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.
References
[1]
Rudolf T, Filler T, Wittkowski W (1993) Pars tuberalis specific cells within the pars distalis of the adenohypophysis. An ontogenetic study. Ann Anat 175: 171–176.
[2]
Sakai T, Inoue K, Kurosumi K (1992) Light and electron microscopic immunocytochemistry of TSH-like cells occurring in the pars tuberalis of the adult male rat pituitary. Arch Histol Cytol 55: 151–157.
[3]
Williams LM, Morgan PJ (1988) Demonstration of melatonin-binding sites on the pars tuberalis of the rat. J Endocrinol 119: R1–3.
[4]
Carlson LL, Weaver DR, Reppert SM (1989) Melatonin signal transduction in hamster brain: inhibition of adenylyl cyclase by a pertussis toxin-sensitive G protein. Endocrinology 125: 2670–2676.
[5]
Klosen P, Bienvenu C, Demarteau O, Dardente H, Guerrero H, et al. (2002) The mt1 melatonin receptor and RORbeta receptor are co-localized in specific TSH-immunoreactive cells in the pars tuberalis of the rat pituitary. J Histochem Cytochem 50: 1647–1657.
[6]
Bartness TJ, Powers JB, Hastings MH, Bittman EL, Goldman BD (1993) The timed infusion paradigm for melatonin delivery: what has it taught us about the melatonin signal, its reception, and the photoperiodic control of seasonal responses? J Pineal Res 15: 161–190.
[7]
Lincoln GA, Clarke IJ (1994) Photoperiodically-induced cycles in the secretion of prolactin in hypothalamo-pituitary disconnected rams: evidence for translation of the melatonin signal in the pituitary gland. J Neuroendocrinol 6: 251–260.
[8]
Bergmann M, Wittkowski W, Hoffmann K (1989) Ultrastructural localization of thyrotropin (TSH)-like immunoreactivity in specific secretory cells of the hypophyseal pars tuberalis in the Djungarian hamster, Phodopus sungorus. Cell Tissue Res 256: 649–652.
[9]
Bockmann J, Bockers TM, Vennemann B, Niklowitz P, Muller J, et al. (1996) Short photoperiod-dependent down-regulation of thyrotropin-alpha and -beta in hamster pars tuberalis-specific cells is prevented by pinealectomy. Endocrinology 137: 1804–1813.
[10]
Arai Y, Kameda Y (2004) Diurnal rhythms of common alpha-subunit mRNA expression in the pars tuberalis of hamsters and chickens. Cell Tissue Res 317: 279–288.
[11]
Aizawa S, Hoshino S, Sakata I, Adachi A, Yashima S, et al. (2007) Diurnal change of thyroid-stimulating hormone mRNA expression in the rat pars tuberalis. J Neuroendocrinol 19: 839–846.
[12]
Nakao N, Ono H, Yamamura T, Anraku T, Takagi T, et al. (2008) Thyrotrophin in the pars tuberalis triggers photoperiodic response. Nature 452: 317–322.
[13]
Yasuo S, Yoshimura T, Ebihara S, Korf HW (2010) Photoperiodic control of TSH-beta expression in the mammalian pars tuberalis has different impacts on the induction and suppression of the hypothalamo-hypopysial gonadal axis. J Neuroendocrinol 22: 43–50.
[14]
Ono H, Hoshino Y, Yasuo S, Watanabe M, Nakane Y, et al. (2008) Involvement of thyrotropin in photoperiodic signal transduction in mice. Proc Natl Acad Sci U S A 105: 18238–18242.
[15]
Ivanov TR, Lawrence CB, Stanley PJ, Luckman SM (2002) Evaluation of neuromedin U actions in energy homeostasis and pituitary function. Endocrinology 143: 3813–3821.
[16]
Graham ES, Turnbull Y, Fotheringham P, Nilaweera K, Mercer JG, et al. (2003) Neuromedin U and Neuromedin U receptor-2 expression in the mouse and rat hypothalamus: effects of nutritional status. J Neurochem 87: 1165–1173.
