Metabolic Regulation of Kisspeptin - Kisspeptin Signaling in Reproductive Biology - page 365

when they also displayed elevated serum leptin concentrations and increased Kiss1
mRNA levels at the hypothalamus, which was associated with a trend for a higher
number of kisspeptin-positive fi bers in the AVPV [ 39 ]. Whether these alterations
stem from nutritional/leptin changes at early postnatal periods and/or during puberty
is yet to be defi ned. Of note, a very recent study of early nutritional manipulation,
roughly similar to our previous study, confi rmed changes in the age of puberty onset
in both male (delayed in the postnatally underfed group) and female rats (advanced in
the postnatally overfed group), but failed to demonstrate any signifi cant change in
hypothalamic Kiss1 mRNA expression among the different experimental models [ 40 ].
It is possible that differences in the timing of tissue sampling for expression analysis
(fi xed d-36 in our study vs. age of external sign of puberty) and/or the setting up of
the litters (100% females in our study vs. 50% females-50% males) might partially
explain the above discrepancies. In addition, relevant reproductive/metabolic param-
eters, such as gonadotropin and leptin levels at puberty, were not evaluated in the
latter study; parameters that may help to clarify these discordances. Finally, a recent
study suggested that the hypothalamic Kiss1 system is particularly sensitive to inhi-
bition by acute fasting during juvenile, rather than the infantile period [ 68 ]. All in
all, the infl uence of different forms of metabolic stress on the early organization and
development of Kiss1 circuits, and the potential relevance of such phenomenon on
the timing of puberty, warrants further investigation.
Other Putative Metabolic Regulators of the Hypothalamic
Kiss1 System
In addition to leptin, other metabolic or nutritional cues may participate also in the
modulation of kisspeptin signaling, although to date this possibility has been
addressed only fragmentarily and further characterization of the whole set of
metabolic signals involved in the control of the Kiss1 system is eagerly awaited.
Among potential candidates, the gut-derived hormone, ghrelin, has been suggested
to inhibit the Kiss1 system in rat hypothalamus. Ghrelin is secreted by specifi c
endocrine (X/A) cells of the gastric mucosa and operates as circulating orexigenic
molecule, with effects that are opposite to those of leptin, thus functioning as signal
for energy insuffi ciency [ 9 ]. In keeping with such a role, we, as well as others, have
documented that ghrelin is a negative modifi er of puberty onset and/or gonadotropin
secretion in a variety of species (including rodents, sheep, monkey, and human),
acting mainly at central levels [ 9 , 69 ]. Recently, ghrelin has been shown to inhibit
hypothalamic Kiss1 mRNA expression in female rats, and this phenomenon, which
needs to be confi rmed, may contribute to the suppression of the HPG axis induced
by elevated levels of ghrelin (see Fig. 17.3 ). The putative molecular mechanisms
and mode of action of ghrelin on Kiss1 neurons remain totally unexplored.
Other potential metabolic regulators of the Kiss1 system are NPY and melanocor-
tins, although the amount of experimental data supporting this possibility is also
scarce. NPY, which operates as potent orexigenic signal in the brain [ 70 , 71 ], may