RESUMO
Kisspeptin and its receptor GPR54 have been described as key hypothalamic components in the regulation of GnRH secretion. Kisspeptin is also present in several regions of the central nervous system and the peripheral organs and has recently been identified in the superior ganglion. Herein, we tested the possibility that ovarian kisspeptin is regulated by the sympathetic nervous system and participates locally in the regulation of ovarian function. Both ovarian and celiac ganglion kisspeptin mRNA levels increase during development, whereas kisspeptin peptide levels and plasma levels decrease during development. In the celiac ganglion, kisspeptin colocalized with tyrosine hydroxylase, indicating potential kisspeptin synthesis and transport within the sympathetic neurons. A continuous (64 h) cold stress induced marked changes within the kisspeptin neural system along the celiac ganglion-ovary axis. In vitro incubation with the ß-adrenergic agonist isoproterenol increased ovarian kisspeptin mRNA and peptide levels, and this increase was inhibited by treatment with the ß-antagonist propranolol. Sectioning the superior ovarian nerve altered the feedback information within the kisspeptin celiac ganglion-ovary axis. In vivo administration of a kisspeptin antagonist to the left ovarian bursa of 22- to 50-d-old unilaterally ovariectomized rats delayed the vaginal opening, decreased the percentage of estrous cyclicity, and decreased plasma, ovarian, and celiac ganglion kisspeptin concentrations but did not modify the LH plasma levels. These results indicate that the intraovarian kisspeptin system may be regulated by sympathetic nerve activity and that the peptide, either from a neural or ovarian origin, is required for proper coordinated ovarian function.
Assuntos
Ciclo Estral/efeitos dos fármacos , Gânglios Simpáticos/efeitos dos fármacos , Kisspeptinas/antagonistas & inibidores , Rede Nervosa/efeitos dos fármacos , Ovário/inervação , Maturidade Sexual/efeitos dos fármacos , Animais , Ciclo Estral/fisiologia , Feminino , Gânglios Simpáticos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Kisspeptinas/genética , Kisspeptinas/metabolismo , Rede Nervosa/metabolismo , Ovário/efeitos dos fármacos , Ovário/metabolismo , Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Maturidade Sexual/fisiologia , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Vagina/metabolismoRESUMO
In rat ovary chronic cold stress increases sympathetic nerve activity, modifies follicular development, and initiates a polycystic condition. To see whether there is a relationship between the previously described changes in follicular development and metabolic changes similar to those in women with polycystic ovary, we have studied the effect of chronic cold stress (4 degrees C for 3 h/day, Monday to Friday, for 4 wk) on insulin sensitivity and the effect of insulin on sympathetic ovarian activity. Although cold-stressed rats ate more than the controls, they did not gain more weight. Insulin sensitivity, determined by hyperinsulinemic-euglycemic clamp, was significantly increased in the stressed animals. Insulin in vitro increased the basal release of norepinephrine from the ovaries of control rats but not from those of stressed rats, suggesting a local neural resistance to insulin in stressed rats. The levels of mRNA and protein for IRS1 and SLC2A4 (also known as GLUT4), molecules involved in insulin signaling, decreased significantly in the ovaries but not in the muscle of stressed rats. This decrease was preferentially located in theca-interstitial cells compared with granulosa cells, indicating that theca cells (the only cells directly innervated by sympathetic nerves) are responsible for the ovarian insulin resistance found in stressed rats. These findings suggest that ovarian insulin resistance produced by chronic stress could be in part responsible for the development of the polycystic condition induced by stress.