Alternative titles; symbols
HGNC Approved Gene Symbol: PMCH
Cytogenetic location: 12q23.2 Genomic coordinates (GRCh38): 12:102,196,459-102,197,833 (from NCBI)
The melanin-concentrating hormone (MCH) is a cyclic neuropeptide isolated initially from salmon pituitary gland and later from rat hypothalamus. In mammals, MCH perikarya are confined largely to the lateral hypothalamus and zona incerta area with extensive neuronal projections throughout the brain, including the neurohypophysis. The anatomic distribution suggests a neurotransmitter or neuromodulator role for MCH in a broad array of neuronal functions directed toward the regulation of goal-directed behavior, such as food intake, and general arousal. MCH and 2 other putative neuropeptides, NEI and NGE, are encoded by the same precursor and appear colocalized in nerve cells and in many instances within the projections. The precursor is designated pro-melanin-concentrating hormone (PMCH) (summary by Nahon et al., 1992).
Using PCR analysis, Miller et al. (1998) found that both the sense PMCH transcript and an antisense transcript (see C12ORF48; 613687) were expressed in human hypothalamus.
In their Figure 1, Miller et al. (1998) showed that the PMCH gene contains 3 exons. Exon 2 encodes NGE and NEI, and exons 2 and 3 encode MCH.
Nahon et al. (1992) used a panel of somatic cell hybrids segregating either human or rat chromosomes to determine the localization of the PMCH gene on human 12q and rat chromosome 7. Pedeutour et al. (1994) assigned the PMCH gene to 12q23-q24 by fluorescence in situ hybridization. They also identified 2 variant PMCH genes located on 5p14 and 5q12-q13 by in situ hybridization. Southern blotting data were consistent with very close homology between these 2 variant genes, symbolized PMCHL1 and PMCHL2, since only 2 hybridizing bands, one corresponding to the authentic gene on chromosome 12 and one to the variant gene, were found after digestion of the human genome with a wide range of restriction enzymes. Whereas there are 3 MCH-related genes in the human, only a single locus is found in the rodent species. It is noteworthy that the authentic PMCH gene is located in the region of the gene for spinocerebellar ataxia, type 2 (SCA2; 183090). Further, certain neurologic diseases have been mapped to the region occupied by the PMCHL2 gene on 5q.
To discover new hypothalamic peptides involved in the regulation of body weight, Qu et al. (1996) used differential display PCR to identify messenger RNAs that are differentially expressed in the hypothalamus of ob/+ mice compared with ob/ob mice, i.e., mice heterozygous versus homozygous for mutation in the ob gene which encodes leptin (164160). They found that one mRNA that is overexpressed in the hypothalamus of ob/ob mice encodes the melanin-concentrating hormone. Fasting further increased expression of MCH mRNA in both normal and obese animals. Neurons containing MCH are located in the zona incerta and in the lateral hypothalamus. These areas are involved in regulation of ingestive behavior, but the role of MCH in mammalian physiology is unknown. To determine whether MCH is involved in the regulation of feeding, Qu et al. (1996) injected MCH into the lateral ventricles of rats and found that their food consumption increased. These findings suggested that MCH participates in the hypothalamic regulation of body weight.
The deficiency of a single component of the pathway that limits food intake, such as leptin or receptors for melanocortin-4 (155541), causes obesity. On the other hand, absence of hypothalamic neuropeptides that promote feeding, so-called orexigenic neuropeptides, appears to be more redundant than those limiting food intake. To define further the physiologic role of MCH and to test the redundancy of orexigenic signals, Shimada et al. (1998) generated mice carrying a targeted deletion of the MCH gene. MCH-deficient mice had reduced body weight and leanness due to hypophagia (reduced feeding) and an inappropriately increased metabolic rate, despite their reduced amount of both leptin and arcuate nucleus proopiomelanocortin mRNA. Results indicated that MCH is a critical regulator of feeding and energy balance that acts downstream of leptin and the melanocortin system, and that deletion of a gene encoding a single orexigenic peptide can result in leanness.
