Kisspeptins are products of the Kiss1 gene, which bind to GPR54, a G protein-coupled
receptor. Kisspeptins and GPR54 have been implicated in the neuroendocrine regulation
of GnRH secretion. To test the hypothesis that testosterone regulates Kiss1 gene expression,
we compared the expression of KiSS-1 mRNA among groups of intact, castrated, and castrated/testosterone
(T)-treated male mice. In the arcuate nucleus (Arc), castration resulted in a significant
increase in KiSS-1 mRNA, which was completely reversed with T replacement, whereas
in the anteroventral periventricular nucleus, the results were the opposite, i.e.
castration decreased and T increased KiSS-1 mRNA expression. In the Arc, the effects
of T on KiSS-1 mRNA were completely mimicked by estrogen but only partially mimicked
by dihydrotestosterone, a nonaromatizable androgen, suggesting that both estrogen
receptor (ER) and androgen receptor (AR) play a role in T-mediated regulation of KiSS-1.
Studies of the effects of T on KiSS-1 expression in mice with either a deletion of
the ERalpha or a hypomorphic allele to the AR revealed that the effects of T are mediated
by both ERalpha and AR pathways, which was confirmed by the presence of either ERalpha
or AR coexpression in most KiSS-1 neurons in the Arc. These observations suggest that
KiSS-1 neurons in the Arc, whose transcriptional activity is inhibited by T, are targets
for the negative feedback regulation of GnRH secretion, whereas KiSS-1 neurons in
the anteroventral periventricular nucleus, whose activity is stimulated by T, may
mediate other T-dependent processes.