Compromised PPARγ Mediated Impaired Placental Glucose Transport via the PI3K/AKT Signaling Pathway is Associated with FGR.

Abstract

Fetal growth restriction (FGR) is a condition in which a fetus cannot grow to its full potential during pregnancy. It is a leading cause of perinatal mortality and morbidity. However, the underlying etiology remains elusive. Here, we report that peroxisome proliferator-activated receptor γ (PPARγ) is inactivated in the trophoblasts of human placenta of FGR-complicated pregnancies. In the FGR placentas, p-PI3K^Tyr458 and p-AKT^Ser473 levels were also lowered. Additionally, there was a reduction in GLUT3 and GLUT4 levels in the cell membrane. Consistently, FGR patients showed decreased glucose concentrations in both the placenta and umbilical cord blood compared to that in normal pregnancy. In mouse models, deletion of PPARγ in trophoblasts and RUPP surgery successfully induced FGR and replicated these changes. Modulating PPARγ activity using rosiglitazone or GW9662 in BeWo cells resulted in the activation or inhibition of the PI3K/AKT signaling pathway, as well as the promotion or reduction of membrane translocation of GLUT3 and GLUT4, ultimately affecting glucose uptake in trophoblast cells. MK-2206 blocked these regulatory effects of rosiglitazone in BeWo cells. Furthermore, the administration of rosiglitazone encapsulated in placenta-targeting nanoparticles improved the growth and development of fetal mice in the RUPP group. In summary, PPARγ in trophoblast cells orchestrates the translocation of GLUT3 and GLUT4 to the cellular membrane via the PI3K/AKT signaling pathway, thereby regulating cellular glucose uptake and transport. Dysfunctions in this mechanism are strongly associated with FGR. Therefore, targeted activation of PPARγ in the placenta may be a potentially efficacious intrauterine intervention for FGR.