Downregulation of Placental Amino Acid Transporter Expression and mTORC1 Signaling Activity Contributes to Fetal Growth Retardation in Diabetic Rats

Abstract

Alterations in placental transport may contribute to abnormal fetal intrauterine growth in pregnancies complicated by diabetes, but it is not clear whether the placental amino acid transport system is altered in diabetic pregnancies. We therefore studied the changes in the expressions of placental amino acid transporters in a rat model of diabetes induced by streptozotocin, and tested the effects of hyperglycemia on trophoblast amino acid transporter in vitro. Our results showed that the expressions for key isoforms of system L amino acid transporters were significantly reduced in the placentas of streptozotocin-induced diabetic pregnant rats, which was associated with the decreased birthweight in the rats. A decreased placental efficiency and decreased placental mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activity were also found in the rat model. In addition, hyperglycemia in vitro could inhibit amino acid transporter expression and mTORC1 activity in human trophoblast. Inhibition of mTORC1 activity led to reduced amino acid transporter expression in placental trophoblast. We concluded that reduced placental mTORC1 activity during pregnancy resulted in decreased placental amino acid transporter expression and, subsequently, contributed to fetal intrauterine growth restriction in pregnancies complicated with diabetes.

Placental, Foetal, and Maternal Serum Metabolomic Profiles in Pregnancy-Associated Cancer: Walker-256 Tumour Model in a Time-Course Analysis

“…Thus, it has been shown that tumour growth during pregnancy can alter the regulation of pathways responsible for amino acid transport through the placenta, which occurs through the activation of p38 MAPK signalling [25,26]. In addition, mTORC1 regulates placental amino acid transport by modulating the isoforms of the system A and system L transporters on the surface of trophoblasts [27,28]. Based on the changes in metabolites observed, the tumour growth during pregnancy was able to decrease the availability of nutrients or alter placental cell activity, leading to foetal impairment.…”

Identification of tRNA-derived small RNAs and their potential roles in porcine skeletal muscle with intrauterine growth restriction

“…In addition, differentially expressed tsRNAs in normal-size and IUGR porcine skeletal muscle were mainly enriched in metabolic pathways, Rap1 signaling pathway, endocytosis, mTOR signaling pathway, and AMPK signaling pathway. It is known that energy metabolism and endocrine abnormalities are the main factors leading to IUGR ( Sharma et al, 2017 ), and the mTOR signaling pathway has been considered the core signaling pathway involved in IUGR ( Xu et al, 2020 ). In addition, signaling pathways and biological processes enriched with differentially expressed tsRNAs and highly expressed tsRNAs highly overlapped.…”

Epigenetic modifications of placenta in women with gestational diabetes mellitus and their offspring

“…The placental IR pathway is altered by hyperinsulinism and activates the downstream endothelial carbon monoxide synthase to stimulate increased placental angiogenesis[ 45 ], thereby affecting placental nutrient metabolism. Animal and in vitro experiments have shown that amino acid transport proteins are downregulated in offspring with growth restriction, and the activity of placental mTORC1 is reduced in STZ-induced GDM rat models, resulting in a decrease in L-system amino acid transport proteins in the placenta, which is associated with intrauterine growth restriction and a reduced birth weight[ 46 ]. It has also been found in human and in vitro experiments that IL-15 is upregulated in the placenta of GDM patients and promotes trophoblast proliferation in vitro through the JAK/STAT signaling pathway, which is negatively correlated with neonatal weight[ 47 ].…”