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inhibition of
TAC3
/
Tac2
mRNA and NKB protein levels in the presence of E
2
or
T [
22
,
40
,
52
-
56
,
59
,
60
] and, consequently, the opposite (i.e., stimulation) is true
in E
2
/T-deprived situations, such as the postmenopausal stage or post-gonadectomy
[
22
,
28
,
52
,
53
,
56
,
59
,
61
-
63
]. Importantly, not only NKB but also its receptor,
NK3R, is subjected to regulation by sex steroids. Thus,
Tacr3
mRNA expression
is inhibited in the presence of E
2
[
22
,
56
]. Of note, this is reminiscent of the regu-
lation of
Kiss1
mRNA expression in the ARC by sex steroids [
64
,
65
], which
indicates that the Kiss1 and NKB systems likely control GnRH release in the
same direction in critical regulatory pathways, such as sex steroid negative feed-
back, through interactions that yet remain to be fully understood. In this sense, an
elegant study published recently by Mittelman-Smith and collaborators demon-
strated that ablation of
K
isspeptin/
N
KB/
Dy
n (KNDy) neurons impairs the com-
pensatory rise of LH after gonadectomy, i.e., the removal of steroid negative
feedback, thus adding further support to the critical role of these ARC neurons in
the control of GnRH release [
66
].
It is striking, nonetheless, that not all NKB neuronal populations in the hypo-
thalamus behave similarly to circulating levels of estradiol. Thus, estrogens signifi -
cantly inhibit NKB neurons in the ARC, as mentioned previously, while other
populations of NKB neurons may display diametrically different regulation. In this
vein, NKB neurons in the LHA exhibit remarkable stimulation of
Tac2
expression
in the presence of E
2
[
67
]. Again, this fact evokes comparisons with the Kiss1 sys-
tem, recalling the dual regulation by sex steroids that
Kiss1
expression undergoes
when comparing ARC vs. AVPV populations [
64
]. The LHA is known to hold neu-
ral centers that control metabolism and, therefore, indirectly, reproductive function
[
68
,
69
]; however, whether the NKB/NK3R system in the LHA exercises a role in
this control remains to be assessed.
The regulation of the NKB system by circulating levels of sex steroids—at least
in the ARC—is not restricted to adult individuals. Studies in mice have depicted a
striking sexual dimorphism of prepubertal animals in the sensitivity of
Tac2
expres-
sion (in the ARC) to E
2
. Thus, in the absence of E
2
after gonadectomy, juvenile
female mice respond with the expected compensatory rise of ARC
Tac2
expression
[
70
], which is accompanied by the rise in ARC
Kiss1
mRNA and plasma LH levels,
just as adult animals would respond [
64
]. However, their male counterparts appear
indisposed to exhibit similar responses, unlike their adult male equivalents [
70
].
This fact not only suggests a clear sexual dimorphism in the physiology of the
Kiss1/NKB neurons in the ARC prepubertally, but may also hold key aspects for the
differential timing in puberty onset (later in males), which also needs to be
investigated in more detail. An important phenomenon that may help to understand
the contribution of the NKB system to puberty onset may rely in the apparent dif-
ferential sensitivity to the negative feedback of sex steroids on the NKB system
compared to the
Kiss1
system. Whereas both genes (
Kiss1
and
Tac2
) are susceptible
to regulation by E
2
prepubertally,
Tac2
expression seems to be less sensitive to the
rising levels of gonadal steroids than
Kiss1
. This may account for a sex steroid-
independent increase in NKB levels that could, possibly, contribute to the activation
of the Kiss1/GnRH axis prepubertally [
71
].
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