Metabolic Regulation of Kisspeptin - Kisspeptin Signaling in Reproductive Biology - page 364

by central injection of l-leucine partially reversed the state of hypogonadotropism
induced by chronic subnutrition; a condition of low leptin levels [ 27 ]. All in all, these
observations are compatible with the existence of a leptin-mTOR-kisspeptin path-
way that may play a physiological role in the metabolic control of puberty onset and
fertility. Admittedly, however, the cellular basis for such pathway, and whether
mTOR operates as modulator within Kiss1 cells and/or in afferent neuronal path-
ways, is yet to be clarifi ed and warrants further investigation.
Another putative molecular modulator of Kiss1 gene expression is the cAMP
responsive element-binding protein-1 (Creb1)-regulated transcription coactivator-1
(Crct1; also termed TORC1, which stands for Transducer of Regulated Creb ). It was
reported in 2008 that Crtc1 KO mice display not only obese and hyperphagic pheno-
types, but are also infertile [ 64 ]. The underlying mechanisms for such a combined
alteration of energy homeostasis and reproduction seem to involve the disturbance (due
to the lack of Crtc1) of the ability of leptin to stimulate the expression of the genes
encoding CART (cocaine- and amphetamine-regulated transcript, which operate as
anorexigenic neuropeptide controlling food intake) and kisspeptins. On the latter, leptin
has been proven to dephosphorylate (and activate) Crtc1, which in turn stimulates the
recruitment of Crct1 to Kiss1 gene promoter. In addition, dephosphorylation of Crtc1
enhanced Kiss1 gene expression in GT1-7 cells, and Crtc1 over-expression increased
Kiss1 promoter activity [ 64 ]. However, an independent report was unable to replicate
the consequences of functional inactivation of Crtc1 on mouse fertility [ 65 ]. This dis-
cordant observation, together with novel expression and functional genomic data sug-
gesting a nondirect mode of action of leptin on Kiss1 neurons, bring some doubts on the
actual physiological role of Crtc1 in mediating leptin effects on the HPG axis in vivo.
In addition to putative molecular mediators, the developmental effects of meta-
bolic signals in the pubertal maturation of the hypothalamic Kiss1 system have been
recently explored. As described elsewhere in this topic, developing Kiss1 neurons
are sensitive to the organizing actions of other key regulators of the HPG axis, such
as sex steroids [ 37 ]. Considering the increasing prevalence of early-onset metabolic
disorders, including childhood obesity that may affect the timing of puberty, and the
proven sensitivity of the hypothalamic Kiss1 system to conditions of metabolic
distress, specifi c analysis of the early origins of alterations of this system linked to
metabolic distress are warranted. In this context, a recent study from our group using
models of postnatal nutritional challenge, by means of manipulation of litter size,
strongly suggested that early changes in body weight and energy homeostasis might
be also an important regulator of later Kiss1 /kisspeptin expression at puberty. Thus,
female rats bred in large litters (as model of early underfeeding) were leaner and
displayed delayed vaginal opening, despite they being allowed to eat ad libitum
from weaning onwards. These animals had also low serum leptin levels and reduced
Kiss1 mRNA levels and kisspeptin-positive neurons at the hypothalamus during
puberty [ 39 ]; roughly similar fi ndings have been recently reported in female mice
subjected to postnatal undernutrition [ 66 ]. In good agreement, gestational undernutri-
tion has been shown to decrease hypothalamic Kiss1 expression and to delay puberty
onset in female rats [ 67 ]. Conversely, female rats bred in small litters (as model of
early postnatal overfeeding) were heavier and showed earlier entry into puberty,