MCH (human, mouse, rat)

Melanin-concentrating hormone (MCH) is a 19 amino acid long peptide found in the brain of animals, including fishes, batrachians, and mammals. MCH is implicated in appetite and/or energy homeostasis. Antagonists at its receptor (MCH-R1) could be major tools (or ultimately drugs) to understand the mechanism of MCH action and to fight the obesity syndrome that is a worldwide societal health problem. Ever since the deorphanisation of the MCH receptor, we cloned, expressed, and characterized the receptor MCH-R1 and started a vast medicinal chemistry program aiming at the discovery of such usable compounds. In the present final work, we describe GPS18169, a pseudopeptide antagonist at the MCH-R1 receptor with an affinity in the nanomolar range and a Ki for its antagonistic effect in the 20 picomolar range. Its metabolic stability is rather ameliorated compared to its initial parent compound, the antagonist S38151. We tested it in an in vivo experiment using high diet mice. GPS18169 was found to be active in limiting the accumulation of adipose tissues and, correlatively, we observed a normalization of the insulin level in the treated animals, while no change in food or water consumption was observed.

Melanin-concentrating hormone (MCH) is a cyclic peptide predominantly expressed in the hypothalamus of mammals. This peptide modulates the stress response and regulates many goal-oriented behaviors in the rat brain. MCH mRNA and peptides generated from the precursor, namely MCH and neuropeptide (N) glutamic acid (E) isoleucine (I) amide (NEI), were also found in rodent peripheral tissues including those in adult testis. In the present study, we first examined the cellular distribution and content of MCH gene products and peptide in the testes of adult rats. Using reverse-transcription polymerase chain reaction with MCH gene primers and in situ hybridization with specific 33P-labeled oligoprobes, we characterized the MCH RNA species. Pro-MCH products were revealed through use of immunoperoxidase detection and an RIA with specific MCH and NEI antisera. Both MCH gene transcripts and MCH peptide were found within germ cells at the periphery of some of the seminiferous tubules of adult rats. We further investigated temporal expression of MCH in 7-microns sections of testes from adult rats and mice. MCH was predominantly found in nuclei of spermatogonia at stages II-IV of spermatogenesis and in nuclei of leptotene and zygotene spermatocytes (at stages IX- XIII). MCH was markedly absent in preleptotene spermatocytes at the stage VII-VIII, and MCH immunoreactivity was no longer detectable as spermatocytes underwent the pachytene step. MCH immunoreactivity was also found in some peritubular cells, mainly at stages II-IV. Finally, we studied MCH expression during puberty in the rat, in sterile mutant mice, and in one adult man. We found predominant staining with MCH antiserum over nuclei of immature germ cells as early as 10 days postpartum in the rat and further confirmed the absence of staining except for that in spermatogonia and early spermatocytes during rat postnatal development. MCH distribution was found to be similar in normal and sterile mutant mice, suggesting that MCH expression is not dependent upon the early steps of spermiogenesis. MCH immunoreactivity was found to be confined to the nuclei of spermatogonia and early spermatocytes in the adult man. Our results indicate that MCH is present predominantly within nuclei of spermatogonia and primary spermatocytes in three mammalian species and that its expression is under strong stage-specific and developmental regulation. This peptide may play a role during stem cell renewal and/or differentiation of early spermatocytes.

Melanin-concentrating hormone (MCH), a neuropeptide secreted by a limited number of neurons within the tuberal hypothalamus, has been drawn in the field of sleep only fairly recently in 2003. Since then, growing experimental evidence indicates that MCH may play a crucial role in the homeostatic regulation of paradoxical sleep (PS). MCH-expressing neurons fire specifically during PS. When injected icv MCH induces a 200% increase in PS quantities in rats and the lack of MCH induces a decrease in sleep quantities in transgenic mice. Here, we review recent studies suggesting a role for MCH in the regulation of the sleep-wake cycle, in particular PS, including insights on (1) the specific activity of MCH neurons during PS; (2) how they might be controlled across the sleep-wake cycle; (3) how they might modulate PS; (4) and finally whether MCH might take part in the expression of some symptoms observed in primary sleep disorders.