Fig. 4.

Roles of placental mTOR and OGT in maternal and fetal health. (A) Mechanistic target of rapamycin (mTOR) signaling is one of several key placental sensors integrating maternal signals and conveying information on the ability of the maternal supply line to deliver nutrients and oxygen to the placenta. mTOR is a master regulator of placental function including mitochondrial respiration, nutrient transport, protein synthesis and hormone secretion, thereby regulating fetal growth and development and impacting the long-term health of the offspring. Importantly, these regulatory loops can function in response to both maternal overnutrition and undernutrition to regulate fetal growth according to the available resources. (B) Placental OGT serves as a key cellular mechanism that senses available energy levels and dynamically alters placental function via multiple mechanisms to broadly regulate maternal homeostasis and impact transplacental signals important for fetal development. Importantly, OGT controls local trophoblast responses to a changing maternal environment where maternal stress hormones activate the glucocorticoid receptor (GR), reducing OGT levels. OGT is a key regulator of transcriptomic pathways via stabilization of the H3K27 methyl transferase EZH2. Reduced OGT results in decreases in EZH2 and the transcriptional repressive histone mark, H3K27me3. As OGT is X chromosome-linked, this transcriptomic regulation is much tighter in female XX trophoblast cells than male XY cells, resulting in dynamic placental responses and transplacental signals to the male fetus. A separate cellular signaling pathway links OGT to activation of annexin A1, an essential component in extracellular vesicle (EV) loading and secretion. EVs secreted by the placenta into maternal circulation contribute to homeostatic regulation, including maternal glucose levels in pregnancy. OGT, O-linked N-acetylglucosamine (O-GlcNAc) transferase; EZH2, enhancer of zeste homolog 2.