Negative Regulation of Neuromedin U mRNA Expression in the Rat Pars Tuberalis by Melatonin

Abstract

The pars tuberalis (PT) is part of the anterior pituitary gland surrounding the median eminence as a thin cell layer. The characteristics of PT differ from those of the pars distalis (PD), such as cell composition and gene expression, suggesting that the PT has a unique physiological function compared to the PD. Because the PT highly expresses melatonin receptor type 1, it is considered a mediator of seasonal and/or circadian signals of melatonin. Expression of neuromedin U (NMU) that is known to regulate energy balance has been previously reported in the rat PT; however, the regulatory mechanism of NMU mRNA expression and secretion in the PT are still obscure. In this study, we examined both the diurnal change of NMU mRNA expression in the rat PT and the effects of melatonin on NMU in vivo. In situ hybridization and quantitative PCR analysis of laser microdissected PT samples revealed that NMU mRNA expression in the PT has diurnal variation that is high during the light phase and low during the dark phase. Furthermore, melatonin administration significantly suppressed NMU mRNA expression in the PT in vivo. On the other hand, 48 h fasting did not have an effect on PT-NMU mRNA expression, and the diurnal change of NMU mRNA expression was maintained. We also found the highest expression of neuromedin U receptor type 2 (NMUR2) mRNA in the third ventricle ependymal cell layer, followed by the arcuate nucleus and the spinal cord. These results suggest that NMU mRNA expression in the PT is downregulated by melatonin during the dark phase and shows diurnal change. Considering that NMU mRNA in the PT showed the highest expression level in the brain, PT-NMU may act on NMUR2 in the brain, especially in the third ventricle ependymal cell layer, with a circadian rhythm.

Neuromedin U: A Multifunctional Neuropeptide with Pleiotropic Roles

“…Moreover, the NmU gene is located close to the clock gene, a transcription factor that regulates circadian rhythm in mice (102 ). These results were supported by studies confirming that NmU mRNA expression levels follow a circadian rhythm, with fluctuation throughout the day in animals subjected to light/ darkness cycles (101,103 ). Similarly oscillating mRNA concentrations were detected in animals housed in complete darkness, suggesting that NmU expression, although affected by circadian rhythm, is at least partly independent of environmental light stimuli (100 ).…”

“…administration of NmU, as well as a phase shift in circadian locomotor activity coupled to increased expression of period homolog 1, a component of the circadian clock mechanism (99,100 ). Melatonin, a hormone known to be expressed under circadian control, also regulated NmU mRNA expression (101 ). Moreover, the NmU gene is located close to the clock gene, a transcription factor that regulates circadian rhythm in mice (102 ).…”

Quantifying the contribution of Neanderthal introgression to the heritability of complex traits

“…60–62 In vivo , NMU shows circadian expression in rat brains in response to melatonin and a genetic overexpression screen in zebrafish larvae identified Nmu to promote hyperactivity through Nmu receptor 2. 63,64 Ultimately, we hypothesize that Neanderthal introgressed alleles or tightly linked alleles downregulate NMUR2 in the brain leading to an association with increased morning person propensity.…”

A unifying hypothesis for control of body weight and reproduction in seasonally breeding mammals

“…26 Alongside TSH, a further peptide hormone has been shown to play a role in the photoperiodic response in F334 rats. 27 Neuromedin U (NMU) is expressed in the same cells in the PT as TSH 28 and is under strong photoperiodic regulation. 29 NMU appears to be an important mediator of the photoperiodic response in the rat, although whether it has a photoperiodic role in other species remains to be determined.…”

“…16 Subsequent studies in sheep and the F344 rat have shown that gene expression of the α-and β-subunits of TSH is similarly strongly regulated by photoperiod, with high expression under long days and low expression under short days. 27 Neuromedin U (NMU) is expressed in the same cells in the PT as TSH 28 and is under strong photoperiodic regulation. 25 Consistent with a unique physiological role for TSH derived from the PT, it has been demonstrated that PT-TSH is distinctly glycosylated relative to TSH from the pars distalis, and that PT-specific TSH is detectable in the circulation but does not stimulate the thyroid gland.…”