Mechanistic Target of Rapamycin Signaling Activity in the Human Placenta Across Gestation and in Maternal Obesity.

Abstract

The mechanistic target of rapamycin (mTOR) system is vital to placental development, formation, and function. Alterations in this system in the placenta have been associated with altered fetal growth. However, changes in placental mTOR signaling across gestation are poorly understood. We collected 81 human placental samples from 4-40 weeks' gestation to test the hypothesis that placental mTOR signaling activity increases over gestation and is activated in maternal obesity in early gestation. Proteins involved in upstream mTOR regulation and mTORC1/2 downstream signaling were quantified using immunoblotting in placentas of male or female fetuses. Readouts of mTORC1 activation, phospho-rpS6 and phospho-4EBP1 were highest in first trimester and decreased across gestation. Phosphorylation of AKT (308 and 473) increased over gestation. Interestingly, abundance of cytochrome c oxidase I and mitochondrial ATP synthase, key subunits of mitochondrial complexes III/IV and V, respectively, were elevated in first trimester obese placentas compared to control, but only in placenta from female fetuses. We suggest that the high placental mTOR signaling activity in early pregnancy may be related to the high anabolism and active trophoblast proliferation and invasion in the second half of the first trimester. In addition, we conclude that maternal obesity has only limited impact on this key placental signaling pathway across gestation in women.