet, compared with control animals on the same diet. MCH-OE mice gain 3–4 g of excess weight compared with control animals. MCH-OE mice also show significant hyperinsulinemia and islet cell hypertrophy, which are out of proportion to the mild obesity. The phenotype of overexpression is quite similar to that of chronic infusion, which has been shown to lead to hyperphagia and obesity in both rats (54) and mice (55). Mice infused with MCH also gain weight when pair fed to control animals, indicating that MCH causes alterations in energy balance beyond feeding. However, despite becoming obese, insulin levels in mice infused with MCH are not substantially higher than those seen in control animals.

Ablation of the rodent MCH receptor, MCHR1, also produces a lean phenotype. This phenotype is similar, but not identical, to that seen with ablation of the pMCH gene. Mice lacking MCHR1 are lean, with decreased fat mass, but surprisingly are hyperphagic compared with control littermates, when fed chow. When placed on a high-fat diet, they eat as much as control animals but gain substantially less weight. Mice lacking MCHR1 also develop osteoporosis and exhibit evidence of increased sympathetic activity, although the precise pathways mediating these effects are unknown.

Interestingly, a recent report indicates that the phenotype of ob/ob mice lacking MCHR1 (56) is somewhat different from that reported in mice lacking MCH (48) or MCH neurons (49). For example, mice lacking leptin and MCHR1 (receptor double null) weigh the same as ob/ob mice and have no difference in overall energy expenditure. However, they have an increase in total activity as seen in mice lacking leptin and pMCH (ligand double null). Also similar to ligand double null animals, receptor double null animals have lower circulating corticosterone levels, higher core temperature, and improved cold tolerance. However, in contrast to the ligand double null animals, there is no decrease in hepatic stearoyl-CoA desaturase-1 expression and no increase in brown adipose tissue uncoupling protein-1 protein expression.

These differences might be explained by the fact that ligand double null animals and ob/ob animals with ablation of MCH neurons lack MCH and also lack NEI and NGE, the two other neuropeptides encoded by the pMCH gene. The phenotype of these two animals is quite similar. In contrast, mice lacking the MCH receptor lack only signals mediated by MCH. Further studies will be necessary to reconcile these differences.

C. MCH and energy balance in fish
A few studies have addressed the potential role of MCH on feeding and weight in fish. In one study in medaka fish, a transgenic construct was used to drive MCH overexpression using a cytomegalovirus promoter (57). MCH-OE fish could be visually distinguished by their light body color. Microscopic examination of the scales revealed concentrated melanosomes. An increase in circulating MCH was demonstrated using a fish scale-based bioassay. However, no changes in body weight, size, or reproductive capacity were seen. In another study, barfin flounder were raised in a white environment, which is known to increase MCH expression and MCH serum levels. These fish showed very light skin pigmentation and increased somatic growth at 5 months compared with fish reared in a light environment (22, 58). In another feeding study performed in goldfish, administration of MCH resulted in a substantial inhibition of food intake (59). Interpretation of these studies is limited by the fact that they are few in number, are performed in different species of fish, and use extremely different techniques. At this point, the role, if any, of MCH in fish energy balance is unclear.

D. Interactions with other systems
The interaction of MCH with other peptidergic systems was initially described in fish scales, where the action of MCH to lighten color is antagonistic to the action of - MSH, which acts to darken skin color. This mutually antagonistic action persists in the mammalian hypothalamus, where the effect is focused on feeding behavior. Thus, although MCH administration increases feeding, -MSH acts to decrease feeding. When the peptides are administered together, depending on the relative dose, one can antagonize the action of the other (15). For example, 10 µg of -MSH completely blocks the feeding effect induced by 5 µg of MCH; however, 10 µg of -MSH has no effect on feeding induced by 25 µg of MCH. Glucagon-like peptide-1 and neurotensin also inhibit the orexigenic effects of MCH (60).

Changes in MCH expression have also been reported in two genetic mouse models of altered energy homeostasis, suggesting that there is regulation of the MCH system by other neuropeptides. MCH expression is markedly decreased in mice without muscarinic 3 receptors, which are lean (61). In contrast, mice lacking the bombesin receptor, BRS3, are obese and show increased hypothalamic expression of MCH and the MCH receptor (62). However, the mechanisms mediating these changes and the relative contribution of MCH to the phenotype are unknown.

Increased MCH levels have also been reported in another obese model, the fat/fat mouse (63). This mouse lacks carboxypeptidase E, and as a result, a number of neuropeptide preprohormones are not processed appropriately. These mice have increased levels of both MCH and NEI but very reduced levels of NGE, and it is possible that MCH contributes to their obesity.

It has also been shown that two compounds affecting glucose and fatty acid oxidation, 2-deoxyglucose and mercaptoacetate, respectively, increase MCH mRNA expression (64, 65). The mechanisms responsible for this up-regulation remain poorly defined, but these studies implicate MCH in the hyperphagic response elicited by administration of these compounds.

	IV. MCH Receptor and Receptor Signaling

Top Abstract I. Historical Perspective II. MCH Genes and... III. MCH and Energy... IV. MCH Receptor and... V. Neuronal Responses VI. Central Effects Not... VII. Peripheral Effects of... VIII. Summary and Conclusion References

 
A. Characterization of the receptor
Initial efforts to identify the rodent MCH receptor involved binding assays using radioactively labeled MCH. However, these efforts were impeded by high nonspecific binding (66, 67), and the nature of the receptor remained obscure until several groups contemporaneously identified a receptor designated MCHR1 (68, 69, 70, 71, 72). This receptor had been previously identified as an orphan G protein-coupled receptor termed SLC-1/GPR24 (73). Like many other receptors for neuropeptides in the central nervous system, it is a seven-transmembrane domain G protein-coupled receptor. The peptide sequence comprises 353 amino acids and is highly conserved in rats, mice, and humans (human-rat, 96% identity; human-mouse, 95% identity) (74). It is most closely related to the somatostatin receptor family with which it shares approximately 35% homology (73).

MCHR1 contains three consensus N-glycosylation sites and several potential phosphorylation sites in its intracellular loops (75). As illustrated in Fig. 6, biochemical analysis has shown that an aspartic acid residue (Asp¹²³) in the third transmembrane domain is crucial for ligand binding (76) and that an asparagine residue (Asn²³) in the extracellular N-terminal region is important for N-linked glycosylation of MCHR1 and for cell surface expression (77). Recent studies have also shown a critical role for an arginine residue (Arg¹⁵⁵) in the second intracellular loop of MCHR1, because mutation of this residue leads to a complete loss of initiation of signal transduction (78). The C-terminal region of MCHR1 has also been shown to be integral for receptor function (79). The actin- and intermediate filament-binding protein, periplakin, appears to be coexpressed with MCHR1 in mouse brain and may interact with the intracellular C terminal of MCHR1 to impede MCHR1-initiated signal transduction (Fig. 6) (80). Calcium mobilization is inhibited by periplakin; however, ERK1/2 phosphorylation is induced normally. In addition, an MCHR1 interacting zinc-finger protein (MIZIP) that interacts with the C terminus of MCHR1 has been identified from human brain and is postulated to be a regulatory molecule in MCHR1 signaling (81). The physiological significance of interactions with both MIZIP and periplakin is unknown.

View larger version (31K): [in this window] [in a new window]   FIG. 6. MCHR1 activates multiple signaling pathways. Through coupling to different intracellular effectors, MCHR1 decreases the activity of adenylate cyclase (AC), increases the levels of intracellular calcium (Cai++), activates ERKs, and interacts with intracellular proteins such as periplakin and MIZIP. Locations of amino acid residues necessary for glycosylation and/or activity of MCHR1 are depicted in red (see text).

Subsequent to the identification of MCHR1, a second 340-amino-acid MCH receptor subtype designated MCHR2 was identified in humans (87, 88, 89, 90, 91, 92). Although the overall homology to MCHR1 is relatively low (38% amino acid identity), MCHR2 expression is similar to that of MCHR1, with the highest expression occurring in the brain, in particular the frontal cortex, amygdala, and nucleus accumbens (87, 88, 91). MCHR2 is also reported to be present in peripheral tissues, including adipose, prostate, and intestine (87, 88). In general, MCHR1 and MCHR2 are coexpressed in the same tissues. However, MCHR1 appears to have a more abundant and wider distribution pattern than MCHR2 (93). Both receptor subtypes are also present in the rhesus monkey (94, 95) as well as in dogs and ferrets (95). Notably, unlike MCHR1, expression of the MCHR2 subtype has not been detected in rodents (95). In addition, whereas MCHR2 increases intracellular Ca²⁺ levels, unlike MCHR1, it does not suppress cAMP (87, 88, 91). Overall, the physiological role of MCHR2 remains unclear. Based on its expression in cortical regions of the brain and the digestive tract, it has been suggested that MCHR2 may potentially have roles in cognitive and emotional aspects of food intake and/or regulation of nutritional homeostasis by MCH (90, 92).

