Background: During pregnancy, the mother must adapt metabolically to support offspring growth. The placenta secretes hormones with metabolic effects, although the precise role of its endocrine function in determining maternal health is largely unknown. Previous work has shown that the imprinted Igf2-H19 locus is involved in controlling placental endocrine function and conceptus development in mice. This study used conditional mis-expression of the Igf2-H19 locus, through deletion of the imprinting control region ICR1, to induce placental endocrine malfunction and study its consequences for maternal metabolism.
Methods: Transgenic mice were crossed to produce entire litters with reduced levels of the H19 gene and activation of the normally silent maternal Igf2 gene in the placental endocrine zone (H19DMRflox/TpbpaCre; Jz-ICR1D). On day 16 of gestation, maternal blood was collected for metabolite analysis, maternal liver for RNAseq analysis, and placentas collected for endocrine cell culture experiments followed by LC-MS on the conditioned media. Data were compared to dams with unaltered placental Igf2-H19 locus expression.
Results: Jz-ICR1D dams had heavier kidney, heart and liver weights compared to pregnant controls. They also displayed higher circulating levels of glucose, insulin, LDL-cholesterol, leptin, progesterone, estradiol and corticosterone. RNAseq analysis showed that genes involved in translation, mitochondrial homeostasis and response to oxidative stress, among others were affected in the maternal liver by Jz-ICR1D. Circulating AST, which indicates liver damage, was lower in dams with Jz-ICR1D. A total of 744 proteins were identified in the media from placental endocrine cell cultures, of which 92 were exclusively detected in the Jz-ICR1D group with 30 previously identified to be secreted. The placental endocrine zone was increased by Jz-ICR1D, but maternal plasma IGF2 and fetal growth were unchanged.
Conclusion: Genetically-induced expansion of the placental endocrine zone alters maternal body composition and whole-body metabolic function in pregnancy.