Maternal overweight induced by a diet with high content of saturated fat activates placental mTOR and eIF2α signaling and increases fetal growth in rats.

Abstract

The mammalian target of rapamycin (mTOR) and the eukaryotic initiation factor 2 (eIF2) signaling pathways control protein synthesis in response to nutrient availability. Moreover mTOR is a positive regulator of placental nutrient transport and is involved in the regulation of fetal growth. We hypothesized that maternal overweight, induced by a diet with high saturated fat content: i) up-regulates placental mTOR activity and nutrient transport resulting in fetal overgrowth; ii) inhibits phosphorylation of eIF2 at its alpha subunit (eIF2alpha) and iii) leads to placental inflammation. Albino Wistar female rats were fed a control or high saturated fat (HF) diet for 7 weeks before mating and during pregnancy. At Gestational Day 21 the HF diet significantly increased maternal and fetal triglyceride, leptin and insulin (but not glucose) levels, maternal and fetal weights, and placental weights trended to increase. Phosphorylated 4EBP1 (T37/46 and S65) was significantly higher and phosphorylated rpS6 (S235/236) trended to increase in the placentas of dams fed a HF diet, indicating an activation of mTOR Complex 1 (mTORC1). Phosphorylation of AMPK and eIF2alpha was reduced in the HF diet group compared to the control. The expression and activity of placental nutrient transporters and lipoprotein lipase (LPL), as well as the activation of inflammatory pathways were not altered by the maternal diet. We conclude that maternal overweight induced by a HF diet stimulates mTORC1 activity and decreases eIF2alpha phosphorylation in rat placentas. We speculate that these changes may up-regulate protein synthesis and contribute to placental and fetal overgrowth.