B. MCH receptor polymorphisms
Several single-nucleotide polymorphisms (SNPs) and infrequent variations have been identified in the coding and/or flanking sequences of MCHR1 and MCHR2 (96, 97, 98). One study has reported a trend toward association of several MCHR1 SNPs with an obese phenotype in independent study groups of obese German children and adolescents (96). However, the same communication reported no association of these SNPs with any obese phenotypes in another German sample group, as well as no association in Danish, Finnish, and American cohorts (96). A separate study has identified two SNPs in MCHR1 but reported no association of these SNPs with obesity-related phenotypes in a population of 541 Caucasians (98). Furthermore, a third study has reported no abnormalities either in receptor binding assays or in functional assays measuring changes in intracellular Ca²⁺ and cAMP in Chinese hamster ovary cells transfected with DNA constructs containing MCHR1 and MCHR2 SNPs (97). Associated phenotypic characteristics, if any, for other SNPs identified in the MCH receptors have yet to be analyzed (97). Additional studies will be required to clarify whether MCH receptor SNPs are indeed associated with any obesity phenotypes.

It is not particularly surprising that thus far, no SNPs associated with MCH receptors and obesity have been identified. Obesity associated with the MCH gene would require a gain of function rather than a loss of function. Typically, mutations in the coding sequence of peptides lead to loss of function. This is what has been reported in human syndromes associated with obesity, including leptin and leptin receptor deficiency, POMC deficiency, and melanocortin receptor mutations. A loss of function of the MCH system would lead to leanness and resistance to DIO. Individuals with these characteristics are likely to be identified as "normal," and genetic studies of such families have not yet been performed.

C. MCH receptor antagonists
Given the data implicating the MCH system in energy homeostasis, it is reasonable to hypothesize that molecules capable of antagonizing the MCH receptor could be potential treatments for obesity. Recently, several pharmaceutical companies have reported the synthesis of potent MCHR1 antagonists. The chemical nature and properties of these compounds are beyond the scope of this review, and interested readers are encouraged to consult a recent review by Handlon and Zhou on this topic (99). In vivo, administration of these compounds decreases food intake and weight gain in rodents (99, 100). Several other studies also describe anxiolytic and antidepressant properties of these compounds, in addition to effects on energy balance (101, 102). These effects are most likely mediated by MCH receptors outside the hypothalamus, such as the prefrontal cortex and the amygdala. These exciting results show the potential of MCHR1 antagonists in treating a diverse array of diseases. It should be noted however, that very few studies have examined the specificity of these compounds in mice lacking MCHR1 (103). Evaluation of MCH receptor antagonists is particularly difficult, because rodents lack MCHR2. Although most of the MCHR1 antagonists synthesized show sufficient selectivity for MCHR1, it is unclear what the effects of these antagonists may be in organisms having another functional MCH receptor. Thus, the potential role of these agents in human obesity remains to be explored.

	V. Neuronal Responses

Top Abstract I. Historical Perspective II. MCH Genes and... III. MCH and Energy... IV. MCH Receptor and... V. Neuronal Responses VI. Central Effects Not... VII. Peripheral Effects of... VIII. Summary and Conclusion References

 
A. Responses of MCH neurons to neurotransmitters and neuropeptides
Several studies have addressed the electrochemical properties of MCH neurons in acute slice preparations. MCH neurons have been identified by selective transduction in vivo of adeno-associated virus-expressing green fluorescent protein, or by immunohistochemistry following slice recording (104, 105). In contrast to previously studied POMC, NPY, and orexin-expressing neurons, MCH neurons are generally quiescent and do not fire spontaneously (105). Application of several neurotransmitters such as norepinephrine, serotonin, and the cholinergic agonists, muscarine and carbachol, all hyperpolarize the MCH membrane potential. Inhibition by NPY via pre- and postsynaptic mechanisms also occurs, whereas POMC has no effect on MCH neurons. Orexin, expressed in a separate but intermingled population of neurons, activates MCH neurons (104, 106). Very recently, it was also reported that increasing concentrations of glucose increase the firing frequency of MCH neurons while exerting the opposite effect on the orexin neurons (107).

Numerous studies have examined the properties of orexin and MCH neurons and have found that these two closely apposed populations of neurons respond in opposite ways to several neurotransmitters. For example, both norepinephrine and acetylcholine inhibit MCH neurons, but activate orexin neurons (106). Glucose also has opposite effects on these two populations of neurons (107). These results suggest that the activity of MCH and orexin neurons would be differentially affected by the noradrenergic and cholinergic arousal systems and therefore participate in different stages of the wake-sleep cycle.

B. Electrophysiological responses of neurons to MCH
The effects of MCH on the electrical properties of neurons have been examined in a few studies. Consistent with the G_i/_o coupling of MCHR1, MCH generally causes an inhibition of neuronal firing by presynaptic and postsynaptic mechanisms. Inhibition of voltage-gated calcium channels has been observed in recording from lateral hypothalamic neurons. This inhibition is pertussis toxin-sensitive, indicating G_i coupling of MCHR1 (108). MCH-mediated inhibition of the voltage-gated calcium channels affects all classes of currents, L, N, and P/Q, with the N-current showing the greatest inhibition (108, 109). A paradigm of rat parental overnutrition (litters were restricted to small numbers of pups) has been used to examine the responses of hypothalamic neurons to neuropeptides involved in energy homeostasis. The results showed that MCH excites medial arcuate (presumably some NPY/AgRP) neurons and inhibits ventromedial hypothalamus and PVN neurons in overnourished rats. As these rats become hyperphagic and obese, the enhanced responsiveness of these neurons to MCH is consistent with its role in promoting feeding and energy conservation (110, 111).

In other brain regions examined, MCH may potentiate synaptic transmission in the dentate gyrus of the hippocampus (112), whereas no effects of MCH have been observed on ventral tegmental area dopaminergic and nondopaminergic neurons (113). Actions in other brain regions expressing high levels of MCH receptors, such as the dorsal and ventral striatum, have not been examined, but should provide interesting clues regarding the proposed effects of MCH on locomotion and goal-directed behaviors.

	VI. Central Effects Not Related to Energy Balance

Top Abstract I. Historical Perspective II. MCH Genes and... III. MCH and Energy... IV. MCH Receptor and... V. Neuronal Responses VI. Central Effects Not... VII. Peripheral Effects of... VIII. Summary and Conclusion References

 
A. Effects of MCH on hypothalamic-pituitary axis
In addition to studies of MCH on energy expenditure, MCH has been evaluated with regard to regulation of the GnRH axis. Initial experiments showed that MCH enhances LH release in ovariectomized, adrenalectomized, and estrogen-primed rats when injected into the medial preoptic area or the median eminence of the hypothalamus but not in the ventromedial hypothalamus (114). This effect can be blocked by concomitant injection of selective antagonists for the melanocortin 5 receptor, showing an interaction between these two important hypothalamic systems (16). Neuroanatomical studies demonstrate the presence of MCHR1 in approximately 50–55% of GnRH neurons and close apposition of MCH-positive synapses on 85% of GnRH neurons (115). Direct injection of leptin into the ZI, a region containing MCH neurons, also stimulates LH release, suggesting that leptin exerts its effects on reproduction in part through MCH actions on GnRH neurons (116). These results suggest that one of the pathways used by MCH to stimulate GnRH release is by acting directly on the gonadotropin-releasing neurons. Additional experiments have shown that MCH also affects GnRH release from cultured median eminences and LH release from anterior pituitaries, pointing to additional ways MCH may influence the reproductive axis (117). Similar experiments examining the effects of MCH on other hypothalamic hormones have demonstrated that MCH suppresses TSH release in vivo when administered ICV, as well as TRH release from hypothalamic explants, and reduces TRH-induced TSH release from dispersed pituitary cultures, consistent with its effects on reducing energy expenditure (118). In contrast, MCH stimulates the hypothalamic-pituitary adrenal axis. In vivo, ACTH levels increase after ICV injection of MCH or direct injection into the rat PVN. Cultured hypothalamic explants release more CRF after addition of MCH, an effect that can be blocked by selective MCHR1 antagonists (119). These studies suggest an important role of the MCH system in the integration of the homeostatic and neuroendocrine responses of the hypothalamus.

B. Other behavioral effects
Given the widespread expression of MCHR1, it is not surprising that MCH affects several behaviors in rodents. One of the first reports addressing potential behavioral effects of MCH used a paradigm of auditory gating in anesthetized rats. During these studies, MCH and -MSH were injected alone, or in combination, into the lateral ventricle, and the evoked potential was recorded in the dorsal hippocampus. In this model, MCH antagonizes the -MSH increase in auditory gating (14). Direct injection of MCH into the ventromedial nucleus of the hypothalamus of female rats stimulates sexual behavior (120), whereas injection of MCH into the hippocampus reverses the amnesic effects of N(G)-nitro-L-arginine (112).

