Effects of placental mTOR alteration on the pancreatic beta cell mass of embryonic day 17.5 mice

Abstract

The fetal environment during development is a strong determinant for health in adulthood. Pancreatic beta cells development in-utero has an important role in the predisposition to Type 2 Diabetes (T2D). The pancreatic endocrine cells are highly sensitive to nutrient flux during development and very early in life. Clinical studies suggest that signaling of mechanistic target of rapamycin (mTOR) in the placenta regulates fetal birth weight and the offsprings’ metabolic course, partly by modulating maternal to fetal nutrient flux.This study aims at exploring the link between placental mTOR activity and beta cell mass at embryonic day (e) 17.5, a gestational period in which beta cells become more abundant in the pancreatic islets. Pancreatic beta cells are known to be impacted by amino acid (AA) levels during development. We hypothesized that alteration of mTOR in the placenta will affect AA transporters (which are essential for amino acid transport for beta cell growth in-utero), thus affecting the gestational growth and development of beta cells in the offspring. Within beta cells, AAs promote mTOR signaling, which regulates cell growth, proliferation, and protein synthesis. We tested our hypothesis by genetically deleting mTOR or activating mTORC1, via deletion of its negative regulator, Tuberous Sclerosis Complex (TSC2), in placental trophoblast cells using placental-specific Cre recombinase, and by characterizing the effects of placental mTOR on pancreas morphology at e17.5. Interestingly, we revealed that the placental-specific knock out of mTOR led to an increase in protein expression of amino acid transporter SNAT-1 and beta cell mass in e17.5 female offspring. However, the placental-specific knock out of TSC2 showed no effect on total beta cell mass of e17.5 embryos. These results suggest that placental mTOR may regulate AA flux to the growing pancreas, but additional experiments are needed to better understand amino acid placental functions and its effects on pancreatic progenitors and beta cell development.