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Endocrinology Vol. 140, No. 4 1731-1738
Copyright © 1999 by The Endocrine Society

ARTICLES

Leptin Modulates the Glucocorticoid-Induced Ovarian Steroidogenesis1

Dalit Barkan, Hui Jia, Ada Dantes, Lily Vardimon, Abraham Amsterdam2 and Menachem Rubinstein3

Department of Molecular Genetics (D.B., M.R.), Weizmann institute of Science, Rehovot 76100, Israel; Department of Molecular Cell Biology (H.J., A.D., A.A.), Weizmann institute of Science, Rehovot 76100, Israel; and Department of Biochemistry (L.V.), Tel Aviv University, Tel Aviv 69978, Israel

Address all correspondence and requests for reprints to: Prof. Menachem Rubinstein, Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel. E-mail: lvrub{at}weizmann.weizmann.ac.il

Leptin regulates food intake and other activities through its hypothalamic receptor. Leptin receptors are also found in other organs, including the ovary. Direct effects of leptin in ovarian steroid production were studied in primary rat granulosa cells and in rat and human granulosa cell lines. Leptin (0.6–18 nM) suppressed ovarian steroid synthesis costimulated by FSH and dexamethasone. Production of pregnenolone, progesterone, and 20{alpha}-hydroxy-4-pregnen-3-one was inhibited by leptin. This inhibition was due at least in part to reduced expression of adrenodoxin, a component of the P450scc system enzyme. Costimulation of progesterone production by forskolin and dexamethasone was also inhibited by leptin, whereas the forskolin-induced cAMP production was not affected. We find that leptin induces c-Jun expression and attenuates the transcriptional activity of the glucocorticoid receptor (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 expression vector, abolished the transcriptional activity of the GR. A leptin-induced elevation of c-Jun modulates the transcriptional activity of the GR, possibly leading to the observed attenuation of steroidogenesis. It was recently shown that glucocorticoids stimulate leptin expression in vivo, which in turn, inhibits cortisol synthesis. A direct action of leptin on the ovary is an additional element of a regulatory network that maintains the homeostasis of steroid production.




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