Gonadotrophin-releasing hormone (GnRH) is the main controller of the 
reproductive axis and stimulates the synthesis and secretion of gonadotrophins. 
Estrogen is the main peripheral factor controlling GnRH secretion, and this 
action is mainly mediated by the transsynaptic pathway through nitric oxide, 
kisspeptin, leptin, among other factors. Kisspeptin is the most potent factor 
known to induce GnRH release. Nitric oxide and leptin also promote GnRH release; 
however, neurons expressing GnRH do not express the leptin receptor (OB-R). 
Leptin seems to modulate the expression of genes and proteins involved in the 
kisspeptin system. However, few kisspeptin-synthesizing cells in the arcuate 
nucleus (ARC) and few cells, if any, in the preoptic area (POA) express OB-R; 
this indicates an indirect mechanism of leptin action on kisspeptin. Nitric 
oxide is an important intermediate in the actions of leptin in the central 
nervous system. Thus, this work aimed to verify the numbers of nNOS cells were 
activated by leptin in different hypothalamic areas; the modulatory effects of 
the nitrergic system on the kisspeptin system; and the indirect regulatory 
effect of leptin on the kisspeptin system via nitric oxide. Ovariectomized rats 
were treated with estrogen or a vehicle and received an intracerebroventricular 
(i.c.v.) injection of a nitric oxide donor, leptin or neuronal nitric oxide 
synthase (nNOS) enzyme inhibitor. Thirty minutes after the injection, the 
animals were decapitated. Leptin acts directly on nitrergic neurons in different 
hypothalamic regions, and the effects on the ventral premammillary nucleus (PMV) 
and ventral dorsomedial hypothalamus (vDMH) are enhanced. The use of a nitric 
oxide donor or the administration of leptin stimulates the expression of the 
kisspeptin mRNA in the ARC of animals with or without estrogenic action; 
however, these changes are not observed in the POA. In addition, the action of 
leptin on the expression of the kisspeptin mRNA in the ARC is blocked by a 
nitric oxide synthesis inhibitor. We concluded that the effects of leptin on the 
central nervous system are at least partially mediated by the nitrergic system. 
Also, nitric oxide acts on the kisspeptin system by modulating the expression of 
the kisspeptin mRNA, and leptin at least partially modulates the kisspeptin 
system through the nitrergic system, particularly in the ARC.