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status and respond to leptin with increased
Kiss1
expression; therefore, they would be
well suited to participate in the afferent networks responsible for the metabolic regu-
lation of GnRH neurons. Yet, whether leptin effects are conducted directly or indi-
rectly on
Kiss1
neurons is presently under considerable debate and investigation.
Metabolic Control of the
Kiss1
System: Evidence
from Expression Studies
As described elsewhere in this textbook, during the last few years,
Kiss1
neurons in
the basal forebrain have been recognized as master elements of the reproductive
brain, which operate as key conduits for transmitting the regulatory actions of
numerous modulators of the HPG axis, from gonadal steroids to photoperiodic stim-
uli [
16
-
18
]. In order to demonstrate if metabolic and nutritional cues, with known
impacts on the reproductive axis, operate via
Kiss1
neurons for their modulation of
the GnRH system, initial expression and functional analyses were conducted to
experimentally test two key issues: (a) whether the hypothalamic
Kiss1
system, as
evaluated by changes in
Kiss1
mRNA expression, is altered in conditions of metabolic
distress known to perturb puberty and/or gonadotropin secretion; and (b) whether
exogenous administration of kisspeptin, as a means to replace its defective endoge-
nous levels, may rescue reproductive defi cits seen in those conditions [
19
].
Studies conducted initially were designed as to provide
proof of principle
for the
above contentions and hence were mainly focused in models of persistent or sub-
stantial negative energy balance, which are linked to different degrees of reproduc-
tive dysfunction. Thus, studies in pubertal male and females rats under acute fasting
documented a signifi cant decrease in the hypothalamic expression of
Kiss1
mRNA
that was associated with lowering of serum LH levels [
20
]. Similar observations
were later obtained in adult female rats [
21
,
22
] and adult male mice, where time-
course analyses of the effects on hypothalamic expression of
Kiss1
gene revealed a
rapid drop in its mRNA levels as soon as 12-h after beginning of food-restriction
[
23
]. Of note, suppression of the hypothalamic expression of
Kiss1
has been also
reported in other models of metabolic stress coupled to negative energy balance and
impaired reproductive function, such as uncontrolled experimental (streptozotocin-
induced) diabetes, where a marked reduction in the hypothalamic
Kiss1
mRNA
expression, coupled to a substantial suppression of circulating LH and sex steroid
levels, has been described in male and female rats [
24
,
25
]. These fi ndings add fur-
ther strength to the contention that energy insuffi ciency inhibits hypothalamic
expression of
Kiss1
gene; a phenomenon that seems to be relevant for the suppres-
sion of the reproductive axis in conditions of sustained energy defi cit.
Although the initial expression studies unveiled the sensitivity of the hypothalamic
Kiss1
system to changes in body energy stores and metabolic cues, these did not thor-
oughly address the neuroanatomical location of the reported alterations of
Kiss1
expression within the hypothalamus. However, this is a relevant aspect, given the dif-
ferent roles and regulatory features of
Kiss1
neurons in the arcuate nucleus (ARC) and
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