Leptin Impairs the Synergistic Stimulation by Transforming Growth Factor-β of Follicle-Stimulating Hormone-Dependent Aromatase Activity and Messenger Ribonucleic Acid Expression in Rat Ovarian Granulosa Cells1

Leptin blocks the insulin-like growth factor-I-induced increase in FSH-dependent estradiol-17beta (E(2)) production by rat ovarian granulosa cells (GC) in vitro. To determine whether the leptin effect extended to another positive modulator of FSH-dependent E(2) production, the direct ovarian effects of leptin on transforming growth factor beta (TGF-beta) were investigated. Reverse transcription-polymerase chain reaction demonstrated that theca-interstitial cells (TIC) from hypophysectomized rats expressed only a nonsignal-transducing isoform (OB-Ra) of leptin receptor mRNA. Leptin had no effect on TIC androgen production. In contrast, mRNAs for OB-Ra and the signal-transducing (OB-Rb) leptin receptor isoforms were expressed in GC. When GC obtained from 26-day-old rats were cultured (48 h) with FSH and androstenedione, both estrone (E(1)) and E(2) levels increased over those in untreated controls. In the presence of FSH (0.1 IU/ml), TGF-beta (10 ng/ml) potentiated E(2) and E(1) accumulation by 2.7- and 1.45-fold, respectively. Leptin did not alter basal or FSH-stimulated E(2) and E(1) levels. However, leptin suppressed the effect of TGF-beta on FSH-dependent E(2) and E(1) production by 39% and 29%, respectively. Aromatase cytochrome P450 (P450(arom)) mRNA expression and P450(arom) activity were increased by FSH and further augmented by the addition of TGF-beta. Leptin abolished the TGF-beta effect on P450(arom) mRNA expression, and it decreased P450(arom) activity by approximately 27%. These data support the hypothesis that leptin antagonizes the stimulatory effects of TGF-beta on FSH-dependent estrogen production by a mechanism involving the leptin-induced attenuation of P450(arom) activity and mRNA expression in GC.