Other behaviors examined after injections of MCH include grooming, locomotor activity, and rearing. MCH injected ICV into rats antagonizes the increase in grooming behavior after -MSH injection. MCH also antagonizes the increase in locomotor activity, grooming, and rearing after injection of NEI (a peptide produced from the same prohormone like MCH) (121).

Genetic inactivation of MCHR1 in mice results in increased spontaneous locomotor activity (122, 123), as well as increased wheel running activity (124). Although mice without MCH show little, if any increase in spontaneous activity, breeding MCH-deficient to leptin-deficient mice not only decreases their body weight but also increases their locomotor activity (48). In addition, feeding MCH^–/– mice a high-fat diet increases both spontaneous activity (125) and wheel running (124). The locomotor effects of MCH might be mediated by its action on the mesolimbic dopamine systems. MCHR1 is highly expressed throughout the striatum and especially in the medial shell of the nucleus accumbens. Injection of MCH directly into the medial shell of the nucleus accumbens increases feeding in sated rats, and injection of MCHR1 antagonist produces the opposite effect, suggesting that this nucleus is an important site of MCH actions (126). MCHR1 ablated mice have also been found to be supersensitive to psychostimulants, such as amphetamine, by measuring the locomotor activity of wild-type and mutant mice after amphetamine injection (127).

In contrast to the metabolic effects of MCH, which consistently show that blocking MCH-MCHR1 interaction by pharmacological or genetic means results in leanness and resistance to DIO, there are conflicting reports on behavioral effects of MCH and MCHR1 antagonists, especially on exploration and anxiety. On elevated plus maze, a test for anxiety, ICV injection of MCH in rats increases the number of entries into the open arms and increases exploration in open field test, both indicative of anxiolytic effects (128).

MCH also produces anxiolytic effects when injected ICV in rats in a test of anxiety called Vogel’s punished drinking test; however, in the same study, no effects on locomotor activity in habituated or nonhabituated rats were observed (129).

Another study utilizing MCH injections in the rat third ventricle reported increased nonspecific ingestive behavior as reflected by increased ethanol and sucrose consumption with no effects observed on elevated plus maze (41).

Paradoxically, MCH antagonists also mimic some of the effects seen with MCH. Administration of the MCHR1 antagonist, SNAP7941, decreases anxiety and depression in rats in a forced swim test, by decreasing the time of immobility in the water; significantly increases rat social interaction; and decreases anxiety in guinea pig pups in a test of maternal separation (101). Similarly to SNAP7941, two novel orally administered MCHR1 antagonists, ATC0065 and ATC0175, also induce anxiolytic and antidepressant effects in rats on elevated plus maze, decrease stress-induced hyperthermia, increase social interaction in unfamiliar rats, and reduce ultrasonic vocalization in guinea pig pups after maternal separation (102).

Antidepressant effects have also been observed after MCHR1 antagonist injection into the medial shell of the nucleus accumbens using a forced swim test; injection of MCH produces the opposite effect, suggesting that some of the behavioral effects of MCH might be mediated by the mesolimbic dopamine system (126). Finally, genetic inactivation of MCHR1 results in anxiolytic effects in mice, as assessed by open field test, elevated plus maze, social interaction, and also triggers stress-induced hyperthermia. A possible decrease in serotonergic transmission has been observed in the prefrontal cortex, indicating a potential region for these complex effects of MCH (130).

It is impossible at the present time to reconcile the differences between the studies outlined above. Several variables could affect the outcome, such as the different species used in these studies (rats vs. mice); various tests used to score the behaviors (open field test, elevated plus maze, social interaction, etc.); different routes of entry (ICV vs. oral administration); the use of small diffusible compounds as antagonists for MCHR1 vs. MCH; and the use of various genetic models of MCHR1 deficiency. Unless the various experimental models are tested side by side in controlled studies, it will be difficult to assign conclusively, the function of MCH in the regulation of anxiety and exploratory behaviors.

Although the pharmacology of MCHR1 antagonists requires further studies, the physiological role of MCH in the behaviors mentioned is even more obscure. Subpopulations of MCH neurons almost certainly exist, performing distinct functions. At the present time, we have very limited knowledge about the nature of inputs into these neurons or their detailed projection pattern, and we do not understand the mechanisms underlying conditions that activate MCH neurons. Therefore, a more detailed understanding of the circuitry of the lateral hypothalamus will be necessary, to assign specific behaviors to subpopulations of MCH neurons.

	VII. Peripheral Effects of MCH

Top Abstract I. Historical Perspective II. MCH Genes and... III. MCH and Energy... IV. MCH Receptor and... V. Neuronal Responses VI. Central Effects Not... VII. Peripheral Effects of... VIII. Summary and Conclusion References

 
The physiological relevance of MCH and its receptors in the periphery remains unclear. Although it is expressed predominantly in the brain, significant levels of MCH mRNA, as well as a potential regulatory molecule of MCHR1 signaling, MIZIP, have also been detected in the stomach, intestine, and testis (81, 131), and there are reports that prepro-MCH is expressed in immune cells (132) and in human endothelial cells (133). Similarly, although expressed predominantly in the central nervous system, MCH receptors are also expressed in the periphery, including, but not limited to pituitary, skeletal muscle, tongue, eye, immune and epithelial cells (73, 85, 132). Two insulinoma cell lines, RINm5F and CRI-G1, as well as rat islets are known to express MCHR1, and MCH is reported to have an insulinotropic effect in the insulinoma cell lines (134). However, other studies have reported no effect of MCH on insulin secretion from isolated rat islets (135).

Expression of MCH receptor has been reported in both a skin cell line (136) and human skin, which also may express MCH (133). In addition, in primary human melanocytes, MCH appears to antagonize the action of MSH to increase melanin production (133). One group has reported antibodies to MCHR1 in patients with vitiligo, a skin disease associated with loss of pigmentation (137). Thus, it is tempting to speculate that MCH might play a role in pigmentation in mammals. However, in knockout models, loss of either MCH or the MCH receptor is not associated with change in coat color, either for the C57BL/6 strain of mouse, which has a black coat color, or for 129/SvEv mice, which have a brown coat. This is in contrast to the effects on coat color caused by agouti protein or melanocortin mutations. Hence, it seems unlikely that MCH has a physiological role in mammalian pigmentation.

MCHR1 is also present on primary rat adipocytes, and MCH can act on these cells to stimulate production of leptin (86). A physiologically relevant regulation of leptin synthesis/secretion by MCH could contribute to overall energy homeostasis. It is known that adipocytes respond to MCH. Adipocytes exposed to MCH in vitro show a 2-fold increase in leptin secretion after 4 h of treatment, which occurs secondary to a rapid and transient increase in ob mRNA.

MCHR1 is also expressed in the murine 3T3-L1 adipocyte cell line, and treatment of these cells with MCH down-regulates MCHR1 expression (138). This effect is acute and persistent up to a 2-h assay endpoint, thus indicating a mechanism of ligand-induced down-regulation for MCHR1. MCH-induced internalization of MCHR1 has also been reported in HEK293 cells stably expressing MCHR1 (70). More recent studies have indicated that MCH-induced internalization of MCHR1 occurs through a protein kinase C-, ß-arrestin-2-, and dynamin1-dependent pathway and that the C-terminal tail of MCHR1 has an important role in the internalization process (139).

In adipocytes, MCH action is mediated by activation of intracellular kinases (140, 141, 142). MCH incubation has been shown to activate both ERKs and pp70 S6 kinase in 3T3-L1 cells. Induction of phosphorylation of ERK1 and ERK2 is 3-fold, whereas induction of pp70 S6 kinase is in the 5-fold range. These respective increases occur acutely (within 5 min) and gradually decline over a 1-h incubation (138). MCH also stimulates ERK phosphorylation in HEK293 cells stably expressing MCHRI as well as in ex vivo brain slices (83). Stimulation of ERK 1/2 phosphorylation has also been reported in a human melanoma cell line endogenously expressing MCHR1 (136). These pathways are potentially important in driving increased leptin expression, because MCH-stimulated leptin promoter-driven luciferase activity can be attenuated in the presence of inhibitors of ERK 1/2 and pp70 S6 kinase activation (138).

