title: Induction of Gnrh mRNA expression by the ω-3 polyunsaturated fatty acid docosahexaenoic acid and the saturated fatty acid palmitate in a GnRH-synthesizing neuronal cell model, mHypoA-GnRH/GFP.
abstract: Gonadotropin-releasing hormone (GnRH) neurons coordinate reproduction. However, whether GnRH neurons directly sense free fatty acids (FFAs) is unknown. We investigated the individual effects of the FFAs docosahexaenoic acid (DHA), palmitate, palmitoleate, and oleate (100 μM each) on Gnrh mRNA expression in the mHypoA-GnRH/GFP neuronal cell model. We report that 2 h exposure to palmitate or DHA increases Gnrh transcription. Using the inhibitors AH7614, K252c, U0126, wortmannin, and LY294002, we demonstrate that the effect of DHA is mediated through GPR120 to downstream PKC/MAPK and PI3K signaling. Our results indicate that the effect of palmitate may depend on palmitoyl-coA synthesis and PI3K signaling. Finally, we demonstrate that both DHA and palmitate increase Gnrh enhancer-derived RNA levels. Overall, these studies provide evidence that GnRH neurons directly sense FFAs. This will advance our understanding of the mechanisms underlying FFA sensing in the brain and provides insight into the links between nutrition and reproductive function.
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Dean Q
authors.initials: DQ
authors.lastname: Tran
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Ernesto H
authors.initials: EH
authors.lastname: Ramos
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Obstetrics and Gynaecology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: d.belsham@utoronto.ca.
authors.forename: Denise D
authors.initials: DD
authors.lastname: Belsham
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000096:biosynthesis / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D019308:Palmitic Acid / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology
chemical_list: C498007:FFAR4 protein, mouse; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D004281:Docosahexaenoic Acids; D019308:Palmitic Acid; D007987:Gonadotropin-Releasing Hormone
keywords: Cell biology; Free fatty acids; Gene expression; GnRH; Neuroendocrine; Signal transduction