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

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.

Suppression of kisspeptin expression and gonadotropic axis sensitivity following exposure to inhibitory day lengths in female Siberian hamsters

“…For example, the immediate early gene, c-Fos, is expressed in GnRH neurons following kisspeptin administration (Irwig et al, 2004;Matsui et al, 2004). Additionally, the GnRH receptor antagonist, acyline, blocks gonadotropin release elicited by kisspeptin (Gottsch et al, 2004;Irwig et al, 2004;Shahab et al, 2005). A large proportion of GnRH cells co-express GPR54 mRNA, further supporting a direct mode of action by kisspeptin on GnRH neurons (Han et al, 2005;Irwig et al, 2004;Messager et al, 2005).…”

“…Hamsters were held in long-(n=12) or short-day (n=19) photoperiods for 8 weeks prior to kisspeptin injections. Animals were injected with either kisspeptin-10 [KiSS-1 (112-121)/metastin (45-54)(human); Phoenix Pharmaceuticals, Inc. Belmont, CA], a peptide known to stimulate GPR54 (Gottsch et al, 2004), or a 0.1 M PBS vehicle injection. Injections were given between 8.5 -11 h prior to lights out in LD animals and 4.5 -7.0 h before lights out in SD animals.…”

Caloric restriction: Impact upon pituitary function and reproduction

“…Centrally administered kisspeptin stimulates GnRH neurons in the mouse, rat, sheep, and primate (Gottsch et al, 2004a;Irwig et al, 2004;Shahab et al, 2005). The integrity of the kisspeptin/GPR54 signaling system is necessary for normal reproduction.…”

“…It had been demonstrated that in mice, kisspeptin neurons (i.e. those that express Kiss1 mRNA) are most numerous in the arcuate nucleus (Arc), but significant numbers are also seen in the periventricular nucleus (PeN) and the anteroventral periventricular nucleus (AVPV) (Gottsch et al, 2004a;Smith et al, 2005a,b). The Arc and AVPVare thought to play important roles in the feedback regulation of GnRH and gonadotropin secretion by estradiol and testosterone, however the exact circuitry that mediates this phenomenon is unclear (Kalra and Kalra, 1989).…”

“…Interestingly, these Kiss neurons are thought to be the primary manner in which hypothalamic neuronal inputs are relayed to the GnRH neurons, which do not appear to express many of the necessary receptors that are required for the induction of the appropriate responses to hormones and factors such as leptin, ghrelin, dopamine, estradiol, and other factors that are related to the nutritional status of the organism (Dungan et al, 2006;Maeda et al, 2007). The activation of Kiss1 gene expression is likely to play an important role in timing the onset of puberty, sexual differentiation of the GnRH/LH surge mechanism, and the preovulatory GnRH/LH surge itself (in females) (Gottsch et al, 2004a;Shahab et al, 2005;Han et al, 2005, Navarro et al, 2004.…”