The Effects of Kisspeptin on Gonadotropin Release in Non-human Mammals - Kisspeptin Signaling in Reproductive Biology - page 77

slower to rise in fasted monkeys compared with fed monkeys. However, both
fed and fasted monkeys responded similarly to human chorionic gonadotropin
(hCG, which has LH-like activity), suggesting that there was no difference in
gonadal sensitivity [ 52 ]. Furthermore, expression of both kisspeptin and its receptor
in the hypothalamus was reduced in fasted monkeys compared with fed animals,
suggesting that the reduced response to exogenous kisspeptin-10 in the fasted state
may have been due to reduced expression of the kisspeptin receptor [ 53 ]. By con-
trast, following a 48 h fast, immature female rats maintain responsiveness to a
1 nmol dose of ICV kisspeptin-10 when compared with ad libitum-fed females [ 54 ].
Similarly, in adult rats fasted for 48 h, a 30 nmol/kg dose of IV kisspeptin-10 stimu-
lates LH secretion to similar level as fed rats, albeit from a lower baseline LH [ 8 ].
These data therefore suggest that monkeys and rodents may respond differently to
exogenous kisspeptin during undernutrition; this may partially be explained by con-
sidering that kisspeptin receptor expression is increased in rodents (rather than
decreased in monkeys) under caloric restriction [ 19 ].
Central administration of 1 nmol of murine kisspeptin-10 to pre-pubertal (30 day
old) male and female Wistar rats stimulated serum LH levels at 15 min post-
injection similarly in both sexes (9.0-10-fold increase). Another group of rats was
food-deprived for 72 h; interestingly, the ability of kisspeptin to induce LH secre-
tion was notably enhanced in these fasted animals, with 50-60-fold increases in LH
in this condition [ 19 ]. In this study, food deprivation reduced endogenous kiss-
peptin expression, but increased kisspeptin receptor expression, perhaps explaining
the heightened response to kisspeptin treatment [ 19 ]. Furthermore, kisspeptin-10
induces greater GnRH release from in vitro hypothalamic fragments taken from
fasted female rats when compared with ad libitum fed rats [ 19 ]. Roa et al. [ 24 ] cen-
trally administered 7.5 nmol/day of kisspeptin-10 by continuous ICV infusion for 7
days to adult female rats. In ad libitum fed animals, LH levels were elevated for the
fi rst 2 days of kisspeptin-10 infusion, but then dropped precipitously, whereas FSH
secretion was increased throughout the 7-day infusion [ 24 ]. Conversely, in rats
exposed to calorie restriction (50% decrease in daily calorie intake), the stimulatory
LH response to kisspeptin was maintained until day 5, but FSH secretion was only
maintained until day 1 [ 24 ]. Hence in female rats, the stimulatory effect of kiss-
peptin on LH secretion is subject to tachyphylaxis, which becomes less pronounced
during undernutrition. Paradoxically, the stimulatory effect of kisspeptin on FSH
was not subject to tachyphylaxis, except during a state of undernutrition [ 24 ].
To summarize, in monkeys, fasting antagonizes the effects of exogenous kiss-
peptin on gonadotropin secretion; however, in the rat, kisspeptin effects are
enhanced by undernutrition. Interestingly, women with hypothalamic amenorrhoea
are more sensitive to acute administration of exogenous kisspeptin when compared
with healthy women, but tachyphylaxis is associated with twice daily administra-
tion [ 28 ]. Further work is needed in order to determine to what extent species,
dosing, and treatment duration infl uence undernutrition's effects on kisspeptin
signaling.