Metabolic Regulation of Kisspeptin - Kisspeptin Signaling in Reproductive Biology - page 367

does not appear to signifi cantly contribute to the regulation of Kiss1 expression, as
suggested by studies in models of diabetic male rats centrally infused with insulin,
which displayed persistently reduced Kiss1 mRNA levels despite insulin adminis-
tration (see Fig. 17.3 ). In addition, insulin failed to stimulate Kiss1 expression in the
hypothalamic cell line, N6, in vitro [ 23 , 24 ].
Kisspeptins and the Control of Food Intake
and Energy Balance: Physiological Relevance?
Recent evidence suggests that, in addition to their primary roles in the control of the
reproductive axis, kisspeptins might also participate in the central networks control-
ling food intake and energy balance. Indeed, bidirectional interactions between the
systems governing energy homeostasis and the HPG axis have been reported for a
large number of neuropeptides and hormones [ 4 ]. Accordingly, initial studies
addressing the roles of kisspeptins in the metabolic control of reproduction evalu-
ated also the potential impact of kisspeptins on food intake and body weight. Yet,
those analyses failed to demonstrate any signifi cant change in the patterns of food
intake or the hypothalamic expression of relevant genes in the control of energy
balance, such as NPY, POMC, Agouti-related peptide (AgRP), and CART, after
central administration of kisspeptin [ 20 , 77 ]. These results questioned the physio-
logical contribution of kisspeptin signaling in the central pathways controlling
energy homeostasis.
This contention, however, has been challenged by recent electrophysiological
analyses that have documented the ability of kisspeptin-10 to activate the popula-
tion of anorexigenic POMC neurons, and to inhibit the orexigenic NPY neurons in
the ARC in rodents [ 78 ]. As complementary fi nding, central injection of kisspeptin
have been shown to suppress nocturnal food intake in mice [ 79 ]. As a whole, the
above data would suggest that, under specifi c conditions, kisspeptins may operate
also as feeding suppressing signals, probably via activation ARC POMC neurons,
which do express Gpr54. While this possibility is appealing, further experimental
analyses, including the assessment of the specifi c roles of Gpr54 signaling in POMC
neurons, are needed in order to confi rm or refute this possibility, and to explain
discrepancies between previous and recent literature.
As fi nal note, it is stressed here that estrogens, which are proven regulators of
central Kiss1 expression [ 37 ], are potent food-intake suppressor signals acting in
different hypothalamic nuclei, so that ovariectomy causes a rapid increase in body
weight in rodents. Very recently, using a toxic ablation approach, Rance and col-
laborators evaluated the consequences of elimination of Kiss1 neurons in the ARC,
which co-express the neuropeptide, neurokinin-B, and its receptor, NK3R, on the
effects of estrogen upon the negative feedback control of gonadotropin secretion
[ 80 ]. Curiously enough, in that study ablation of ARC Kiss1 neurons abolished the
effects of gonadectomy (increase) and estrogen (reduction) on body weight. This
observation would suggest that the integrity of ARC kisspeptin pathways is necessary