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Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama City 700-8558, Japan

(Requests for offprints should be addressed to F Otsuka; Email: fumiotsu{at}md.okayama-u.ac.jp)

Involvement of peroxisome proliferator-activated receptor- (PPAR- ) activation and bone morphogenetic protein (BMP) signaling in regulating cell proliferation and hormonal production of pituitary tumors has been reported, although the underlying mechanism remains poorly understood. Here, we investigated regulatory roles of PPAR and PPAR in gonadotropin transcription and cell mitosis modulated by pituitary activin/BMP systems using a mouse gonadotropinoma cell line Lß T2, which expresses activin/BMP receptors, transcription factor Smads, PPAR , and PPAR . In Lß T2 cells, BMP signaling shown by Smad1/5/8 phosphorylation and Id-1 transcription was readily activated by BMPs. A PPAR agonist, pioglitazone significantly reduced BMP-induced DNA synthesis by Lß T2; whereas the PPAR agonist, fenofibric acid, did not. In accordance with the effects on cell mitosis, pioglitazone but not fenofibric acid significantly decreased BMP-induced Id-1-Luc activation. Neither fenofibric acid nor pioglitazone affected activin signaling detected by (CAGA)⁹-Luc activity. Both PPAR and PPAR ligands directly suppressed transcriptional activities of FSHß , LHß , and GnRHR. Activation of PPAR and PPAR increased mRNA levels of follistatin, but did not affect the expression of follistatin-related gene. Thus, PPAR agonists not only directly suppress gonadotropin transcription and BMP signaling, but also inhibit the biological actions of activins which facilitate gonadotropin transcription through upregulating follistatin expression. In addition, pioglitazone increased BMP ligands mRNA, but decreased activin-ß B mRNA in Lß T2 cells. Collectively, PPAR activation differentially regulates gonadotrope cell proliferation and gonadotropin transcription in a ligand-dependent manner.

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