Leptin modulates the glucocorticoid-induced ovarian steroidogenesis

Leptin regulates food intake and other activities through its hypothalamic receptor. Leptin receptors are also found in other organs, including the ov ary. Direct effects of leptin in ovarian steroid production were studied in primary rat granulosa cells and in rat and human granulosa cell lines. Lep tin (0.6-18 nM) suppressed ovarian steroid synthesis costimulated by FSH an d dexamethasone. Production of pregnenolone, progesterone, and 20 alpha-hyd roxy-4-pregnen-3-one was inhibited by leptin. This inhibition was due at le ast in part to reduced expression of adrenodoxin, a component of the P450sc c system enzyme. Costimulation of progesterone production by forskolin and dexamethasone was also inhibited by leptin, whereas the forskolin-induced c AMP production was not affected. We find that leptin induces c-Jun expressi on and attenuates the transcriptional activity of the glucocorticoid recept or(GR) in granulosa cells. Elevation of c-Jun expression by other means, e. g. 12-O tetradecanoyl phorbol-13-acetate or transfecting with a c-Jun expre ssion vector, abolished the transcriptional activity of the GR. A leptin-in duced elevation of c-Jun modulates the transcriptional activity of the GR, possibly leading to the observed attenuation of steroidogenesis. It was rec ently shown that glucocorticoids stimulate leptin expression in vivo, which in turn, inhibits cortisol synthesis. A direct action of leptin on the ova ry is an additional element of a regulatory network that maintains the home ostasis of steroid production.