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Fig. 16.5
NKB activates KNDy-GFP neurons via NK3 receptors. (
a
) Traces show an NKB-
responsive cell from a GDX mouse, in which the NK3R antagonist, SB222200 (3
M, 15 min),
attenuated the response to a subsequent (at 22 min) application of NKB. (
b
) Bar chart summarizes
the antagonist effect of SB222200, which reduced the NKB response to less than 35% of control
value in the cells tested. (
c
) Shows a cell that was strongly activated by senktide (1
μ
M, 15 s), a
selective NK3R receptor agonist, further confi rming the presence of an NK3R-mediated activation
in ARC-KNDy neurons
μ
treatment for hypothalamic amenorrhea [
44
]. However, the mechanism(s) via which
leptin regulates reproductive functions remain unclear. Multiple studies have con-
cluded that GnRH neurons do not express LepRb [
11
,
45
,
46
] focusing attention on
kisspeptin neurons, although a recent study casts doubt on the role of kisspeptin
neurons, at least in mediating the effects of leptin on puberty [
47
]. Manipulation of
leptin levels consistently regulates
Kiss1
mRNA message—fasting suppresses
Kiss1
mRNA expression and leptin restores these levels. Lep
ob/ob
mice also show
reduced
Kiss1
mRNA levels in the ARC that are partially restored by leptin treat-
ment [
8
]; total hypothalamic
Kiss1
expression (which included both the ARC and
the AVPV) does not change signifi cantly, signifying dilution of the effect by extra-
ARC regions [
48
]. Leptin also enhances
Kiss1
mRNA levels in conditions associ-
ated with reduced energy stores, such as in streptozotocin-induced diabetic rats [
49
].
Studies detailed below suggest complex mechanisms may underlie the effects of
leptin on reproductive functions.
Kisspeptin neurons of RP3V have consistently been shown not to express leptin
receptors [
50
], and the proportion of ARC-KNDy cells expressing leptin receptors
is controversial. For example, Smith et al. reported LepRb expression in up to 40%
of ARC-KNDy neurons [
8
], whereas Louis et al. found that LepR co-localizes in
only 0-6% of ARC-KNDy neurons in mice and ewes [
11
]. Backholer et al. reported
a high level of leptin receptor expression in ARC-Kiss1 cells of the ewe [
10
].
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