[17]
Minamino N, Kangawa K, Matsuo H (1985) Neuromedin U-8 and U-25: novel uterus stimulating and hypertensive peptides identified in porcine spinal cord. Biochem Biophys Res Commun 130: 1078–1085.
[18]
Minamino N, Sudoh T, Kangawa K, Matsuo H (1985) Neuromedins: novel smooth-muscle stimulating peptides identified in porcine spinal cord. Peptides 6 Suppl 3245–248.
[19]
Conlon JM, Domin J, Thim L, DiMarzo V, Morris HR, et al. (1988) Primary structure of neuromedin U from the rat. J Neurochem 51: 988–991.
[20]
Minamino N, Kangawa K, Honzawa M, Matsuo H (1988) Isolation and structural determination of rat neuromedin U. Biochem Biophys Res Commun. 156: 355–360.
[21]
Hashimoto T, Kurosawa K, Sakura N (1995) Structure-activity relationships of neuromedin U. II. Highly potent analogs substituted or modified at the N-terminus of neuromedin U-8. Chem Pharm Bull (Tokyo) 43: 1154–1157.
[22]
Hanada R, Teranishi H, Pearson JT, Kurokawa M, Hosoda H, et al. (2004) Neuromedin U has a novel anorexigenic effect independent of the leptin signaling pathway. Nat Med 10: 1067–1073.
[23]
Kowalski TJ, Spar BD, Markowitz L, Maguire M, Golovko A, et al. (2005) Transgenic overexpression of neuromedin U promotes leanness and hypophagia in mice. J Endocrinol 185: 151–164.
[24]
Austin C, Oka M, Nandha KA, Legon S, Khandan-Nia N, et al. (1994) Distribution and developmental pattern of neuromedin U expression in the rat gastrointestinal tract. J Mol Endocrinol 12: 257–263.
[25]
Domin J, Ghatei MA, Chohan P, Bloom SR (1987) Neuromedin U–a study of its distribution in the rat. Peptides 8: 779–784.
[26]
Benito-Orfila MA, Domin J, Nandha KA, Bloom SR (1991) The motor effect of neuromedin U on rat stomach in vitro. Eur J Pharmacol 193: 329–333.
[27]
Maggi CA, Patacchini R, Giuliani S, Turini D, Barbanti G, et al. (1990) Motor response of the human isolated small intestine and urinary bladder to porcine neuromedin U-8. Br J Pharmacol 99: 186–188.
[28]
Sumi S, Inoue K, Kogire M, Doi R, Takaori K, et al. (1987) Effect of synthetic neuromedin U-8 and U-25, novel peptides identified in porcine spinal cord, on splanchnic circulation in dogs. Life Sci 41: 1585–1590.
[29]
Brown DR, Quito FL (1988) Neuromedin U octapeptide alters ion transport in porcine jejunum. Eur J Pharmacol 155: 159–162.
[30]
Howard AD, Wang R, Pong SS, Mellin TN, Strack A, et al. (2000) Identification of receptors for neuromedin U and its role in feeding. Nature 406: 70–74.
[31]
Niimi M, Murao K, Taminato T (2001) Central administration of neuromedin U activates neurons in ventrobasal hypothalamus and brainstem. Endocrine 16: 201–206.
[32]
Ozaki Y, Onaka T, Nakazato M, Saito J, Kanemoto K, et al. (2002) Centrally administered neuromedin U activates neurosecretion and induction of c-fos messenger ribonucleic acid in the paraventricular and supraoptic nuclei of rat. Endocrinology 143: 4320–4329.
[33]
Kojima M, Haruno R, Nakazato M, Date Y, Murakami N, et al. (2000) Purification and identification of neuromedin U as an endogenous ligand for an orphan receptor GPR66 (FM3). Biochem Biophys Res Commun 276: 435–438.
[34]
Hanada T, Date Y, Shimbara T, Sakihara S, Murakami N, et al. (2003) Central actions of neuromedin U via corticotropin-releasing hormone. Biochem Biophys Res Commun 311: 954–958.