These findings suggest that adipocytes contain an intact MCH signaling pathway that is mediated by MCHR1 (Fig. 7) and suggest that there may be a functional role for MCHR1 in the periphery. Expression of MCH has been reported in intestine and in testis (131) and it is possible that MCH, or a MCH-like peptide circulates in rat plasma (86). A separate study has also reported the presence of MCH in plasma from both lean and obese Zucker rats, with increased circulating levels of MCH being present in obese Zucker rats compared with lean rats (143). Although another report suggests that MCH circulates in human plasma and correlates with body weight (144), an earlier study using column-extracted plasma detected no activity in either rat or human samples (145). Furthermore, another report has questioned the validity of the RIA used to measure MCH in the human study (146). Thus, if MCH does play a role in the periphery, it seems unlikely that it circulates. However, it may be present in nerve terminals or secreted as a paracrine factor.

View larger version (27K): [in this window] [in a new window]   FIG. 7. A proposed model of MCH-stimulated leptin secretion in adipocytes. MCH binds to its cell-surface receptor, MCHR1, and increases ob mRNA synthesis and leptin secretion. This process is potentially mediated by signaling components downstream of ERK1 and ERK2 and p70 S6 kinase, which are both activated by MCH. ER, Endoplasmic reticulum.

	VIII. Summary and Conclusion

Top Abstract I. Historical Perspective II. MCH Genes and... III. MCH and Energy... IV. MCH Receptor and... V. Neuronal Responses VI. Central Effects Not... VII. Peripheral Effects of... VIII. Summary and Conclusion References

 
In mammals, MCH is a neuropeptide exclusively expressed in magnocellular neurons of the lateral hypothalamus. This interesting set of neurons makes many monosynaptic projections throughout the neuraxis, including rostrally to cognitive, olfactory, and motor centers and caudally to brain stem areas involved in the regulation of sympathetic tone (Fig. 8). These areas coincide with sites of expression of the receptor. The distribution of these projections led to early speculation that MCH would be involved in motivated behavior. Accumulating evidence confirms that MCH regulates feeding behavior and more broadly energy homeostasis. Furthermore, increasing evidence suggests that MCH has a role in modulating more complex behaviors such as anxiety and aggression. Studies using pharmacological agents indicate that the MCH system can be targeted by agonists and antagonists to induce changes in both eating behavior and more complex behaviors. In aggregate, these findings suggest that it may be possible to manipulate the MCH system in humans, with the aim of treating obesity and potentially disorders of cognitive and motor function.

View larger version (47K): [in this window] [in a new window]   FIG. 8. Schematic illustration of MCH effects on cognitive behaviors, sensory processing, and energy balance.

	Acknowledgments

 
We thank Francis E. Marino for his assistance in constructing the figures. This work was supported by National Institutes of Health Grants RO1 DK 69983-01 and DK56113, as well as PO1 DK 56116-06 (to E.M.-F.) and KO1 DK 063080-03 (to R.L.B.).

	Footnotes

 
P.P. and R.L.B. have nothing to disclose. E.M.-F. has received lecture fees from Bristol-Myers Squibb.

First Published Online June 20, 2006

¹ P.P. and R.L.B. contributed equally to this work.

Abbreviations: AgRP, Agouti-related polypeptide; DIO, diet-induced obesity; ICV, intracerebroventricularly; MCH, melanin-concentrating hormone; MCH-OE, MCH overexpressing; MCHR1, MCH receptor type 1; MIZIP, MCHR1 interacting zinc-finger protein; MSH, melanocyte-stimulating hormone; NEI, neuropeptide E-I; NGE, neuropeptide G-E; NPY, neuropeptide Y; POMC, preproopiomelanocortin; PVN, paraventricular nucleus; SNP, single-nucleotide polymorphism; ZI, zona incerta.

	References

Top Abstract I. Historical Perspective II. MCH Genes and... III. MCH and Energy... IV. MCH Receptor and... V. Neuronal Responses VI. Central Effects Not... VII. Peripheral Effects of... VIII. Summary and Conclusion References

 

