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Genetic studies in humans or in vivo studies using animals have shown that kisspeptin released from the hypothalamus controls secretion of gonadotropin-releasing hormone (GnRH) from GnRH neurons, and subsequently GnRH induces gonadotropin secretion from the anterior pituitary. Kisspeptin did not stimulate GnRH expression in the GnRH-producing cell line GT1-7. Thus, we cultured GnRH and kisspeptin neurons from whole fetal rat brain and examined the regulation of GnRH and kisspeptin. Expression of GnRH messenger RNA (mRNA) was unchanged by estradiol (E2) treatment in these primary cultures. In contrast, kisspeptin mRNA expression was increased 2.00 ± 0.23-fold by E2 treatment. When these cultures were stimulated by kisspeptin-10, GnRH mRNA was significantly increased up to 1.51 ± 0.35-fold. Expression of GnRH mRNA was also stimulated 1.84 ± 0.33-fold by GnRH itself. Interestingly, kisspeptin mRNA was significantly increased up to 2.43 ± 0.40-fold by kisspeptin alone. In addition, kisspeptin mRNA expression was significantly increased by stimulation with GnRH (1.46 ± 0.21-fold). Our observations demonstrated that kisspeptin, but not GnRH, was upregulated by E2 and that kisspeptin stimulates GnRH mRNA expression in primary cultures of whole fetal rat brain. Furthermore, GnRH and kisspeptin stimulate their own neurons to produce GnRH or kisspeptin, respectively.

Pituitary adenylate cyclase-activating polypeptide (PACAP) was first identified as a hypophysiotropic factor that regulates pituitary cell functions and has been subsequently shown to be widely distributed and have multiple functions. The PACAP is known to be expressed in placental tissues and is suggested to have a critical role in physiological function of the placenta. In addition to PACAP, the hypothalamic peptides kisspeptin and gonadotropin-releasing hormone (GnRH) are also expressed in placental cells. In this study, we used primary cultures of placental tissues from rats of 16 to 18 days gestation and examined the regulation and function of PACAP. The PACAP messenger RNA (mRNA) expression and PACAP-immunoreactive cells were detected in primary cultures of rat placental cells. The PACAP mRNA expression in placental cells was upregulated in the presence of the sex steroids estradiol and progesterone; however, their combined treatment failed to enhance their individual effects. When the cells were stimulated with kisspeptin, PACAP mRNA expression was increased. Similarly, GnRH had a stimulatory effect on PACAP expression. Conversely, kisspeptin expression in placental cells was increased by PACAP stimulation, whereas PACAP failed to stimulate GnRH mRNA expression in these cells. Finally, we found that PACAP had a stimulatory effect on human chorionic gonadotropin expression in placental cells. Our current observations suggest that the hypothalamic peptides PACAP, kisspeptin, and GnRH are interrelated and maintain placental functions., (© The Author(s) 2016.)