Metabolic Regulation of Kisspeptin - Kisspeptin Signaling in Reproductive Biology - page 359

The fi rst evidence in this front came from our studies on the effects of repeated
icv injections of kisspeptin-10 to immature female rats, submitted to chronic subnu-
trition during the pubertal transition; a manipulation that was suffi cient to rescue
vaginal opening (in a signifi cant proportion of cases) and to induce potent gonado-
tropic and estrogenic responses, despite the prevailing suppression of circulating
levels of gonadotropins due to malnutrition [ 20 ]. In the same vein, repeated admin-
istration of kisspeptin-10 to hypogonadotropic diabetic male rats ameliorated tes-
ticular and prostate weights, and normalized circulating LH and testosterone levels
[ 24 ]. Indeed, central injection of kisspeptin-10 to uncontrolled diabetic male and
female rats was able to reverse its hypogonadotropic state [ 24 , 25 ]. Of note, in both
models of metabolic distress (subnutrition and diabetes) rescue of the reproductive
indices was achieved in spite of the lack of direct effects of chronic kisspeptin treat-
ment on body weights or any improvement of other metabolic parameters.
The functionality of the Kiss1 system in different situations of metabolic stress
has been also evaluated by monitoring acute gonadotropin responses to kisspeptin-10
administration. Thus, gonadotropin responses to acute injection of kisspeptin in
fasted male and female rats were not only preserved but even enhanced, despite the
drop of gonadotropins levels due to food deprivation [ 20 , 42 ]. Moreover, the dura-
tion of LH responses to kisspeptin-10 was protracted in female rats subjected to
chronic subnutrition [ 43 ], suggesting that conditions of persistent energy defi cit
modify the patterns of desensitization to continuous/repeated kisspeptin stimula-
tion. The above evidence may suggest a state of hyper-responsiveness to kisspeptin
in situations of negative energy balance, a phenomenon also observed in terms of
GnRH secretion by hypothalamic explants from fasted rats [ 20 ]. While this phe-
nomenon might be related with sensitization at the receptor level ( see below ), the
possibility that such enhanced responses to kisspeptin may derive from a greater
accumulation of GnRH and/or gonadotropin stores due to the prevailing state of
negative energy balance cannot be excluded either.
One possible explanation for such hyper-responsiveness is that conditions of
negative energy balance evoke a decrease of the endogenous kisspeptin tone, which
would induce a compensatory state of augmented responsiveness to the neuropep-
tide. This phenomenon might involve an increase in the expression of Gpr54 (i.e.,
Kiss1r ), as protracted fasting in pubertal rats elicited an increase in its hypothalamic
mRNA levels [ 20 ]. Of note, however, shorter protocols of fasting in adult mice have
been shown to reduce Gpr54 mRNA expression [ 23 ], suggesting a complex dynam-
ics in the changes of kisspeptin release and receptor sensitivity during the course of
conditions of persistent negative energy balance. As further illustration of such a
complexity, it has been reported that, contrary to rodents, fasting decreases the net
responsiveness of the HPG axis to kisspeptin stimulation in the monkey [ 44 ].
Several factors, including differences in terms of species, age and duration of fast-
ing, may account for some the above discrepancies. In any event, it seems clear that
metabolic stress does not only alter Kiss1 /kisspeptin expression at the hypothala-
mus, but also causes functional alterations in terms of GnRH/gonadotropin respon-
siveness to the stimulatory effects of kisspeptins in different species.