Metabolic Regulation of Kisspeptin - Kisspeptin Signaling in Reproductive Biology - page 368

for the conduction of the anorexigenic action of estradiol. These fi ndings, however,
seem diffi cult to reconcile with the facts that estrogen inhibits Kiss1 expression in
the ARC, and that kisspeptins (as is the case for estrogens) are thought to conduct a
primary anorexigenic action in the hypothalamus [ 79 ]. The possibility that the
above phenomenon may stem from elimination of other co-transmitters of ARC
Kiss1 neurons, such as dynorphin, warrants further investigation.
Concluding Remarks
While the infl uence of body weight on puberty and fertility has been intuitively
known for ages, the neuroendocrine mechanisms underlying the metabolic control of
the reproductive axis have begun to be exposed only in the past decades, in which the
discovery of leptin and, more recently, kisspeptins, are considered important mile-
stones. Indeed, in the last few years we have learnt that Kiss1 neurons can sense
extreme metabolic conditions and are likely to participate in the transmission of such
metabolic information to GnRH neurons. Among the peripheral signals involved in
the control of Kiss1 neurons, compelling evidence from proof-of-principle studies,
addressing the effects of either the lack of leptin or its supplementation, strongly sug-
gest that, in keeping with its key roles in energy homeostasis and body weight control,
leptin participates in the metabolic regulation of the hypothalamic Kiss1 system.
By virtue of leptin ability to stimulate Kiss1 expression, it is likely that it allows the
proper functioning of the reproductive axis in conditions of energy suffi ciency.
The reality, however, is probably not so simple and, certainly, the metabolic con-
trol of the Kiss1 system likely goes beyond the regulatory actions of leptin, just as
much as the metabolic control of puberty and fertility is not all about kisspeptin
regulation. For instance, very recently, we have become aware that Kiss1 neurons
might not be direct targets of leptin, which in turn may operate (largely) via indirect
mechanisms. But, is this the case in all species, and if so, what is the reason for the
apparent expression of leptin receptors in Kiss1 neurons? Similarly, we have learnt
that some of the positive effects of leptin on Kiss1 expression are detectable only at
rather high (probably pharmacological) levels, but this does not preclude a physio-
logical role of this adipose hormone in the metabolic control of reproductive onset
and fertility. On the other hand, although the fi eld of the metabolic control of the
Kiss1 system has been largely dominated by leptin studies, mounting, but as yet
limited, evidence has pointed out that other metabolic signals besides leptin can also
participate in the control of Kiss1 neurons. If so, what is the basis and physiological
relevance of such actions? These are but few examples of “uncertainties” and open
questions in the fi eld of the metabolic control of kisspeptins that warrant specifi c
investigation and are likely to draw considerable attention in the near future.
Acknowledgments The authors are indebted with the members of the research team at the
Physiology Section of the University of Cordoba, who actively participated in the generation of
experimental data discussed herein. The work from the authors' laboratory summarized in this