Metabolic Regulation of Kisspeptin - Kisspeptin Signaling in Reproductive Biology - page 357

anteroventral periventricular area (AVPV). Notwithstanding, studies in leptin-defi cient
(ob/ob) male mice showed back in 2006 a signifi cant reduction of Kiss1 mRNA levels
at the ARC in this model of congenital absence of leptin [ 26 ]. Likewise, a severe
decrease of Kiss1 mRNA expression in the ARC was observed in chronically under-
fed rats during the pubertal transition [ 27 ]. On the other hand, adult OVX female rats
replaced with estrogen and submitted to short-term fasting displayed reduced Kiss1
mRNA levels at the AVPV [ 28 ]. Moreover, 50% caloric restriction resulted in
decreased Kiss1 mRNA levels in the ARC and AVPV in rats [ 12 ], a phenomenon that
was also observed during lactation, another condition of negative energy balance [ 29 ].
Finally, sheep under dietary restriction experienced a robust suppression of Kiss1
mRNA levels at the ARC and preoptic area [ 30 ]. Altogether, these evidences suggest
that Kiss1 neurons in both the ARC and rostral/AVPV may be targets for metabolic
regulation. It is yet to be defi ned whether metabolic-induced changes in these two
populations of Kiss1 neurons are similar in magnitude or whether they depend on sex,
prevailing metabolic status and/or stage of development.
As related issue, most of the studies conducted so far on the metabolic regulation
of the Kiss1 system have addressed changes in its hypothalamic mRNA levels follow-
ing various forms of metabolic stress. To what extend these mRNA changes translate
into alterations of kisspeptin content, or even kisspeptin release, at these hypothalamic
sites remains scarcely evaluated. Notwithstanding, it has been documented that
48-h fasting in pubertal female rats induces a signifi cant suppression of kisspeptin-
immunoreactivity (IR) and the number of kisspeptin-positive neurons in the ARC
[ 31 ]. Admittedly, however, no obvious decrease in kisspeptin-IR was detectable in
adult female rats after a similar period of food deprivation. The fact that, in that particu-
lar study, animals were adult and gonadal-intact (and thus subjected to compensatory
changes in endogenous sex steroid milieu), as well as the features of the immunohis-
tochemical analyses that did not allow for proper detection of discrete quantitative
changes in kisspeptin protein expression but rather gross changes in the numbers of
kisspeptin-positive cells, may explain this discrepancy [ 31 ]. Of note, more protracted
conditions of negative energy balance, such as lactation, have been reported to cause
a decrease in kisspeptin-IR in the ARC [ 29 ]. Indeed, the ARC population of Kiss1
neurons is also sensitive to other forms of metabolic stress, as evidenced by the
decrease in the number of kisspeptin-IR detected in adult male rats submitted to an
acute infl ammatory challenge by administration of bacterial LPS [ 32 ].
Finally, expression analyses targeting the hypothalamic Kiss1 system have been also
conducted in conditions of obesity; yet, rather limited data have been produced so far on
the effects of situations of persistent overweight on the hypothalamic expression of
Kiss1 . These analyses, however, are particularly interesting, given the rising prevalence
of obesity and its potential reproductive comorbidities, which are likely to include per-
turbed pubertal timing and sub-fertility [ 33 - 36 ]. To our knowledge, the fi rst evidence
suggesting (subtle) alterations of the hypothalamic Kiss1 system in conditions of energy
excess came from our studies in long-term diet-induced obese mice that, despite very
low levels of circulating testosterone, displayed roughly preserved levels of hypotha-
lamic Kiss1 mRNA. Considering that severely decreased testosterone levels should have
brought about an increase in the hypothalamic expression of Kiss1 mRNA [ 37 ], the