Keeping Puberty on Time: Novel Signals and Mechanisms Involved - Current Topics in Developmental Biology - page 312

by in vitro work, showing that leptin increases Kiss1 mRNAexpression in suit-
able neuronal cell lines ( Luque et al., 2007 ), and is able to induce the electrical
firing of Kiss1 neurons via activation of TRPC channels in the guinea pig
( Qiu, Fang, Bosch, Ronnekleiv, & Kelly, 2011 ).
Recent data, however, seem to suggest that the actions of leptin on the
hypothalamic Kiss1 system might be predominantly indirect. Thus, selective
congenital elimination of Ob-Rb in Kiss1 cells failed to prevent the normal
occurrence of puberty onset and the attainment of fertility ( Donato et al.,
2011 ). Admittedly, however, the latter approach using the Cre-loxP technol-
ogy cannot guarantee the selective ablation of Ob-Rb in postnatal Kiss1 neu-
rons in the hypothalamus, as the Kiss1 gene is widely expressed in other brain
and other peripheral tissues at early stages of development. Furthermore, since
knockout of Ob-Rb was induced congenitally in Kiss1 cells, the possibility of
compensatory changes that may have masked the impact of the lack of leptin
signaling in this neuronal population cannot be ruled out. In any event, an
independent study mapping the distribution of the functional Ob-Rs in var-
ious hypothalamic areas failed to demonstrate substantial expression of leptin
receptors in GnRH or Kiss1 neurons, except for a small fraction of Kiss1 cells
in the ARC ( Louis et al., 2011 ). Intriguingly, the latter study found an as yet
uncharacterized population of ObRb-expressing neurons in the ARC and
RP3V, in the proximity of Kiss1 neurons ( Louis et al., 2011 ). Thus, it is pos-
sible that a part of the positive effects of leptin on the hypothalamic expression
of Kiss1 /kisspeptin is conducted indirectly and transmitted via intermediate
circuits ( Louis et al., 2011 ), whose nature and transmission await further clar-
ification. Interestingly, a recent report has suggested that direct leptin signaling
in Kiss1 neurons may arise after puberty ( Cravo et al., 2013 ), suggesting an
intriguing switch between indirect and direct effects of leptin on Kiss1 circuits
during the time of pubertal maturation, whose physiological relevance is yet to
be exposed. On the other hand, solid experimental evidence has documented
that part of the reproductive effects of leptin are primarily transmitted via
hypothalamic areas other than the major Kiss1-expressing nuclei, such as
the ventral premammillary nucleus (PMV). Extensive description of the roles
of PMV as a relay for the reproductive effects of leptin can be found elsewhere
( Donato et al., 2011, 2009 ). Of important note, recent evidence strongly sug-
gests that PMV projections participate in the regulation of Kiss1 neurons
( Donato et al., 2013 ) and, hence, may contribute to the transmission of
leptin effects onto Kiss1 circuits, as discussed above.
The central molecular mediators for the metabolic control of puberty in
general, and of the Kiss1 system in particular, have also been studied, and