PPARs and mTOR interact in the rat decidua during early organogenesis

SABRINA LORENA ROBERTI; HUGO SATO; ROMINA HIGA; ALICIA JAWERBAUM

Puerto Varas

Congreso; VII Latin American Symposium on Maternal Fetal Interaction and Placenta (SLIMP); 2017

During embryoorganogenesis, before the establishment of a mature placenta, the decidua servesfor the embryonic histotrophic nutrition. Peroxisome proliferator activatedreceptors (PPARs) are nuclear receptors essential for development that regulatemetabolic processes. Mammalian target of rapamycin (mTOR) signaling is relevantin embryo nutrition and growth. Objectives:Aiming to assess whether PPARs and mTOR signaling pathways are interrelated inrat decidua during early organogenesis, we studied the effect of in vivo inhibition of mTOR, PPARg and PPARd signaling. Methods: Female Wistar rats received subcutaneousinjections of rapamycin (mTOR inhibitor), T0070907 (PPARg inhibitor), GSK0660 (PPARd inhibitor) or vehicle during days 7, 8, and 9 of pregnancy. On day 9,decidua was explanted and level of proteins phosphorylated by the mTORC1pathway (ribosomal protein S6 (RPS6) and eukaryotic initiation factor4E-binding protein 1 (4E-BP1)) and by the mTORC2pathway (glucocorticoid-inducible kinase 1 (SGK1)), as well as adipophilin (aPPAR target)) were evaluated by western blot. Results: Rapamycin administration increased decidua PPARg (36%, P<0.01,n = 7), PPARd (87%, P<0.001,n = 7) and adipophilin levels (26%, P<0.01,n = 7). Administration of T0070907 inhibited mTORC1 and mTORC2 signaling, asshown by the reduced levels of phosphorylated RPS6 (25%, P<0.05, n = 7) and SGK1 (50%, P<0.01, n = 7). Administration of GSK0660 inhibited mTORC2signalling, as shown by the reduced levels of phosphorylated SGK1 (53%, P<0.001, n = 7) but stimulated mTORC1signalling, as shown by the increased levels of phosphorylated 4EBP (73%, P<0.001, n = 7). Conclusions: A complex interaction of nutrient signaling pathwaysoccurs under mTOR, PPARg and PPARd inhibition, leading to stimulation or inhibition ofdecidua alternative pathways for embryo nutrition.