Developmental and Hormonally Regulated Messenger Ribonucleic Acid Expression of KiSS-1 and Its Putative Receptor, GPR54, in Rat Hypothalamus and Potent Luteinizing Hormone-Releasing Activity of KiSS-1 Peptide

TLDR

The gonadotropic axis is centrally controlled by a complex network of excitatory and inhibitory signals activated at puberty, yet the expression pattern and functional role of the KiSS‑1/GPR54 system in the rat hypothalamus remain unexplored. The study aimed to analyze KiSS‑1 and GPR54 gene expression across physiological and experimental conditions and assess the effect of central KiSS‑1 peptide on LH release. Expression analyses were performed in various physiological and experimental settings, and central administration of KiSS‑1 peptide was evaluated in vivo. Persistent, developmentally regulated expression of KiSS‑1 and GPR54 mRNAs peaks at puberty, varies with estrous cycle and gonadectomy, is modulated by sex steroids and neonatal estrogen imprinting, and central KiSS‑1 peptide administration dramatically increases serum LH in prepubertal and adult rats, supporting its pivotal role in gonadotropic regulation.

Abstract

Abstract The gonadotropic axis is centrally controlled by a complex regulatory network of excitatory and inhibitory signals that is activated at puberty. Recently, loss of function mutations of the gene encoding G protein-coupled receptor 54 (GPR54), the putative receptor for the KiSS-1-derived peptide metastin, have been associated with lack of puberty onset and hypogonadotropic hypogonadism. Yet the pattern of expression and functional role of the KiSS-1/GPR54 system in the rat hypothalamus remain unexplored to date. In the present work, expression analyses of KiSS-1 and GPR54 genes were conducted in different physiological and experimental settings, and the effects of central administration of KiSS-1 peptide on LH release were assessed in vivo. Persistent expression of KiSS-1 and GPR54 mRNAs was detected in rat hypothalamus throughout postnatal development, with maximum expression levels at puberty in both male and female rats. Hypothalamic expression of KiSS-1 and GPR54 genes changed throughout the estrous cycle and was significantly increased after gonadectomy, a rise that was prevented by sex steroid replacement both in males and females. Moreover, hypothalamic expression of the KiSS-1 gene was sensitive to neonatal imprinting by estrogen. From a functional standpoint, intracerebroventricular administration of KiSS-1 peptide induced a dramatic increase in serum LH levels in prepubertal male and female rats as well as in adult animals. In conclusion, we provide novel evidence of the developmental and hormonally regulated expression of KiSS-1 and GPR54 mRNAs in rat hypothalamus and the ability of KiSS-1 peptide to potently stimulate LH secretion in vivo. Our current data support the contention that the hypothalamic KiSS-1/GPR54 system is a pivotal factor in central regulation of the gonadotropic axis at puberty and in adulthood.