Metabolic Regulation of Kisspeptin - Kisspeptin Signaling in Reproductive Biology - page 360

Leptin Signaling and the Hypothalamic Kiss1 System
The signals responsible for the metabolic control of the hypothalamic Kiss1 system
have been actively investigated. For obvious reasons, because of its paramount
physiological relevance in the metabolic gating of puberty and fertility, the fi rst
efforts in this front aimed to evaluate whether leptin might operate as major regula-
tor of Kiss1 expression, as surrogate marker of kisspeptin signaling activity. As
mentioned earlier in this chapter, by the time of identifi cation of the reproductive
dimension of kisspeptin, it had been thoroughly documented that leptin is an impor-
tant signal of energy suffi ciency for the HPG axis [ 4 ]. Moreover, (indirect) evidence
for its capacity to stimulate/facilitate GnRH neuron fi ring at the hypothalamus had
been presented at that time [ 3 , 4 , 8 , 45 ]. However, the apparent absence of func-
tional leptin receptors in GnRH neurons, as conclusively demonstrated recently
[ 15 ], suggested the potential involvement of afferent pathways (sensitive to leptin
actions) for conveying its effects onto GnRH neurons.
Initial studies provided signifi cant and convincing evidence for a putative role of
Kiss1 neurons in such afferent pathways (see Fig. 17.2 ). Yet, it must be stressed that
most of these initial studies involved rather extreme in vivo models of leptin defi -
ciency, as well as some in vitro experiments using immortalized cell lines. Moreover,
the use of rather high doses of leptin (as proof-of-principle approach) might ques-
tion the physiological relevance of some of the reported stimulatory effects of leptin
on the Kiss1 system under certain conditions, such as the exit from situations of
negative energy balance [ 12 ]. While we believe that these features do not preclude
the usefulness of most of the experimental approaches reported so far, they bring a
call of caution when directly extrapolating these observations to “real” regulatory
networks and physiological conditions.
The fi rst study to demonstrate direct actions of leptin on Kiss1 neurons was car-
ried out in gonadectomized ob/ob mice. The results of this work showed (a) a
signifi cant suppression of Kiss1 mRNA levels at the ARC in the absence of
leptin; (b) the restoration of Kiss1 mRNA expression by leptin administration; and
(c) the expression of functional leptin receptors in a signifi cant proportion (>40%)
of Kiss1 neurons in the ARC [ 26 ]. It is important to note that in that study, the ani-
mals were gonadectomized in order to prevent fl uctuations in endogenous testoster-
one levels as potential confounding factor for analysis of Kiss1 mRNA levels [ 26 ].
The fact that, at least a fraction of Kiss1 neurons do express the gene encoding leptin
receptors has been recently confi rmed in ARC Kiss1 neurons [ 46 ]. In the latter
study, the analyses were carried out in transgenic mice that allowed GFP tagging
and subsequent isolation of Kiss1 neurons in vivo [ 46 ]. However, according to that
study, only a modest subset (<15%) of Kiss1 neurons displayed conventional
pSTAT3 responses to leptin treatment, whereas Kiss1 neurons in the AVPV did not
apparently express the leptin receptor gene [ 46 ].
As additional proof of the sensitivity of the hypothalamic Kiss1 system to the
regulatory actions of leptin, central infusion of leptin (at doses previously used in