Placental mitochondrial respiration is inhibited in mice with trophoblast specific AdipoR2 overexpression
Hiroshi Shimada1, Toshihide Sakuragi2, Kenneth Barentsen3
1Department of Obstetrics and Gynecology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA; Department of Obstetrics & Gynecology, Sapporo Medical University, Sapporo, Japan.
Maternal circulating levels of adiponectin are inversely correlated with fetal growth mediated by its effect on placental function. The cellular effects of adiponectin on trophoblast are mainly mediated by adiponectin receptor isoform 2 (AdipoR2) resulting in the activation of PPARα and synthesis of ceramides, which inhibit insulin and mTOR signaling. We have recently demonstrated that trophoblast-specific overexpression of AdipoR2 in pregnant mice inhibits placental mTORC1 signaling and nutrient transport, resulting in fetal growth restriction. Trophoblast mTORC1 signaling is a positive regulator of mitochondrial respiration. However, it is unknown if placental adiponectin signaling is mechanistically linked to mitochondrial function. We hypothesized that trophoblast-specific overexpression of AdipoR2 in pregnant mice decreases placental oxidative phosphorylation. At Embryonic day (E) 3.5, blastocysts from super-ovulated, time-mated B6D2F1 female mice were collected and transduced with lentivirus constructs for AdipoR2-overexpression (AdipoR2-OX) or scramble (SCR) sequences. The blastocysts were surgically transferred to pseudo-pregnant CD-1 recipient dams. Following euthanasia at E18.5, we separated the labyrinth and the junctional zone. In the labyrinth, AdipoR2 overexpression significantly inhibited placental mitochondrial GMPP respiration as determined by high-resolution respirometry. Moreover, placental AdiopoR2-OX decreased GLUD1, TOM22 and PGC1α protein expression. In the junctional zone, we found no significant differences between control (SCR) and AdipoR2-OX groups. In conclusion, our data suggests that maternal adiponectin signaling in the trophoblast decreases placental mitochondrial respiration, specifically in the labyrinth zone. This effect is possibly mediated by inhibition of mTORC1 and decreased expression of PGC1α.
Maternal circulating levels of adiponectin are inversely correlated with fetal growth mediated by its effect on placental function. The cellular effects of adiponectin on trophoblast are mainly mediated by adiponectin receptor isoform 2 (AdipoR2) resulting in the activation of PPARα and synthesis of ceramides, which inhibit insulin and mTOR signaling. We have recently demonstrated that trophoblast-specific overexpression of AdipoR2 in pregnant mice inhibits placental mTORC1 signaling and nutrient transport, resulting in fetal growth restriction. Trophoblast mTORC1 signaling is a positive regulator of mitochondrial respiration. However, it is unknown if placental adiponectin signaling is mechanistically linked to mitochondrial function. We hypothesized that trophoblast-specific overexpression of AdipoR2 in pregnant mice decreases placental oxidative phosphorylation. At Embryonic day (E) 3.5, blastocysts from super-ovulated, time-mated B6D2F1 female mice were collected and transduced with lentivirus constructs for AdipoR2-overexpression (AdipoR2-OX) or scramble (SCR) sequences. The blastocysts were surgically transferred to pseudo-pregnant CD-1 recipient dams. Following euthanasia at E18.5, we separated the labyrinth and the junctional zone. In the labyrinth, AdipoR2 overexpression significantly inhibited placental mitochondrial GMPP respiration as determined by high-resolution respirometry. Moreover, placental AdiopoR2-OX decreased GLUD1, TOM22 and PGC1α protein expression. In the junctional zone, we found no significant differences between control (SCR) and AdipoR2-OX groups. In conclusion, our data suggests that maternal adiponectin signaling in the trophoblast decreases placental mitochondrial respiration, specifically in the labyrinth zone. This effect is possibly mediated by inhibition of mTORC1 and decreased expression of PGC1α.