1. Kawauchi H, Kawazoe I, Tsubokawa M, Kishida M, Baker BI 1983 Characterization of melanin-concentrating hormone in chum salmon pituitaries. Nature 305:321–323[CrossRef][Medline]
2. Hogben L, Slome D 1931 The pigmentary effectro system. VI. The dual character of endocrine coordination in amphibian colour change. Proc Roy Soc London Ser B 108
3. Imai K 1958 Extraction of melanophore concentrating hormone (MCH) from the pituitary of fishes. Endocrinol Japan 5:34–48
4. Westerfield DB, Pang PK, Burns JM 1980 Some characteristics of melanophore-concentrating hormone (MCH) from teleost pituitary glands. Gen Comp Endocrinol 42:494–499[CrossRef][Medline]
5. Baker BI, Ball JN 1975 Evidence for a dual pituitary control of teleost melanophores. Gen Comp Endocrinol 25:147–152[CrossRef][Medline]
6. Matsunaga TO, Hruby VJ, Lebl M, Castrucci AM, Hadley ME 1992 Synthesis and bioactivity studies of two isosteric acyclic analogues of melanin concentrating hormone. Life Sci 51:679–685[CrossRef][Medline]
7. Kawauchi H, Baker BI 2004 Melanin-concentrating hormone signaling systems in fish. Peptides 25:1577–1584[CrossRef][Medline]
8. Holmqvist BI, Ekstrom P 1991 Galanin-like immunoreactivity in the brain of teleosts: distribution and relation to substance P, vasotocin, and isotocin in the Atlantic salmon (Salmo salar). J Comp Neurol 306:361–381[CrossRef][Medline]
9. Vaughan JM, Fischer WH, Hoeger C, Rivier J, Vale W 1989 Characterization of melanin-concentrating hormone from rat hypothalamus. Endocrinology 125:1660–1665[Abstract/Free Full Text]
10. Nahon JL 1994 The melanin-concentrating hormone: from the peptide to the gene. Crit Rev Neurobiol 8:221–262[Medline]
11. Jezova D, Bartanusz V, Westergren I, Johansson BB, Rivier J, Vale W, Rivier C 1992 Rat melanin-concentrating hormone stimulates adrenocorticotropin secretion: evidence for a site of action in brain regions protected by the blood-brain barrier. Endocrinology 130:1024–1029[Abstract/Free Full Text]
12. Kristensen P, Judge ME, Thim L, Ribel U, Christjansen KN, Wulff BS, Clausen JT, Jensen PB, Madsen OD, Vrang N, Larsen PJ, Hastrup S 1998 Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 393:72–76[CrossRef][Medline]
13. Parkes DG, Vale WW 1993 Contrasting actions of melanin-concentrating hormone and neuropeptide-E-I on posterior pituitary function. Ann NY Acad Sci 680:588–590[Medline]
14. Miller CL, Hruby VJ, Matsunaga TO, Bickford PC 1993 -MSH and MCH are functional antagonists in a CNS auditory gating paradigm. Peptides 14:431–440[CrossRef][Medline]
15. Ludwig DS, Mountjoy KG, Tatro JB, Gillette JA, Frederich RC, Flier JS, Maratos-Flier E 1998 Melanin-concentrating hormone: a functional melanocortin antagonist in the hypothalamus. Am J Physiol 274:E627–E633
16. Murray JF, Hahn JD, Kennedy AR, Small CJ, Bloom SR, Haskell-Luevano C, Coen CW, Wilson CA 2006 Evidence for a stimulatory action of melanin-concentrating hormone on luteinising hormone release involving MCH1 and melanocortin-5 receptors. J Neuroendocrinol 18:157–167[CrossRef][Medline]
17. Tsukamura H, Thompson RC, Tsukahara S, Ohkura S, Maekawa F, Moriyama R, Niwa Y, Foster DL, Maeda K 2000 Intracerebroventricular administration of melanin-concentrating hormone suppresses pulsatile luteinizing hormone release in the female rat. J Neuroendocrinol 12:529–534[CrossRef][Medline]
18. Ono M, Wada C, Oikawa I, Kawazoe I, Kawauchi H 1988 Structures of two kinds of mRNA encoding the chum salmon melanin-concentrating hormone. Gene 71:433–438[CrossRef][Medline]
19. Takayama Y, Wada C, Kawauchi H, Ono M 1989 Structures of two genes coding for melanin-concentrating hormone of chum salmon. Gene 80:65–73[CrossRef][Medline]
20. Baker B, Levy A, Hall L, Lightman S 1995 Cloning and expression of melanin-concentrating hormone genes in the rainbow trout brain. Neuroendocrinology 61:67–76[Medline]
21. Minth CD, Qiu H, Akil H, Watson SJ, Dixon JE 1989 Two precursors of melanin-concentrating hormone: DNA sequence analysis and in situ immunochemical localization. Proc Natl Acad Sci USA 86:4292–4296[Abstract/Free Full Text]
22. Takahashi A, Tsuchiya K, Yamanome T, Amano M, Yasuda A, Yamamori K, Kawauchi H 2004 Possible involvement of melanin-concentrating hormone in food intake in a teleost fish, barfin flounder. Peptides 25:1613–1622[CrossRef][Medline]
23. Groneveld D, Eckhardt ER, Coenen AJ, Martens GJ, Balm PH, Wendelaar Bonga SE 1995 Expression of tilapia prepro-melanin-concentrating hormone mRNA in hypothalamic and neurohypophysial cells. J Mol Endocrinol 14:199–207[Abstract/Free Full Text]
24. Balm PH, Groneveld D 1998 The melanin-concentrating hormone system in fish. Ann NY Acad Sci 839:205–209[CrossRef][Medline]
25. Nahon JL, Presse F, Bittencourt JC, Sawchenko PE, Vale W 1989 The rat melanin-concentrating hormone messenger ribonucleic acid encodes multiple putative neuropeptides coexpressed in the dorsolateral hypothalamus. Endocrinology 125:2056–2065[Abstract/Free Full Text]
26. Thompson RC, Watson SJ 1990 Nucleotide sequence and tissue-specific expression of the rat melanin concentrating hormone gene. DNA Cell Biol 9:637–645[Medline]
27. Presse F, Nahon JL, Fischer WH, Vale W 1990 Structure of the human melanin-concentrating hormone mRNA. Mol Endocrinol 4:632–637[Abstract/Free Full Text]
28. Breton C, Schorpp M, Nahon JL 1993 Isolation and characterization of the human melanin-concentrating hormone gene and a variant gene. Brain Res Mol Brain Res 18:297–310[Medline]
29. Jeon JY, Bradley RL, Kokkotou EG, Marino FE, Wang X, Pissios P, Maratos-Flier E 2006 MCH–/– mice are resistant to aging-associated increases in body weight and insulin resistance. Diabetes 55:428–434[Abstract/Free Full Text]
30. Toumaniantz G, Bittencourt JC, Nahon JL 1996 The rat melanin-concentrating hormone gene encodes an additional putative protein in a different reading frame. Endocrinology 137:4518–4521[Abstract]
31. Borsu L, Presse F, Nahon JL 2000 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[Abstract/Free Full Text]
32. Miller CL, Burmeister M, Thompson RC 1998 Antisense expression of the human pro-melanin-concentrating hormone genes. Brain Res 803:86–94[CrossRef][Medline]
33. Viale A, Courseaux A, Presse F, Ortola C, Breton C, Jordan D, Nahon JL 2000 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 17:1626–1640[Abstract/Free Full Text]
34. Nahon JL 2003 Birth of ‘human-specific’ genes during primate evolution. Genetica 118:193–208[CrossRef][Medline]
35. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM 1994 Positional cloning of the mouse obese gene and its human homologue [see comments]. Nature [Erratum (1995) 374:479] 372:425–432
36. Qu D, Ludwig DS, Gammeltoft S, Piper M, Pelleymounter MA, Cullen MJ, Mathes WF, Przypek R, Kanarek R, Maratos-Flier E 1996 A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 380:243–247[CrossRef][Medline]
37. Rossi M, Choi SJ, O’Shea D, Miyoshi T, Ghatei MA, Bloom SR 1997 Melanin-concentrating hormone acutely stimulates feeding, but chronic administration has no effect on body weight. Endocrinology 138:351–355[Abstract/Free Full Text]
38. Abbott CR, Kennedy AR, Wren AM, Rossi M, Murphy KG, Seal LJ, Todd JF, Ghatei MA, Small CJ, Bloom SR 2003 Identification of hypothalamic nuclei involved in the orexigenic effect of melanin-concentrating hormone. Endocrinology 144:3943–3949[Abstract/Free Full Text]
39. Zheng H, Patterson LM, Morrison C, Banfield BW, Randall JA, Browning KN, Travagli RA, Berthoud HR 2005 Melanin concentrating hormone innervation of caudal brainstem areas involved in gastrointestinal functions and energy balance. Neuroscience 135:611–625[CrossRef][Medline]
40. Clegg DJ, Air EL, Benoit SC, Sakai RS, Seeley RJ, Woods SC 2003 Intraventricular melanin-concentrating hormone stimulates water intake independent of food intake. Am J Physiol Regul Integr Comp Physiol 284:R494–R499
41. Duncan EA, Proulx K, Woods SC 2005 Central administration of melanin-concentrating hormone increases alcohol and sucrose/quinine intake in rats. Alcohol Clin Exp Res 29:958–964[CrossRef][Medline]
42. Sakamaki R, Uemoto M, Inui A, Asakawa A, Ueno N, Ishibashi C, Hirono S, Yukioka H, Kato A, Shinfuku N, Kasuga M, Katsuura G 2005 Melanin-concentrating hormone enhances sucrose intake. Int J Mol Med 15:1033–1039[Medline]
