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Submitted on March 14, 2005
Accepted on July 7, 2005
Unité de Physiologie de la Reproduction et des Comportements, Institut National de la Recherche Agronomique, 37380 Nouzilly, France.; Laboratory of molecular cancer biology, VIB 01, PRJ7, Technologiepark, 927 9052 Ghent, Belgium; U671 INSERM, Centre Biomédical des Cordeliers, 75270 Paris, France
* To whom correspondence should be addressed. 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 
1/2 subunits and the proteins are found in the ovaries. Immunohistochemistry localized the 1 AMPK subunit in granulosa cells, corpus luteum, oocyte, and less abundantly in theca cells. Treatment with AICAR (5-amino-imidazole-4-carboxyamide-1--D-ribofuranoside, 1 mM), an activator of AMPK, increased dose-dependent and time-dependent phosphorylation of AMPK1 on Thr 172 in primary granulosa cells. Simultaneously, phosphorylation of Acetyl-CoA Carboxylase at Ser-79 was also increased. AICAR treatment for 48 h halved progesterone secretion, 3-HSD protein and mRNA levels and phosphorylation of both basal MAPK ERK1/2 and p38 and in response to IGF-1 and/or FSH in granulosa cells. AICAR treatment (1 mM) had no detectable effect on basal and FSH- and/or IGF-1-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, 3-HSD protein production, and MAPK ERK1/2 and p38 phosphorylation. Moreover, we showed using specific inhibitors of ERK1/2 and p38 MAPK that the MAPK ERK1/2 and not p38 is involved in progesterone secretion and 3-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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