title: Unsaturated fatty acids disrupt Smad signaling in gonadotrope cells leading to inhibition of FSHβ gene expression.
abstract: Reproductive function is highly dependent on nutritional input. We recently provided evidence that the unsaturated ω6 fatty acid (FA), linoleic acid (linoleic), interferes with transcription and secretion of the gonadotropin LH, highlighting the existence of a lipid sensing in pituitary gonadotropes. Here, we show, using a combination of in vivo and in vitro models, that linoleic differentially regulates Lhb and Fshb expression. Central exposure of rats to linoleic over 7 days was associated with increase of Lhb but not Fshb transcript levels. Consistently, exposure of rat pituitary cells or LβT2 cells to linoleic increased Lhb, whereas it dramatically decreased Fshb transcript levels without affecting its stability. This effect was also induced by ω9 and ω3-polyunsaturated FA but not by saturated palmitic acid. Analysis of the underlying mechanisms in LβT2 cells using small interfering RNA revealed that early growth response protein 1 mediates linoleic stimulation of Lhb expression. Furthermore, we demonstrated that linoleic counteracts activin and bone morphogenetic protein-2 stimulation of Fshb expression. Using Western blotting and Smad-responsive reporter gene assays, linoleic was shown to decrease basal Smad2/3 phosphorylation levels as well as activin- and bone morphogenetic protein-2-dependent activation of Smad, uncovering a new FA-sensitive signaling cascade. Finally, the protein phosphatase magnesium-dependent 1A was shown to mediate linoleic inhibition of basal Smad phosphorylation and Fshb expression, identifying protein phosphatase magnesium-dependent 1A as a new target of FA in gonadotropes. Altogether, this study provides a novel mechanism by which FAs target gene expression and underlines the relevant role of pituitary gonadotropes in mediating the effects of nutritional FA on reproductive function.
authors.affiliation: Physiology of the Gonadotrope Axis (G.G., V.S., C.D., M.I., J.C.-T.), Nervous and Endocrine Regulation of Energy Homeostasis (C.R., C.M., S.M., C.C.-G.), and Molecular and Cellular Responses to Xenobiotics (J.D.), Université Paris-Diderot, Sorbonne Paris Cité, Biologie Fonctionnelle et Adaptative, Equipe d'Accueil Conventionnée par le Centre National de la Recherche Scientifique 4413, 75205 Paris Cedex 13, France.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Garrel
authors.forename: Violaine
authors.initials: V
authors.lastname: Simon
authors.forename: Chantal
authors.initials: C
authors.lastname: Denoyelle
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ishaq
authors.forename: Claude
authors.initials: C
authors.lastname: Rouch
authors.forename: Julien
authors.initials: J
authors.lastname: Dairou
authors.forename: Christophe
authors.initials: C
authors.lastname: Magnan
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Migrenne
authors.forename: Céline
authors.initials: C
authors.lastname: Cruciani-Guglielmacci
authors.forename: Joëlle
authors.initials: J
authors.lastname: Cohen-Tannoudji
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D037201:Follicle Stimulating Hormone, beta Subunit / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D052681:Gonadotrophs / Q000187:drug effects / Q000378:metabolism*; D019787:Linoleic Acid / Q000494:pharmacology*; D008297:Male; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051785:Smad Proteins / Q000378:metabolism*
chemical_list: D005231:Fatty Acids, Unsaturated; D037201:Follicle Stimulating Hormone, beta Subunit; D051785:Smad Proteins; D019787:Linoleic Acid