43. Shimada M, Tritos NA, Lowell BB, Flier JS, Maratos-Flier E 1998 Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature 396:670–674[CrossRef][Medline]
44. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS 1996 Role of leptin in the neuroendocrine response to fasting. Nature 382:250–252[CrossRef][Medline]
45. Friedman JM, Halaas JL 1998 Leptin and the regulation of body weight in mammals. Nature 395:763–770[CrossRef][Medline]
46. Schwartz MW, Seeley RJ, Campfield LA, Burn P, Baskin DG 1996 Identification of targets of leptin action in rat hypothalamus. J Clin Invest 98:1101–1106[Medline]
47. Thornton JE, Cheung CC, Clifton DK, Steiner RA 1997 Regulation of hypothalamic proopiomelanocortin mRNA by leptin in ob/ob mice. Endocrinology 138:5063–5066[Abstract/Free Full Text]
48. Segal-Lieberman G, Bradley RL, Kokkotou E, Carlson M, Trombly DJ, Wang X, Bates S, Myers Jr MG, Flier JS, Maratos-Flier E 2003 Melanin-concentrating hormone is a critical mediator of the leptin-deficient phenotype. Proc Natl Acad Sci USA 100:10085–10090[Abstract/Free Full Text]
49. Alon T, Friedman JM 2006 Late-onset leanness in mice with targeted ablation of melanin concentrating hormone neurons. J Neurosci 26:389–397[Abstract/Free Full Text]
50. Qian S, Chen H, Weingarth D, Trumbauer ME, Novi DE, Guan X, Yu H, Shen Z, Feng Y, Frazier E, Chen A, Camacho RE, Shearman LP, Gopal-Truter S, MacNeil DJ, Van der Ploeg LH, Marsh DJ 2002 Neither agouti-related protein nor neuropeptide Y is critically required for the regulation of energy homeostasis in mice. Mol Cell Biol 22:5027–5035[Abstract/Free Full Text]
51. Gropp E, Shanabrough M, Borok E, Xu AW, Janoschek R, Buch T, Plum L, Balthasar N, Hampel B, Waisman A, Barsh GS, Horvath TL, Bruning JC 2005 Agouti-related peptide-expressing neurons are mandatory for feeding. Nat Neurosci 8:1289–1291[CrossRef][Medline]
52. Luquet S, Perez FA, Hnasko TS, Palmiter RD 2005 NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 310:683–685[Abstract/Free Full Text]
53. Ludwig DS, Tritos NA, Mastaitis JW, Kulkarni R, Kokkotou E, Elmquist J, Lowell B, Flier JS, Maratos-Flier E 2001 Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance. J Clin Invest 107:379–386[Medline]
54. Della-Zuana O, Presse F, Ortola C, Duhault J, Nahon JL, Levens N 2002 Acute and chronic administration of melanin-concentrating hormone enhances food intake and body weight in Wistar and Sprague-Dawley rats. Int J Obes Relat Metab Disord 26:1289–1295[CrossRef][Medline]
55. Gomori A, Ishihara A, Ito M, Mashiko S, Matsushita H, Yumoto M, Ito M, Tanaka T, Tokita S, Moriya M, Iwaasa H, Kanatani A 2003 Chronic intracerebroventricular infusion of MCH causes obesity in mice. Melanin-concentrating hormone. Am J Physiol Endocrinol Metab 284:E583–E588
56. Bjursell M, Gerdin AK, Ploj K, Svensson D, Svensson L, Oscarsson J, Snaith M, Tornell J, Bohlooly-Y M 2006 Melanin-concentrating hormone receptor 1 deficiency increases insulin sensitivity in obese leptin-deficient mice without affecting body weight. Diabetes 55:725–733[Abstract/Free Full Text]
57. Kinoshita M, Morita T, Toyohara H, Hirata T, Sakaguchi M, Ono M, Inoue K, Wakamatsu Y, Ozato K 2001 Transgenic medaka overexpressing a melanin-concentrating hormone exhibit lightened body color but no remarkable abnormality. Mar Biotechnol (NY) 3:536–543
58. Amiya N, Amano M, Takahashi A, Yamanome T, Kawauchi H, Yamamori K 2005 Effects of tank color on melanin-concentrating hormone levels in the brain, pituitary gland, and plasma of the barfin flounder as revealed by a newly developed time-resolved fluoroimmunoassay. Gen Comp Endocrinol 143:251–256[CrossRef][Medline]
59. Matsuda K, Shimakura SI, Maruyama K, Miura T, Uchiyama M, Kawauchi H, Shioda S, Takahashi A 2006 Central administration of melanin-concentrating hormone (MCH) suppresses food intake, but not locomotor activity, in the goldfish, Carassius auratus. Neurosci Lett 399:259–263[CrossRef][Medline]
60. Tritos NA, Vicent D, Gillette J, Ludwig DS, Flier ES, Maratos-Flier E 1998 Functional interactions between melanin-concentrating hormone, neuropeptide Y, and anorectic neuropeptides in the rat hypothalamus. Diabetes 47:1687–1692[Abstract]
61. 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 2001 Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean. Nature 410:207–212[CrossRef][Medline]
62. Maekawa F, Quah HM, Tanaka K, Ohki-Hamazaki H 2004 Leptin resistance and enhancement of feeding facilitation by melanin-concentrating hormone in mice lacking bombesin receptor subtype-3. Diabetes 53:570–576[Abstract/Free Full Text]
63. Rovere C, Viale A, Nahon J, Kitabgi P 1996 Impaired processing of brain proneurotensin and promelanin-concentrating hormone in obese fat/fat mice. Endocrinology 137:2954–2958[Abstract]
64. Presse F, Sorokovsky I, Max JP, Nicolaidis S, Nahon JL 1996 Melanin-concentrating hormone is a potent anorectic peptide regulated by food deprivation and glucopenia in the rat. Neuroscience 71:735–745[CrossRef][Medline]
65. Sergeyev V, Broberger C, Gorbatyuk O, Hokfelt T 2000 Effect of 2-mercaptoacetate and 2-deoxy-D-glucose administration on the expression of NPY, AGRP, POMC, MCH and hypocretin/orexin in the rat hypothalamus. Neuroreport 11:117–121[Medline]
66. Hintermann E, Drozdz R, Tanner H, Eberle AN 1999 Synthesis and characterization of new radioligands for the mammalian melanin-concentrating hormone (MCH) receptor. J Recept Signal Transduct Res 19:411–422[Medline]
67. Kokkotou E, Mastaitis JW, Qu D, Hoersch D, Slieker L, Bonter K, Tritos NA, Maratos-Flier E 2000 Characterization of [Phe(13), Tyr(19)]-MCH analog binding activity to the MCH receptor. Neuropeptides 34:240–247[CrossRef][Medline]
68. Bachner D, Kreienkamp H, Weise C, Buck F, Richter D 1999 Identification of melanin concentrating hormone (MCH) as the natural ligand for the orphan somatostatin-like receptor 1 (SLC-1). FEBS Lett 457:522–524[CrossRef][Medline]
69. Chambers J, Ames RS, Bergsma D, Muir A, Fitzgerald LR, Hervieu G, Dytko GM, Foley JJ, Martin J, Liu WS, Park J, Ellis C, Ganguly S, Konchar S, Cluderay J, Leslie R, Wilson S, Sarau HM 1999 Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1. Nature 400:261–265[CrossRef][Medline]
70. Lembo PM, Grazzini E, Cao J, Hubatsch DA, Pelletier M, Hoffert C, St-Onge S, Pou C, Labrecque J, Groblewski T, O’Donnell D, Payza K, Ahmad S, Walker P 1999 The receptor for the orexigenic peptide melanin-concentrating hormone is a G-protein-coupled receptor. Nat Cell Biol 1:267–271[CrossRef][Medline]
71. Saito Y, Nothacker HP, Wang Z, Lin SH, Leslie F, Civelli O 1999 Molecular characterization of the melanin-concentrating-hormone receptor. Nature 400:265–269[CrossRef][Medline]
72. Shimomura Y, Mori M, Sugo T, Ishibashi Y, Abe M, Kurokawa T, Onda H, Nishimura O, Sumino Y, Fujino M 1999 Isolation and identification of melanin-concentrating hormone as the endogenous ligand of the SLC-1 receptor. Biochem Biophys Res Commun 261:622–626[CrossRef][Medline]
73. Kolakowski Jr LF, Jung BP, Nguyen T, Johnson MP, Lynch KR, Cheng R, Heng HH, George SR, O’Dowd BF 1996 Characterization of a human gene related to genes encoding somatostatin receptors. FEBS Lett 398:253–258[CrossRef][Medline]
74. Pissios P, Maratos-Flier E 2003 Melanin-concentrating hormone: from fish skin to skinny mammals. Trends Endocrinol Metab 14:243–248[CrossRef][Medline]
75. Lakaye B, Minet A, Zorzi W, Grisar T 1998 Cloning of the rat brain cDNA encoding for the SLC-1 G protein-coupled receptor reveals the presence of an intron in the gene. Biochim Biophys Acta 1401:216–220[Medline]
76. Macdonald D, Murgolo N, Zhang R, Durkin JP, Yao X, Strader CD, Graziano MP 2000 Molecular characterization of the melanin-concentrating hormone/receptor complex: identification of critical residues involved in binding and activation. Mol Pharmacol 58:217–225[Abstract/Free Full Text]
77. Saito Y, Tetsuka M, Yue L, Kawamura Y, Maruyama K 2003 Functional role of N-linked glycosylation on the rat melanin-concentrating hormone receptor 1. FEBS Lett 533:29–34[CrossRef][Medline]
78. Saito Y, Tetsuka M, Saito S, Imai K, Yoshikawa A, Doi H, Maruyama K 2005 Arginine residue 155 in the second intracellular loop plays a critical role in rat melanin-concentrating hormone receptor 1 activation. Endocrinology 146:3452–3462[Abstract/Free Full Text]
