175-LB: Altered Glycogen Cell Number in Placental mTOR Signaling Deficiency Model in Mice

Abstract

Fetal Growth Restriction (FGR) is a determinant for the development of chronic diseases, such as type II diabetes in adulthood. FGR is caused by the failure of the placenta to provide adequate nutrients and oxygen for fetal development. mTOR regulates cell metabolism and growth, and it is reduced in the FGR placenta. We previously reported that placental mTOR ablation induces insulin resistance and glucose intolerance in adult mice. We hypothesize that mTOR signaling regulates glucose utilization in the placenta, which stores glucose reservoirs as glycogen. Appropriate localization and breakdown of glycogen cells is crucial for normal fetal growth. We leveraged our mouse model lacking placental mTOR signaling to ask whether glycogen cell number was altered. First, we found that critical glycogenesis and glycogenolysis enzymes, as well as the glucagon receptor, were expressed in placental tissue, indicating the capability for glycogen cell synthesis and breakdown, like glycogen-rich tissues such as the liver. Next, we show increased glycogen cell counts in the junctional zone of the mTORKO placenta compared to littermate controls by IHC. However, whole placental glycogen content, measured by ELISA, demonstrates no changes between KO and control. These data suggest that mTOR signaling modulates the localization and migration of glycogen cells during high metabolic needs. Glucagon mRNA is expressed in the placenta, with significant increases in the male KO placenta, indicating the placenta may produce its own glucagon. However, IHC staining indicates increased glucagon levels in female KO placenta in the labyrinth zone. Together, these data suggest that the placenta may have the capability to regulate its own glycogen breakdown by altering glucagon expression. Our results indicate that the FGR placenta induced by mTOR deletion has altered glycogen cell content and mislocalization, which mimics the phenotypes of placenta impacted by gestational diabetes, suggesting a shared mechanistic pathway. Disclosure B. Clifton: None. M. Beetch: None. E. Alejandro: None. Funding National Institutes of Health (R01DK115720)