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Comparative Study
. 2004 Dec 1;561(Pt 2):379-86.
doi: 10.1113/jphysiol.2004.072298. Epub 2004 Oct 14.

Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54

V M Navarro  1 , R Fernández-Fernández, J M Castellano, J Roa, A Mayen, M L Barreiro, F Gaytan, E Aguilar, L Pinilla, C Dieguez, M Tena-Sempere
Affiliations
Comparative Study

Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54

V M Navarro et al. J Physiol. .

Abstract

The awakening of the gonadotrophic axis at puberty is the end-point of a complex cascade of sex developmental events that leads to the attainment of reproductive capacity. Recently, loss-of-function mutations of the gene encoding GPR54, the putative receptor for the KiSS-1-derived peptide metastin, have been linked to hypogonadotrophic hypogonadism, both in rodents and humans. However, the actual role of the KiSS-1/GPR54 system in the timing of puberty onset remains unexplored. We report herein that chronic central administration of KiSS-1 peptide to immature female rats induced the precocious activation of the gonadotrophic axis, as estimated by advanced vaginal opening, elevated uterus weight, and increased serum levels of luteinizing hormone (LH) and oestrogen. The central effect of KiSS-1 upon LH release appeared to be mediated via the hypothalamic LH-releasing hormone. In contrast, despite the well-documented permissive role of body fat stores and the adipocyte-derived hormone leptin in puberty maturation, acute activation of the gonadotrophic axis by KiSS-1 was persistently observed in pubertal animals under food deprivation, after central immunoneutralization of leptin, and in a model of leptin resistance. Overall, the present results, together with our recent data on maximum expression of KiSS-1 and GPR54 genes in the hypothalamus at puberty, provide novel evidence for a role of the KiSS-1 system as a downstream element in the hypothalamic network triggering the onset of puberty.

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Figures

Figure 1
Figure 1. Compilation of indices of pubertal maturation recorded in immature female rats chronically i.c.v. injected with 1 nmol KiSS-1 peptide or vehicle
Dates of vaginal opening (expressed as a percentage of total number of animals per experimental group) are shown in the left panels. Administration of 1 nmol KiSS-1 every 12 h between 26 and 31 days postpartum induced vaginal opening in ∼75% of females at the age of 31 days, an age-point when none of the animals injected with vehicle presented canalization of the vagina (inset). Data on body and uterus weights, as well as serum LH and oestradiol (OE2) levels, in vehicle- and KiSS-1-injected animals are shown in the right panels. Values are the mean ±s.e.m. of at least 15 independent determinations per group. **P < 0.01 versus vehicle-injected group (Student's unpaired t test).
Figure 2
Figure 2. Effects of the blockade of endogenous LHRH actions upon the ability of KiSS-1 to acutely stimulate LH secretion
Immature female rats were subcutaneously treated with a potent LHRH antagonist, ORG 30276 (ANT; 5 mg kg−1 24 h, 2 doses) or vehicle (Veh), and were subsequently i.c.v. injected with vehicle or 1 nmol KiSS-1. Hormonal values are the mean ±s.e.m. of at least 10 independent determinations per group. Groups with different symbols (* and †) are significantly different (P < 0.01, ANOVA followed by Student-Newman-Keuls multiple range test).
Figure 3
Figure 3. Effects of acute central administration of KiSS-1 peptide upon LH secretion in different models of leptin insufficiency
In A, immature female rats were subjected to fasting (food-restriction: FD) for 48 h. The animals were subsequently i.c.v. injected with vehicle or 1 nmol KiSS-1 and serum LH levels determined at 15 and 60 min after injection. For comparative purposes, serum LH levels in control pair-aged female rats fed ad libitum are also shown. Hormonal values are the mean ±s.e.m. of at least 10 independent determinations. **P < 0.01 versus corresponding control fed group; †P < 0.01 versus fasting animals i.c.v. injected with vehicle. In B, immunoneutralization of endogenous leptin was conducted in immature female rats by means of central administration of a specific antileptin antibody (Anti-LEP). Thereafter, anti-LEP-treated female rats were i.c.v. injected with vehicle or 1 nmol KiSS-1 and serum LH levels determined at 15 min after injection. For comparative purposes, serum LH levels in control pair-aged female rats i.c.v. injected with normal rabbit serum are also shown. Hormonal values are the mean ±s.e.m. of at least 10 independent determinations. **P < 0.01 versus corresponding control group; †P < 0.01 versus anti-LEP treated animals. In C, i.c.v. injection of vehicle or 1 nmol KiSS-1 was carried out in leptin-resistant Zucker (fa–/–) rats and their corresponding lean (fa?/+) controls, and serum LH levels were determined at 15-min after injection. Hormonal values are the mean ±s.e.m. of at least 10 independent determinations. **P < 0.01 versus corresponding vehicle-injected group (ANOVA followed by Student-Newman-Keuls multiple range test).
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