OR04-5 Unsaturated fatty acids strongly inhibit Fshb gene expression by counteracting Activin and BMP2 signaling in rat pituitary and LβT2 gonadotrope cell line

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR04-GnRH & Gonadotroph Biology & Signaling
Basic/Translational
Saturday, June 15, 2013: 11:30 AM-1:00 PM
Presentation Start Time: 12:30 PM
Room 135 (Moscone Center)
Joelle Cohen-Tannoudji*, Violaine Simon, Chantal Denoyelle, Muhammad Ishaq and Ghislaine Garrel
University Paris 7, France
We have recently shown using a rat model of central lipid overload combined with in vitro studies on gonadotrope cells that unsaturated fatty acids (UFA) directly act on rodent pituitary to stimulate Lhb subunit gene expression and LH secretion, providing the first demonstration of a pituitary “lipid sensing” (1). Unexpectedly, we report here that UFA regulate FSH expression in an opposite manner. Indeed, kinetics studies using linoleate in primary cultures of rat pituitary cells revealed that the Lhb transcript increase was concomitant with a dramatic decrease of Fshb transcript. A 4 h-treatment with 200 microM linoleate dose-dependently reduced Fshb transcript levels in LbetaT2 gonadotrope cell line and rat pituitary cell cultures, with a maximum of 60 to 80% inhibition depending on the cell model. In contrast, the saturated fatty acid palmitate was ineffective. Because activin and Bone-Morphogenetic Protein 2 (BMP2) are major regulators of Fshb gene expression in gonadotrope cells, we wondered whether linoleate could interfere with the signaling of these hormones. Interestingly, in both cellular models, linoleate counteracted by about 50% the strong stimulatory effect of activin and BMP2 on Fshb gene expression. Analysis of the underlying mechanisms in LbetaT2 cells revealed that linoleate treatment decreased Smad recruitment by activin and BMP2. This was evidenced by a reduced phosphorylation of Smad2/3 and Smad1/5/8 in response to activin and BMP2, respectively. Linoleate also impaired basal phosphorylation level of Smad2/3. Altogether, this suggests that linoleate regulate Smad-specific phosphatases in gonadotrope cells. We also demonstrated that linoleate significantly increased (~50%) follistatin transcript levels, suggesting that neutralization of activin and BMP2 by an excess of follistatin contributes to reduced Fshb gene expression. This works highlights for the first time, the ability of UFA to differentially regulate the expression of the two gonadotropin beta-subunit genes. This suggests that UFA may disturb reproductive function by altering the balance between gonadotropin hormones. Altogether, our study underlines the relevant role of pituitary in the sensing of nutritional information and especially nutrients.

(1) Garrel G et al., Endocrinology 2011; 152 (10):3905.

Nothing to Disclose: JC, VS, CD, MI, GG

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