[35]
Wren AM, Small CJ, Abbott CR, Jethwa PH, Kennedy AR, et al. (2002) Hypothalamic actions of neuromedin U. Endocrinology. 143: 4227–4234.
[36]
Nakazato M, Hanada R, Murakami N, Date Y, Mondal MS, et al. (2000) Central effects of neuromedin U in the regulation of energy homeostasis. Biochem Biophys Res Commun 277: 191–194.
[37]
Aizawa S, Sakai T, Sakata I (2012) Glutamine and glutamic acid enhance thyroid-stimulating hormone beta subunit mRNA expression in the rat pars tuberalis. J Endocrinol 212: 383–394.
[38]
Graham ES, Webster CA, Hazlerigg DG, Morgan PJ (2002) Evidence for the biosynthesis of a prolactin-releasing factor from the ovine pars tuberalis, which is distinct from thyrotropin-releasing hormone. J Neuroendocrinol 14: 945–954.
[39]
Yoshimura T, Yasuo S, Watanabe M, Iigo M, Yamamura T, et al. (2003) Light-induced hormone conversion of T4 to T3 regulates photoperiodic response of gonads in birds. Nature 426: 178–181.
[40]
Nakahara K, Hanada R, Murakami N, Teranishi H, Ohgusu H, et al. (2004) The gut-brain peptide neuromedin U is involved in the mammalian circadian oscillator system. Biochem Biophys Res Commun 318: 156–161.
[41]
McNulty S, Ross AW, Barrett P, Hastings MH, Morgan PJ (1994) Melatonin regulates the phosphorylation of CREB in ovine pars tuberalis. J Neuroendocrinol 6: 523–532.
[42]
McNulty S, Ross AW, Shiu KY, Morgan PJ, Hastings MH (1996) Phosphorylation of CREB in ovine pars tuberalis is regulated both by cyclic AMP-dependent and cyclic AMP-independent mechanisms. J Neuroendocrinol 8: 635–645.
[43]
Kim MK, McClaskey JH, Bodenner DL, Weintraub BD (1993) An AP-1-like factor and the pituitary-specific factor Pit-1 are both necessary to mediate hormonal induction of human thyrotropin beta gene expression. J Biol Chem 268: 23366–23375.
[44]
Hashimoto K, Zanger K, Hollenberg AN, Cohen LE, Radovick S, et al. (2000) cAMP response element-binding protein-binding protein mediates thyrotropin-releasing hormone signaling on thyrotropin subunit genes. J Biol Chem 275: 33365–33372.
[45]
Sakamoto S, Nakamura K, Inoue K, Sakai T (2000) Melatonin stimulates thyroid-stimulating hormone accumulation in the thyrotropes of the rat pars tuberalis. Histochem Cell Biol 114: 213–218.
[46]
Szekeres PG, Muir AI, Spinage LD, Miller JE, Butler SI, et al. (2000) Neuromedin U is a potent agonist at the orphan G protein-coupled receptor FM3. J Biol Chem 275: 20247–20250.
[47]
Brighton PJ, Szekeres PG, Willars GB (2004) Neuromedin U and its receptors: structure, function, and physiological roles. Pharmacol Rev 56: 231–248.
[48]
Aguado LI, Schoebitz K, Rodriguez EM (1981) Intercellular channels in the pars tuberalis of the rat hypophysis and their relationship to the subarachnoid space. Cell Tissue Res 218: 345–354.
[49]
Guerra M, Blazquez JL, Peruzzo B, Pelaez B, Rodriguez S, et al. (2010) Cell organization of the rat pars tuberalis. Evidence for open communication between pars tuberalis cells, cerebrospinal fluid and tanycytes. Cell Tissue Res 339: 359–381.
[50]
Yasuo S, Korf HW (2011) The hypophysial pars tuberalis transduces photoperiodic signals via multiple pathways and messenger molecules. Gen Comp Endocrinol 172: 15–22.
[51]
Nogueiras R, Tovar S, Mitchell SE, Barrett P, Rayner DV, et al. (2006) Negative energy balance and leptin regulate neuromedin-U expression in the rat pars tuberalis. J Endocrinol 190: 545–553.