79. Tetsuka M, Saito Y, Imai K, Doi H, Maruyama K 2004 The basic residues in the membrane-proximal C-terminal tail of the rat melanin-concentrating hormone receptor 1 are required for receptor function. Endocrinology 145:3712–3723[Abstract/Free Full Text]
80. Murdoch H, Feng GJ, Bachner D, Ormiston L, White JH, Richter D, Milligan G 2005 Periplakin interferes with G protein activation by the melanin-concentrating hormone receptor-1 by binding to the proximal segment of the receptor C-terminal tail. J Biol Chem 280:8208–8220[Abstract/Free Full Text]
81. Bachner D, Kreienkamp HJ, Richter D 2002 MIZIP, a highly conserved, vertebrate specific melanin-concentrating hormone receptor 1 interacting zinc-finger protein. FEBS Lett 526:124–128[CrossRef][Medline]
82. Hawes BE, Kil E, Green B, O’Neill K, Fried S, Graziano MP 2000 The melanin-concentrating hormone receptor couples to multiple G proteins to activate diverse intracellular signaling pathways. Endocrinology 141:4524–4532[Abstract/Free Full Text]
83. Pissios P, Trombly DJ, Tzameli I, Maratos-Flier E 2003 Melanin-concentrating hormone receptor 1 activates extracellular signal-regulated kinase and synergizes with G(s)-coupled pathways. Endocrinology 144:3514–3523[Abstract/Free Full Text]
84. Hervieu GJ, Cluderay JE, Harrison D, Meakin J, Maycox P, Nasir S, Leslie RA 2000 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 12:1194–1216[CrossRef][Medline]
85. Saito Y, Nothacker HP, Civelli O 2000 Melanin-concentrating hormone receptor: an orphan receptor fits the key. Trends Endocrinol Metab 11:299–303[CrossRef][Medline]
86. Bradley RL, Kokkotou EG, Maratos-Flier E, Cheatham B 2000 Melanin-concentrating hormone regulates leptin synthesis and secretion in rat adipocytes. Diabetes 49:1073–1077[Abstract]
87. An S, Cutler G, Zhao JJ, Huang SG, Tian H, Li W, Liang L, Rich M, Bakleh A, Du J, Chen JL, Dai K 2001 Identification and characterization of a melanin-concentrating hormone receptor. Proc Natl Acad Sci USA 98:7576–7581[Abstract/Free Full Text]
88. Hill J, Duckworth M, Murdock P, Rennie G, Sabido-David C, Ames RS, Szekeres P, Wilson S, Bergsma DJ, Gloger IS, Levy DS, Chambers JK, Muir AI 2001 Molecular cloning and functional characterization of MCH2, a novel human MCH receptor. J Biol Chem 276:20125–20129[Abstract/Free Full Text]
89. Mori M, Harada M, Terao Y, Sugo T, Watanabe T, Shimomura Y, Abe M, Shintani Y, Onda H, Nishimura O, Fujino M 2001 Cloning of a novel G protein-coupled receptor, SLT, a subtype of the melanin-concentrating hormone receptor. Biochem Biophys Res Commun 283:1013–1018[CrossRef][Medline]
90. Rodriguez M, Beauverger P, Naime I, Rique H, Ouvry C, Souchaud S, Dromaint S, Nagel N, Suply T, Audinot V, Boutin JA, Galizzi JP 2001 Cloning and molecular characterization of the novel human melanin-concentrating hormone receptor MCH2. Mol Pharmacol 60:632–639[Abstract/Free Full Text]
91. Sailer AW, Sano H, Zeng Z, McDonald TP, Pan J, Pong SS, Feighner SD, Tan CP, Fukami T, Iwaasa H, Hreniuk DL, Morin NR, Sadowski SJ, Ito M, Ito M, Bansal A, Ky B, Figueroa DJ, Jiang Q, Austin CP, MacNeil DJ, Ishihara A, Ihara M, Kanatani A, Van der Ploeg LH, Howard AD, Liu Q 2001 Identification and characterization of a second melanin-concentrating hormone receptor, MCH-2R. Proc Natl Acad Sci USA 98:7564–7569[Abstract/Free Full Text]
92. Wang S, Behan J, O’Neill K, Weig B, Fried S, Laz T, Bayne M, Gustafson E, Hawes BE 2001 Identification and pharmacological characterization of a novel human melanin-concentrating hormone receptor, mch-r2. J Biol Chem 276:34664–34670[Abstract/Free Full Text]
93. Schlumberger SE, Talke-Messerer C, Zumsteg U, Eberle AN 2002 Expression of receptors for melanin-concentrating hormone (MCH) in different tissues and cell lines. J Recept Signal Transduct Res 22:509–531[CrossRef][Medline]
94. Fried S, O’Neill K, Hawes BE 2002 Cloning and characterization of rhesus monkey MCH-R1 and MCH-R2. Peptides 23:1401–1408[CrossRef][Medline]
95. Tan CP, Sano H, Iwaasa H, Pan J, Sailer AW, Hreniuk DL, Feighner SD, Palyha OC, Pong SS, Figueroa DJ, Austin CP, Jiang MM, Yu H, Ito J, Ito M, Ito M, Guan XM, MacNeil DJ, Kanatani A, Van der Ploeg LH, Howard AD 2002 Melanin-concentrating hormone receptor subtypes 1 and 2: species-specific gene expression. Genomics 79:785–792[CrossRef][Medline]
96. Wermter AK, Reichwald K, Buch T, Geller F, Platzer C, Huse K, Hess C, Remschmidt H, Gudermann T, Preibisch G, Siegfried W, Goldschmidt HP, Li WD, Price RA, Biebermann H, Krude H, Vollmert C, Wichmann HE, Illig T, Sorensen TI, Astrup A, Larsen LH, Pedersen O, Eberle D, Clement K, Blundell J, Wabitsch M, Schafer H, Platzer M, Hinney A, Hebebrand J 2005 Mutation analysis of the MCHR1 gene in human obesity. Eur J Endocrinol 152:851–862[Abstract/Free Full Text]
97. Hawes BE, Green B, O’Neill K, Fried S, Arreaza MG, Qiu P, Simon JS 2004 Identification and characterization of single-nucleotide polymorphisms in MCH-R1 and MCH-R2. Obes Res 12:1327–1334[Medline]
98. Gibson WT, Pissios P, Trombly DJ, Luan J, Keogh J, Wareham NJ, Maratos-Flier E, O’Rahilly S, Farooqi IS 2004 Melanin-concentrating hormone receptor mutations and human obesity: functional analysis. Obes Res 12:743–749[Medline]
99. Handlon AL, Zhou H 2006 Melanin-concentrating hormone-1 receptor antagonists for the treatment of obesity. J Med Chem 49:4017–4022[CrossRef][Medline]
100. Palani A, Shapiro S, McBriar MD, Clader JW, Greenlee WJ, Spar B, Kowalski TJ, Farley C, Cook J, van Heek M, Weig B, O’neill K, Graziano M, Hawes B 2005 Biaryl ureas as potent and orally efficacious melanin concentrating hormone receptor 1 antagonists for the treatment of obesity. J Med Chem 48:4746–4749[CrossRef][Medline]
101. Borowsky B, Durkin MM, Ogozalek K, Marzabadi MR, DeLeon J, Lagu B, Heurich R, Lichtblau H, Shaposhnik Z, Daniewska I, Blackburn TP, Branchek TA, Gerald C, Vaysse PJ, Forray C 2002 Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist. Nat Med [Erratum (2002) 8:1039] 8:825–830
102. Chaki S, Funakoshi T, Hirota-Okuno S, Nishiguchi M, Shimazaki T, Iijima M, Grottick AJ, Kanuma K, Omodera K, Sekiguchi Y, Okuyama S, Tran TA, Semple G, Thomsen W 2005 Anxiolytic- and antidepressant-like profile of ATC0065 and ATC0175: nonpeptidic and orally active melanin-concentrating hormone receptor 1 antagonists. J Pharmacol Exp Ther 313:831–839[Abstract/Free Full Text]
103. Mashiko S, Ishihara A, Gomori A, Moriya R, Ito M, Iwaasa H, Matsuda M, Feng Y, Shen Z, Marsh DJ, Bednarek MA, MacNeil DJ, Kanatani A 2005 Antiobesity effect of a melanin-concentrating hormone 1 receptor antagonist in diet-induced obese mice. Endocrinology 146:3080–3086[Abstract/Free Full Text]
104. van den Pol AN, Acuna-Goycolea C, Clark KR, Ghosh PK 2004 Physiological properties of hypothalamic MCH neurons identified with selective expression of reporter gene after recombinant virus infection. Neuron 42:635–652[CrossRef][Medline]
105. Eggermann E, Bayer L, Serafin M, Saint-Mleux B, Bernheim L, Machard D, Jones BE, Muhlethaler M 2003 The wake-promoting hypocretin-orexin neurons are in an intrinsic state of membrane depolarization. J Neurosci 23:1557–1562[Abstract/Free Full Text]
106. Bayer L, Eggermann E, Serafin M, Grivel J, Machard D, Muhlethaler M, Jones BE 2005 Opposite effects of noradrenaline and acetylcholine upon hypocretin/orexin versus melanin concentrating hormone neurons in rat hypothalamic slices. Neuroscience 130:807–811[CrossRef][Medline]
107. Burdakov D, Gerasimenko O, Verkhratsky A 2005 Physiological changes in glucose differentially modulate the excitability of hypothalamic melanin-concentrating hormone and orexin neurons in situ. J Neurosci 25:2429–2433[Abstract/Free Full Text]
108. Gao XB, van den Pol AN 2002 Melanin-concentrating hormone depresses L-, N-, and P/Q-type voltage-dependent calcium channels in rat lateral hypothalamic neurons. J Physiol 542:273–286[Abstract/Free Full Text]
109. Gao XB, van den Pol AN 2001 Melanin concentrating hormone depresses synaptic activity of glutamate and GABA neurons from rat lateral hypothalamus. J Physiol 533:237–252[Abstract/Free Full Text]
110. Davidowa H, Li Y, Plagemann A 2002 Hypothalamic ventromedial and arcuate neurons of normal and postnatally overnourished rats differ in their responses to melanin-concentrating hormone. Regul Pept 108:103–111[CrossRef][Medline]
