A Role for Kisspeptins in the Regulation of Gonadotropin Secretion in the Mouse

TLDR

Kisspeptins, products of the KiSS‑1 gene, bind the GPR54 receptor, and loss of GPR54 function causes hypogonadotropic hypogonadism, indicating a key role in gonadotropin regulation. The study aimed to determine how kisspeptin‑54 and kisspeptin‑10 influence gonadotropin secretion and to map KiSS‑1 mRNA distribution in the mouse hypothalamus. Researchers administered kisspeptins intracerebroventricularly and performed in situ hybridization to chart KiSS‑1 mRNA expression. Both peptides stimulated LH secretion, kisspeptin‑54 also induced LH and FSH at femtomolar doses and this effect was blocked by the GnRH antagonist acyline; KiSS‑1 mRNA was localized to hypothalamic nuclei involved in GnRH regulation, supporting a role for kisspeptin‑GPR54 signaling in the hypothalamic control of gonadotropin release.

Abstract

Kisspeptins are products of the KiSS-1 gene, which bind to a G protein-coupled receptor known as GPR54. Mutations or targeted disruptions in the GPR54 gene cause hypogonadotropic hypogonadism in humans and mice, suggesting that kisspeptin signaling may be important for the regulation of gonadotropin secretion. To examine the effects of kisspeptin-54 (metastin) and kisspeptin-10 (the biologically active C-terminal decapeptide) on gonadotropin secretion in the mouse, we administered the kisspeptins directly into the lateral cerebral ventricle of the brain and demonstrated that both peptides stimulate LH secretion. Further characterization of kisspeptin-54 demonstrated that it stimulated both LH and FSH secretion, at doses as low as 1 fmol; moreover, this effect was shown to be blocked by pretreatment with acyline, a potent GnRH antagonist. To learn more about the functional anatomy of kisspeptins, we mapped the distribution of KiSS-1 mRNA in the hypothalamus. We observed that KiSS-1 mRNA is expressed in areas of the hypothalamus implicated in the neuroendocrine regulation of gonadotropin secretion, including the anteroventral periventricular nucleus, the periventricular nucleus, and the arcuate nucleus. We conclude that kisspeptin-GPR54 signaling may be part of the hypothalamic circuitry that governs the hypothalamic secretion of GnRH.