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Adenosine 5'-Monophosphate-Activated Protein Kinase Regulates Progesterone Secretion in Rat Granulosa Cells

Unité de Physiologie de la Reproduction et des Comportements (L.T., P.S., J.D.), Institut National de la Recherche Agronomique, 37380 Nouzilly, France; Laboratory of Molecular Cancer Biology (P.Fr.), Technologiepark, 927 9052 Ghent, Belgium; and Unité 671 Institut National de la Santé et de la Recherche Médicale (P.Fe., F.F.), Centre Biomédical des Cordeliers, 75270 Paris, France

Address all correspondence and requests for reprints to: Joëlle Dupont, Ph.D., Unité de Physiologie de la Reproduction et des Comportements, Institut National de la Recherche Agronomique, Nouzilly, 37380, France. E-mail: jdupont{at}tours.inra.fr.

The AMP-activated protein kinase (AMPK) is a major regulator of energy metabolism involved in fatty acid and cholesterol synthesis. In the ovary, cholesterol plays a key role in steroid production. We report the presence of AMPK in rat ovaries, and we have investigated its role in granulosa cells. We show using RT-PCR and Western blot that the mRNAs for the 1/2 and ß1/2 subunits and the proteins are found in the ovaries. Immunohistochemistry localized the 1 AMPK subunit in granulosa cells, corpus luteum, and oocyte and less abundantly in theca cells. Treatment with 1 mM 5-amino-imidazole-4-carboxyamide-1-ß-D-ribofuranoside (AICAR), an activator of AMPK, increased dose-dependent and time-dependent phosphorylation of AMPK1 on Thr172 in primary granulosa cells. Simultaneously, phosphorylation of acetyl-coenzyme A carboxylase at Ser79 was also increased. AICAR treatment for 48 h halved progesterone secretion, 3ß-HSD protein and mRNA levels, and phosphorylation of both basal MAPK ERK1/2 and p38 and in response to IGF-I and/or FSH in granulosa cells. AICAR treatment (1 mM) had no detectable effect on basal and FSH- and/or IGF-I-induced estradiol production and on granulosa cell proliferation or viability. Adenovirus-mediated expression of dominant negative AMPK totally abolished the effects of AICAR on progesterone secretion, 3ß-HSD protein production, and MAPK ERK1/2 and p38 phosphorylation. Moreover, we showed using specific in- hibitors of ERK1/2 and p38 MAPK that the MAPK ERK1/2 and not p38 is involved in progesterone secretion and 3ß-HSD expression, strongly suggesting that the activation of AMPK in response to AICAR reduces progesterone production through the MAPK ERK1/2 signaling pathway in rat granulosa cells.

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