111. Davidowa H, Li Y, Plagemann A 2003 Altered responses to orexigenic (AGRP, MCH) and anorexigenic (-MSH, CART) neuropeptides of paraventricular hypothalamic neurons in early postnatally overfed rats. Eur J Neurosci 18:613–621[CrossRef][Medline]
112. Varas M, Perez M, Ramirez O, de Barioglio SR 2002 Melanin concentrating hormone increase hippocampal synaptic transmission in the rat. Peptides 23:151–155[CrossRef][Medline]
113. Korotkova TM, Sergeeva OA, Eriksson KS, Haas HL, Brown RE 2003 Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexins/hypocretins. J Neurosci 23:7–11[Abstract/Free Full Text]
114. Gonzalez MI, Baker BI, Wilson CA 1997 Stimulatory effect of melanin-concentrating hormone on luteinising hormone release. Neuroendocrinology 66:254–262[Medline]
115. Williamson-Hughes PS, Grove KL, Smith MS 2005 Melanin concentrating hormone (MCH): a novel neural pathway for regulation of GnRH neurons. Brain Res 1041:117–124[CrossRef][Medline]
116. Murray JF, Mercer JG, Adan RA, Datta JJ, Aldairy C, Moar KM, Baker BI, Stock MJ, Wilson CA 2000 The effect of leptin on luteinizing hormone release is exerted in the zona incerta and mediated by melanin-concentrating hormone. J Neuroendocrinol 12:1133–1139[CrossRef][Medline]
117. Chiocchio SR, Gallardo MG, Louzan P, Gutnisky V, Tramezzani JH 2001 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[Abstract/Free Full Text]
118. Kennedy AR, Todd JF, Stanley SA, Abbott CR, Small CJ, Ghatei MA, Bloom SR 2001 Melanin-concentrating hormone (MCH) suppresses thyroid stimulating hormone (TSH) release, in vivo and in vitro, via the hypothalamus and the pituitary. Endocrinology 142:3265–3268[Abstract/Free Full Text]
119. Kennedy AR, Todd JF, Dhillo WS, Seal LJ, Ghatei MA, O’Toole CP, Jones M, Witty D, Winborne K, Riley G, Hervieu G, Wilson S, Bloom SR 2003 Effect of direct injection of melanin-concentrating hormone into the paraventricular nucleus: further evidence for a stimulatory role in the adrenal axis via SLC-1. J Neuroendocrinol 15:268–272[CrossRef][Medline]
120. Gonzalez MI, Baker BI, Hole DR, Wilson CA 1998 Behavioral effects of neuropeptide E-I (NEI) in the female rat: interactions with -MSH, MCH and dopamine. Peptides 19:1007–1016[CrossRef][Medline]
121. Sanchez M, Baker BI, Celis M 1997 Melanin-concentrating hormone (MCH) antagonizes the effects of -MSH and neuropeptide E-I on grooming and locomotor activities in the rat. Peptides 18:393–396[CrossRef][Medline]
122. Marsh DJ, Weingarth DT, Novi DE, Chen HY, Trumbauer ME, Chen AS, Guan XM, Jiang MM, Feng Y, Camacho RE, Shen Z, Frazier EG, Yu H, Metzger JM, Kuca SJ, Shearman LP, Gopal-Truter S, MacNeil DJ, Strack AM, MacIntyre DE, Van der Ploeg LH, Qian S 2002 Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. Proc Natl Acad Sci USA 99:3240–3245[Abstract/Free Full Text]
123. Chen Y, Hu C, Hsu CK, Zhang Q, Bi C, Asnicar M, Hsiung HM, Fox N, Slieker LJ, Yang DD, Heiman ML, Shi Y 2002 Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity. Endocrinology 143:2469–2477[Abstract/Free Full Text]
124. Zhou D, Shen Z, Strack AM, Marsh DJ, Shearman LP 2005 Enhanced running wheel activity of both Mch1r- and Pmch-deficient mice. Regul Pept 124:53–63[CrossRef][Medline]
125. Kokkotou E, Jeon JY, Wang X, Marino FE, Carlson M, Trombly DJ, Maratos-Flier E 2005 Mice with MCH ablation resist diet-induced obesity through strain-specific mechanisms. Am J Physiol Regul Integr Comp Physiol 289:R117–R124
126. Georgescu D, Sears RM, Hommel JD, Barrot M, Bolanos CA, Marsh DJ, Bednarek MA, Bibb JA, Maratos-Flier E, Nestler EJ, DiLeone RJ 2005 The hypothalamic neuropeptide melanin-concentrating hormone acts in the nucleus accumbens to modulate feeding behavior and forced-swim performance. J Neurosci 25:2933–2940[Abstract/Free Full Text]
127. Smith DG, Tzavara ET, Shaw J, Luecke S, Wade M, Davis R, Salhoff C, Nomikos GG, Gehlert DR 2005 Mesolimbic dopamine super-sensitivity in melanin-concentrating hormone-1 receptor-deficient mice. J Neurosci 25:914–922[Abstract/Free Full Text]
128. Monzon ME, De Barioglio SR 1999 Response to novelty after i.c.v. injection of melanin-concentrating hormone (MCH) in rats. Physiol Behav 67:813–817[CrossRef][Medline]
129. Kela J, Salmi P, Rimondini-Giorgini R, Heilig M, Wahlestedt C 2003 Behavioural analysis of melanin-concentrating hormone in rats: evidence for orexigenic and anxiolytic properties. Regul Pept 114:109–114[CrossRef][Medline]
130. Roy M, David NK, Danao JV, Baribault H, Tian H, Giorgetti M 2006 Genetic inactivation of melanin-concentrating hormone receptor subtype 1 (MCHR1) in mice exerts anxiolytic-like behavioral effects. Neuropsychopharmacology 31:112–120[Medline]
131. Hervieu G, Nahon JL 1995 Pro-melanin concentrating hormone messenger ribonucleic acid and peptides expression in peripheral tissues of the rat. Neuroendocrinology 61:348–364[Medline]
132. Verlaet M, Adamantidis A, Coumans B, Chanas G, Zorzi W, Heinen E, Grisar T, Lakaye B 2002 Human immune cells express ppMCH mRNA and functional MCHR1 receptor. FEBS Lett 527:205–210[CrossRef][Medline]
133. Hoogduijn MJ, Ancans J, Suzuki I, Estdale S, Thody AJ 2002 Melanin-concentrating hormone and its receptor are expressed and functional in human skin. Biochem Biophys Res Commun 296:698–701[CrossRef][Medline]
134. Tadayyon M, Welters HJ, Haynes AC, Cluderay JE, Hervieu G 2000 Expression of melanin-concentrating hormone receptors in insulin-producing cells: MCH stimulates insulin release in RINm5F and CRI-G1 cell-lines. Biochem Biophys Res Commun 275:709–712[CrossRef][Medline]
135. Colombo M, Gregersen S, Xiao J, Hermansen K 2003 Effects of ghrelin and other neuropeptides (CART, MCH, orexin A and B, and GLP-1) on the release of insulin from isolated rat islets. Pancreas 27:161–166[CrossRef][Medline]
136. Saito Y, Wang Z, Hagino-Yamagishi K, Civelli O, Kawashima S, Maruyama K 2001 Endogenous melanin-concentrating hormone receptor SLC-1 in human melanoma SK-MEL-37 cells. Biochem Biophys Res Commun 289:44–50[CrossRef][Medline]
137. Kemp EH, Waterman EA, Hawes BE, O’Neill K, Gottumukkala RV, Gawkrodger DJ, Weetman AP, Watson PF 2002 The melanin-concentrating hormone receptor 1, a novel target of autoantibody responses in vitiligo. J Clin Invest 109:923–930[CrossRef][Medline]
138. Bradley RL, Mansfield JP, Maratos-Flier E, Cheatham B 2002 Melanin-concentrating hormone activates signaling pathways in 3T3–L1 adipocytes. Am J Physiol Endocrinol Metab 283:E584–E592
139. Saito Y, Tetsuka M, Li Y, Kurose H, Maruyama K 2004 Properties of rat melanin-concentrating hormone receptor 1 internalization. Peptides 25:1597–1604[CrossRef][Medline]
140. Blaukat A, Barac A, Cross MJ, Offermanns S, Dikic I 2000 G protein-coupled receptor-mediated mitogen-activated protein kinase activation through cooperation of G(q) and G(i) signals. Mol Cell Biol 20:6837–6848[Abstract/Free Full Text]
141. Lopez-Ilasaca M 1998 Signaling from G-protein-coupled receptors to mitogen-activated protein (MAP)-kinase cascades. Biochem Pharmacol 56:269–277[CrossRef][Medline]
142. Lopez-Ilasaca M, Crespo P, Pellici PG, Gutkind JS, Wetzker R 1997 Linkage of G protein-coupled receptors to the MAPK signaling pathway through PI 3-kinase . Science 275:394–397[Abstract/Free Full Text]
143. Stricker-Krongrad A, Dimitrov T, Beck B 2001 Central and peripheral dysregulation of melanin-concentrating hormone in obese Zucker rats. Brain Res Mol Brain Res 92:43–48[Medline]
144. Gavrila A, Chan JL, Miller LC, Heist K, Yiannakouris N, Mantzoros CS 2005 Circulating melanin-concentrating hormone, agouti-related protein, and -melanocyte-stimulating hormone levels in relation to body composition: alterations in response to food deprivation and recombinant human leptin administration. J Clin Endocrinol Metab 90:1047–1054[Abstract/Free Full Text]
145. Takahashi K, Suzuki H, Totsune K, Murakami O, Satoh F, Sone M, Sasano H, Mouri T, Shibahara S 1995 Melanin-concentrating hormone in human and rat. Neuroendocrinology 61:493–498[Medline]
146. Waters SM, Krause JE 2005 Letter: melanin-concentrating hormone and energy balance. J Clin Endocrinol Metab 90:6337; author reply, 6337[Free Full Text]

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