To test the hypothesis that chronic overexpression of MCH in mice causes obesity, Ludwig et al. (2001) produced transgenic mice that overexpressed MCH in the lateral hypothalamus at approximately 2-fold higher levels than normal mice. Homozygous transgenic mice fed a high-fat diet ate 10% more and were 12% heavier at 13 weeks of age than wildtype animals, and they had higher systemic leptin levels. Blood glucose levels were higher both preprandially and after an intraperitoneal glucose injection. Overexpressed-MCH animals were insulin-resistant and also exhibited a 2-fold increase in islet size. Heterozygous C57BL/6J mice expressing the transgene showed increased body weight on a standard diet.
Silva et al. (2009) showed that Foxa2 (600288), a downstream target of insulin signaling, regulates the expression of orexin (602358) and MCH. During fasting, Foxa2 binds to MCH and orexin promoters and stimulates their expression. In fed and in hyperinsulinemic obese mice, insulin signaling led to nuclear exclusion of Foxa2 and reduced expression of MCH and orexin. Constitutive activation of Foxa2 in the brain resulted in increased neuronal MCH and orexin expression and increased food consumption, metabolism, and insulin sensitivity. Spontaneous physical activity of these animals in the fed state was significantly increased and was similar to that in fasted mice. Conditional activation of Foxa2 through the T156A mutation expression in the brain of obese mice also resulted in improved glucose homeostasis, decreased fat, and increased lean body mass. Silva et al. (2009) concluded that Foxa2 can act as a metabolic sensor in neurons of the lateral hypothalamic area to integrate metabolic signals, adaptive behavior, and physiologic responses.
Ludwig, D. S., Tritos, N. A., Mastaitis, J. W., Kulkarni, R., Kokkotou, E., Elmquist, J., Lowell, B., Flier, J. S., Maratos-Flier, E. Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance. J. Clin. Invest. 107: 379-386, 2001. [PubMed: 11160162] [Full Text: https://doi.org/10.1172/JCI10660]
Miller, C. L., Burmeister, M., Thompson, R. C. Antisense expression in the human pro-melanin-concentrating hormone genes. Brain Res. 803: 86-94, 1998. [PubMed: 9729295] [Full Text: https://doi.org/10.1016/s0006-8993(98)00626-x]
Nahon, J.-L., Joly, C., Levan, G., Szpirer, J., Szpirer, C. Pro-melanin-concentrating hormone gene (PMCH) is localized on human chromosome 12q and rat chromosome 7. Genomics 12: 846-848, 1992. [PubMed: 1572663] [Full Text: https://doi.org/10.1016/0888-7543(92)90323-k]
Pedeutour, F., Szpirer, C., Nahon, J.-L. Assignment of the human pro-melanin-concentrating hormone gene (PMCH) to chromosome 12q23-q24 and two variant genes (PMCHL1 and PMCHL2) to chromosome 5p14 and 5q12-q13. Genomics 19: 31-37, 1994. [PubMed: 8188237] [Full Text: https://doi.org/10.1006/geno.1994.1008]
Qu, D., Ludwig, D. S., Gammeltoft, S., Piper, M., Pelleymounter, M. A., Cullen, M. J., Mathes, W. F., Przypek, J., Kanarek, R., Maratos-Flier, E. A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 380: 243-247, 1996. [PubMed: 8637571] [Full Text: https://doi.org/10.1038/380243a0]
Shimada, M., Tritos, N. A., Lowell, B. B., Flier, J. S., Maratos-Flier, E. Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature 396: 670-674, 1998. [PubMed: 9872314] [Full Text: https://doi.org/10.1038/25341]
Silva, J. P., von Meyenn, F., Howell, J., Thorens, B., Wolfrum, C., Stoffel, M. Regulation of adaptive behaviour during fasting by hypothalamic Foxa2. Nature 462: 646-650, 2009. [PubMed: 19956259] [Full Text: https://doi.org/10.1038/nature08589]