Diet-induced obesity alters the maternal metabolome and early placenta transcriptome and decreases placenta vascularity in the mouse†

Abstract

Maternal obesity is associated with an increased risk of obesity and metabolic disease in offspring. Increasing evidence suggests that the placenta plays an active role in fetal programming. In this study, we used a mouse model of diet-induced obesity to demonstrate that the abnormal metabolic milieu of maternal obesity sets the stage very early in pregnancy by altering the transcriptome of placenta progenitor cells in the preimplantation (trophectoderm [TE]) and early postimplantation (ectoplacental cone [EPC]) placenta precursors, which is associated with later changes in placenta development and function. Sphingolipid metabolism was markedly altered in the plasma of obese dams very early in pregnancy as was expression of genes related to sphingolipid processing in the early placenta. Upregulation of these pathways inhibits angiogenesis and causes endothelial dysfunction. The expression of many other genes related to angiogenesis and vascular development were disrupted in the TE and EPC. Other key changes in the maternal metabolome in obese dams that are likely to influence placenta and fetal development include a marked decrease in myo and chiro-inositol. These early metabolic and gene expression changes may contribute to phenotypic changes in the placenta, as we found that exposure to a high-fat diet decreased placenta microvessel density at both mid and late gestation. This is the first study to demonstrate that maternal obesity alters the transcriptome at the earliest stages of murine placenta development.

Maternal Overweight Downregulates MME (Neprilysin) in Feto-Placental Endothelial Cells and in Cord Blood

“…On the other hand, MME located at the cell membrane seems to participate in signaling events and has been shown to prevent FAK (focal adhesion kinase) activation and attenuates PKB (protein kinase B) signaling, causing reduced migration and angiogenesis (reviewed by Maguer-Satta et al [48]). Several reports describe distinct placental vascular structure as a result of obesity in human and animals, with either increased [49][50][51] or decreased [52][53][54] vascularity, suggesting that placental angiogenesis and vascular development is susceptible towards maternal metabolic and pro-inflammatory changes, but the effective result may depend on the specific situation, i.e., moderate vs. severe metabolic changes. In any event, altered angiogenesis in the placenta will generate distinct placental vascular structure and architecture, ultimately affecting hemodynamics.…”

Epigenetics and Epigenomics: Implications for Diabetes and Obesity

“…Maternal obesity in rodents increases adiposity in offspring via effects on both the maternal intrauterine environment and oocyte (47-50). Maternal obesity has an even greater impact on the developing placenta, altering transcription and metabolism, particularly within lipid metabolic pathways, and increasing inflammation (51).…”

Exercise prevents the adverse effects of maternal obesity on placental vascularization and fetal growth

“…The placental function is impaired as a result of maternal obesity (MO), which impedes vasculogenic/angiogenic development of the placenta (Stuart et al . ). Obesity and a high‐fat diet (HFD) intake further up‐regulate placental nutrient transporters, such as glucose transporter (GLUT)1 and GLUT3, and also stimulate the placental mammalian target of rapamycin complex 1 (mTORC1) signalling pathway, inducing placental and fetal overgrowth (Aye et al .…”