Metabolic Regulation of Kisspeptin - Kisspeptin Signaling in Reproductive Biology - page 358

above observations were interpreted as evidence for some degree of impairment of the
Kiss1 system, and particularly of its responses to key regulators, such as sex steroids, in
obesity [ 23 ]. More recently, persistent obesity in DBA/2J mice (a strain that is prone to
obesity-induced infertility) has been shown to evoke a signifi cant reduction of Kiss1
mRNA levels in the ARC and AVPV, as well as in the number of immunoreactive Kiss1
neurons in the AVPV [ 38 ]. On the other hand, studies in male rats transiently exposed to
high fat diet have shown increases of Kiss1 mRNA levels at the hypothalamus [ 21 ]. In
the same vein, our fi ndings in peripubertal female rats subjected to early postnatal over-
feeding suggested a putative correlation between early-onset overweight, advanced
vaginal opening (as index of pubertal maturation) and increased Kiss1 mRNA levels in
the hypothalamus, as well as possibly increased numbers of kisspeptin fi bers in the
AVPV [ 39 ]. Yet, a recent report has failed to detect signifi cant changes in Kiss1 mRNA
levels in the ARC or AVPV at the time of vaginal opening in female rats submitted to
postnatal overnutrition [ 40 ]. In any event, the above observations in various models of
increased body weight/obesity in rodents illustrate that, depending on the degree and
duration of obesity, stimulatory or inhibitory responses in terms of Kiss1 expression and
gonadotropic function might be observed. Admittedly, however, the mechanisms for
Kiss1 alterations in conditions of obesity are likely different from those of metabolic
distress associated to energy insuffi ciency. Likewise, the potential impact of the adapta-
tive/pathological changes frequently linked to obesity on the hypothalamic Kiss1 system
has not been explored. On note, obesity (and type-2 diabetes) have been suggested to
affect the hypothalamic Kiss1 system in humans [ 41 ]; yet, this hypothesis needs to be
experimentally validated.
Metabolic Control of the Kiss1 System: Evidence
from Functional Analyses
In spite of the wealth of expression data, demonstration of any causal link between
the perturbations of the hypothalamic Kiss1 system and alterations of the reproduc-
tive axis in conditions of metabolic distress would require additional functional
analyses. With this aim, a number of (mainly pharmacological) proof - of - principle
studies have been conducted in order to evaluate whether prevention of the expected
drop of kisspeptin levels in situations of energy insuffi ciency, by means of its exog-
enous administration, would be suffi cient to ameliorate or normalize different
reproductive parameters in those situations. These studies, in rather extreme
metabolic conditions, have nonetheless illustrated that by enhancing the endogenous
kisspeptin tone, without any other neuroendocrine manipulation, several indices of
pubertal/reproductive failure can be rescued, thus reinforcing the pathophysiologi-
cal relevance of Kiss1 alterations in such situations. As a call of caution, studies in
this area have used protocols of central administration of high doses of the peptide,
which might have caused an elevation of the endogenous kisspeptin tone over
physiological levels.