Ovarian signalling pathways regulated by leptin during the ovulatory process.

Leptin, a protein secreted by different tissues, is able to exert both stimulatory and inhibitory effects on the ovulatory process. Thus, we investigated whether these opposite effects involve changes in the ovarian signalling pathways in response to different levels of leptin. To this end, we performed both in vivo and in vitro assays using immature rats primed with gonadotrophins to induce ovulation. The acute treatment with leptin, which inhibits the ovulatory process, caused a significant decrease in the phosphorylation of both STAT3 and ERK1/2 and a simultaneous increase in suppressors of cytokine signalling 3 (SOCS3) protein. However, daily administration of a low dose of leptin, which induces the ovulatory process, showed increased phosphorylation of both STAT3 and ERK1/2 and a decreased expression of SOCS3 protein. Using ovarian explant cultures, we also found that leptin was able to activate both STAT3 and ERK1/2 at 10 ng/ml but only STAT3 at 300-500 ng/ml. In addition, at 100-300 ng/ml, leptin increased protein but not mRNA expression of SOCS3. The addition of specific inhibitors of JAK/STAT and MAPK signalling pathways suppressed both the increase and the decrease in leptin-induced progesterone secretion. These results indicate that i) different levels of leptin are able to regulate STAT3, ERK1/2 and SOCS3 at both intra- and extra-ovarian level and that ii) the dual action of leptin on steroidogenesis seems to occur, at least in part, through both the ERK and STAT cascades.