title: Cell proliferation and progesterone synthesis depend on lipid metabolism in bovine granulosa cells.
abstract: In dairy cows, lipids are essential to support energy supplies for all biological functions, especially during early lactation. Lipid metabolism is crucial for sustaining proper reproductive function. Alteration of lipid metabolism impacts follicular development and affects oocyte developmental competence. Indeed, nonesterified fatty acids are able to decrease granulosa cell (GC) proliferation and affect estradiol synthesis, thus potentially affecting follicular growth and viability. The objective of this study was to assess the impact of lipid metabolism on bovine GCs, through the use of the lipid metabolism inhibitors etomoxir, an inhibitor of fatty acid (FA) oxidation through inhibition of carnitine palmitoyl transferase 1 (CPT1), and C75, an inhibitor of FA synthesis through inhibition of fatty acid synthase. We showed that etomoxir and C75 significantly inhibited DNA synthesis in vitro; C75 also significantly decreased progesterone synthesis. Both inhibitors significantly reduced AMPK (5' adenosine monophosphate-activated protein kinase) and acetyl-CoA carboxylase phosphorylation. Etomoxir also affected the AKT (protein kinase B) signaling pathway. Combined, these data suggest that both FA oxidation and synthesis are important for the bovine GCs to express a proliferative and steroidogenic phenotype and, thus, for sustaining follicular growth. Despite these findings, it is important to note that the changes caused by the inhibitors of FA metabolism on GCs in vitro are globally mild, suggesting that lipid metabolism is not as critical in GCs as was observed in the oocyte-cumulus complex. Further studies are needed to investigate the detailed mechanisms by which lipid metabolism interacts with GC functions.
authors.affiliation: INRA, UMR 85 Physiologie de la Reproduction et des Comportements, Nouzilly, France; CNRS, UMR 7247 Physiologie de la Reproduction et des Comportements, Nouzilly, France; Université François Rabelais de Tours, UMR Physiologie de la Reproduction et des Comportements, Nouzilly, France; IFCE, UMR Physiologie de la Reproduction et des Comportements, Nouzilly, France. Electronic address: sebastien.elis@tours.inra.fr.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Elis
authors.affiliation: INRA, UMR 85 Physiologie de la Reproduction et des Comportements, Nouzilly, France; CNRS, UMR 7247 Physiologie de la Reproduction et des Comportements, Nouzilly, France; Université François Rabelais de Tours, UMR Physiologie de la Reproduction et des Comportements, Nouzilly, France; IFCE, UMR Physiologie de la Reproduction et des Comportements, Nouzilly, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Desmarchais
authors.affiliation: INRA, UMR 85 Physiologie de la Reproduction et des Comportements, Nouzilly, France; CNRS, UMR 7247 Physiologie de la Reproduction et des Comportements, Nouzilly, France; Université François Rabelais de Tours, UMR Physiologie de la Reproduction et des Comportements, Nouzilly, France; IFCE, UMR Physiologie de la Reproduction et des Comportements, Nouzilly, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Maillard
authors.affiliation: INRA, UMR 85 Physiologie de la Reproduction et des Comportements, Nouzilly, France; CNRS, UMR 7247 Physiologie de la Reproduction et des Comportements, Nouzilly, France; Université François Rabelais de Tours, UMR Physiologie de la Reproduction et des Comportements, Nouzilly, France; IFCE, UMR Physiologie de la Reproduction et des Comportements, Nouzilly, France.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Uzbekova
authors.affiliation: INRA, UMR 85 Physiologie de la Reproduction et des Comportements, Nouzilly, France; CNRS, UMR 7247 Physiologie de la Reproduction et des Comportements, Nouzilly, France; Université François Rabelais de Tours, UMR Physiologie de la Reproduction et des Comportements, Nouzilly, France; IFCE, UMR Physiologie de la Reproduction et des Comportements, Nouzilly, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Monget
authors.affiliation: INRA, UMR 85 Physiologie de la Reproduction et des Comportements, Nouzilly, France; CNRS, UMR 7247 Physiologie de la Reproduction et des Comportements, Nouzilly, France; Université François Rabelais de Tours, UMR Physiologie de la Reproduction et des Comportements, Nouzilly, France; IFCE, UMR Physiologie de la Reproduction et des Comportements, Nouzilly, France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Dupont
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002417:Cattle / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006107:Granulosa Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D050356:Lipid Metabolism; D010078:Oxazines; D011374:Progesterone / Q000096:biosynthesis*; D015398:Signal Transduction; D013194:Staining and Labeling
chemical_list: C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D010078:Oxazines; D011374:Progesterone; C054207:etomoxir; D015107:4-Butyrolactone; C044808:nile red
keywords: Dairy cows; Fatty acid oxidation; Granulosa cell; Lipid metabolism; Signaling pathway; Steroidogenesis