Metabolic Regulation of Kisspeptin - Kisspeptin Signaling in Reproductive Biology - page 363

Regardless of the predominant (direct and/or indirect) mode of action of leptin
on Kiss1 neurons, the infl uence of the adipocyte hormone on the hypothalamic
Kiss1 system might not only have physiological relevance, but also pathophysiolog-
ical implications. Indeed, marked changes in leptin levels have been related to
diverse reproductive disorders, including anorexia nervosa, extreme physical exer-
cise, or low body weight [ 52 , 53 ]. In those conditions, endogenous kisspeptin levels
would be expected to be low and kisspeptin analogues might have also potential
therapeutic implications, given the preserved, if not augmented, responses to kiss-
peptins in situations of energy defi ciency, at least in rodents [ 20 , 42 ]. In addition, it
has been reported that leptin is able to restore ovarian cyclicity in women with
hypothalamic amenorrhea linked to conditions of energy defi cit [ 53 , 54 ]. In this
scenario, it is tenable (although yet to be proven) that exogenous kisspeptin might
conduct similar positive effects in affected humans, in good agreement with recent
data of acute LH responses to kisspeptin in women with hypothalamic amenorrhea
[ 55 ], and previous results in rodent models of subnutrition in puberty [ 20 ].
As fi nal note in this section, it is stressed that the above evidence does not pre-
clude that part of leptin effects on the GnRH system might be conducted in a
kisspeptin-independent manner. For instance, leptin receptor-expressing cells have
detected in the ventral premammillary nucleus (PMV). This area is a target for leptin
effects and, despite the lack of Kiss1 neurons at this site, seems to play an essential
role in conveying leptin effects onto GnRH neurons and, hence, the reproductive
axis [ 49 , 56 ]. Admittedly, however, it remains possible that PMV circuits and those
involving Kiss1 neurons, in other hypothalamic nuclei, may interplay/cooperate in
the central control of puberty and fertility by leptin and/or other metabolic cues.
Molecular Mediators and Developmental Aspects of Leptin/
Metabolic Control of the Kiss1 System
In spite of the ongoing debate on whether leptin acts, in some cases, directly on
Kiss1 neurons or modulate afferents to these neurons, putative molecular mediators
for such direct and/or indirect effects on the Kiss1 system have been exposed in
recent years. As example, the cellular energy sensor, mammalian target of rapamy-
cin (mTOR), which has been shown to operate as cellular metabolic gauge [ 57 - 61 ],
and mediator of some of the effects of leptin in the central control of food intake
[ 62 , 63 ], is likely involved in conveying part of the regulatory effects of leptin on the
reproductive brain, by virtue of its ability to regulate Kiss1 expression.
Persistent blockade of central mTOR signaling resulted in delayed puberty and
reduced LH levels; yet, gonadotropin responsiveness to key activators of the gonado-
tropic axis, such as kisspeptins, was preserved following mTOR blockade, suggesting
specifi city for these inhibitory effects. In the same vein, central inhibition of mTOR
signaling prevented the permissive/stimulatory effects of leptin on puberty onset, and
caused a substantial suppression of Kiss1 mRNA levels in key hypothalamic centers,
such as the ARC and (to a lesser extent) the AVPV. Conversely, activation of mTOR