Critical role of mTOR, PPAR gamma and PPAR delta signaling in regulating early pregnancy decidual function, embryo viability and feto-placental growth

ROBERTI S; HIGA R; WHITE V; POWELL T; JANSSON T; JAWERBAUM A

MOLECULAR HUMAN REPRODUCTION.

OXFORD UNIV PRESS

Lugar: Oxford; Año: 2018 vol. 24 p. 327 - 340

1360-9947

STUDY QUESTION: Which are the consequences of inhibiting the mechanistic target of rapamycin (mTOR), peroxisome proliferator activated receptor (PPAR) gamma and PPARdelta pathways in the early post-implantation period on decidual function, embryo viability and feto-placental growth in the rat? SUMMARY ANSWER: mTOR inhibition from day 7 to day 9 of pregnancy in rats caused decidual PPARγ and PPARδ upregulation on day 9 of pregnancy and resulted in embryo resorption on day 14 of pregnancy. PPARgamma and PPARdelta inhibition differentially affected decidual mTOR signaling and levels of target proteins relevant to lipid histotrophic nutrition and led to reduced feto-placental weights on day 14 of pregnancy. WHAT IS KNOWN ALREADY: Although mTOR, PPARdelta and PPARgamma are nutrient sensors important during implantation, the role of these signaling pathways in decidual function and how they interact in the early post-implantation period are unknown. Perilipin 2 (PLIN2) and fatty acid binding protein 4 (FABP4), two adipogenic proteins involved in lipid histotrophic nutrition, are targets of mTOR and PPAR signaling pathways in a variety of tissues. STUDY DESIGN; SIZE; DURATION: Rapamycin (mTOR inhibitor, 0.75 mg/kg, sc), T0070907 (PPARgamma inhibitor, 0.001 mg/kg, sc), GSK 0660 (PPARdelta inhibitor, 0.1 mg/kg, sc) or vehicle was injected daily to pregnant rats from day 7 to 9 of pregnancy and the studies were performed on day 9 of pregnancy (n=7 per group) or day 14 of pregnancy (n=7 per group). PARTICIPANTS/MATERIALS, SETTING, METHODS: On day 9 of pregnancy, rat decidua were collected and prepared for Western Blot and immunohistochemical studies. On day 14 of pregnancy, the resorption rate, number of viable fetuses, crown-rump length and placental and decidual weights were determined. MAIN RESULTS AND THE ROLE OF CHANCE: Inhibition of mTOR in the early post-implantation period led to a reduction in FABP4 protein levels, an increase in PLIN2 levels and an upregulation of PPARγ and PPARδ in 9-day-pregnant rat decidua. Most embryos were viable on day 9 of pregnancy but had resorbed on day 14 of pregnancy. This denotes a key function of mTOR in the post-implantation period and suggests that activation of PPAR signaling was insufficient to compensate for impaired nutritional/survival signaling induced by mTOR inhibition. Inhibition of PPARγ signaling resulted in decreased decidual PLIN2 and FABP4 protein expression as well as in inhibition of decidual mTOR signaling in day 9 of pregnancy. This treatment also reduced feto-placental growth on day 14 of pregnancy, revealing the relevance of PPARgamma signaling in sustaining post-implantation growth. Moreover, following inhibition ofdeltaPPARδ, PLIN2 levels were decreased and mTOR complex1 and 2 signaling was altered in decidua on day 9 of pregnancy. On day 14 of pregnancy, PPARdelta inhibition caused reduced feto-placental weight, increased decidual weight and increased resorption rate, suggesting a key role of PPARdelta in sustaining post-implantation development. LARGE SCALE DATA: Not applicableLIMITATIONS, REASONS FOR CAUTION: This is an in vivo animal study and the relevance of the results for humans remains to be established. WIDER IMPLICATIONS OF THE FINDINGS:The early post-implantation period is a critical window of development and changes in the intrauterine environment may cause embryo resorption and lead to placental and fetal growth restriction. mTOR, PPARgamma and PPARdelta signaling are decidual nutrient sensors with extensive cross-talk that regulates adipogenic proteins involved in histotrophic nutrition and important for embryo viability and early placental and fetal development and growth. STUDY FUNDING/COMPETING INTERESTS: Funding was provided by the Agencia Nacional de Promoción Científica y Tecnológica de Argentina (PICT 2014-411 and PICT 2015-0130), and by the International Cooperation Grants CONICET-NIH-2014 and CONICET-NIH-2017 (AJ-TJ) The authors have no conflicts of interest