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Research Article |
Unité de Physiologie de la Reproduction et des Comportements,3 Institut National de la Recherche Agronomique, 37380 Nouzilly, France
U671 INSERM,4 Centre Biomédical des Cordeliers, 75270 Paris, France
ABSTRACT
Metformin is an anti-diabetic drug commonly used to treat cycle disorders and anovulation in women with polycystic ovary syndrome. However, the effects and molecular mechanism of metformin in the ovary are not entirely understood. We investigated the effects of this drug on steroidogenesis and proliferation in rat granulosa cells. Metformin (10 mM) treatment for 48 h reduced progesterone and estradiol (E2) production in both basal conditions and under FSH stimulation. It also decreased the levels of the HSD3B, CYP11A1, STAR, and CYP19A1 proteins in response to FSH (10–8 M) and of HSD3B in the basal state only. Metformin treatment (10 mM, 24 h) also reduced cell proliferation and the levels of CCND2 and CCNE proteins without affecting cell viability, both in the basal state and in response to FSH. Furthermore, metformin treatment for 1 h simultaneously increased the Thr172 phosphorylation of PRKAA (adenosine 5' monophosphate-activated protein kinase alpha) and the Ser79 phosphorylation of ACACA (acetyl-Coenzyme A carboxylase alpha). The adenovirus-mediated production of dominant-negative PRKAA totally abolished the effects of metformin on progesterone secretion, HSD3B and STAR protein production, and MAPK3/1 phosphorylation. Conversely, total inhibition of PRKAA Thr172 phosphorylation with the dominant-negative PRKAA adenovirus did not restore the decrease in E2 production and cell proliferation induced by metformin. Our results therefore strongly suggest that metformin reduces progesterone production via a PRKAA-dependent mechanism, whereas PRKAA activation is not essential for the decrease in E2 production and cell growth induced by metformin in rat granulosa cells.
adenosine 5', monophosphate-activated protein kinase, follicle-stimulating hormone, granulosa cells, kinases, mechanisms of hormone action, ovary, progesterone, steroid hormones
1 Supported by the Région Centre to L.T.
2 Correspondence. FAX: 33 2 47 42 77 43; jdupont{at}tours.inra.fr
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