Maternal obesity disrupts trophoblast differentiation and causes female-specific labyrinth defects in the mouse placenta.

Maternal obesity (MO) alters the intrauterine environment and increases the risk of a variety of developmental outcomes; however, the effects on placental cell population and development remain unclear. In this study, we investigated the impact of MO on placental cellular composition, development, and morphology in C57BL/6J mice fed a control or high-fat diet. Single-cell RNA sequencing of embryonic day (E) 13.5 placentas identified 16 transcriptionally distinct cell populations and revealed a reduction in the trophoblast progenitor cell population in MO placentas. MO suppressed trophoblast genes involved in placental development and mitochondrial oxidative phosphorylation, accompanied by decreased protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a key regulator of mitochondrial biogenesis. Furthermore, MO reduced the expression of Hand1 and Tfap2c, transcription factors involved in trophoblast differentiation and placental development, whereas increasing prolactin-family gene expression and STAT5 phosphorylation. At E17.5, MO caused female-specific reductions in placental weight and labyrinth zone area, along with increased Tnf expression and sustained suppression of Hand1 in female placentas. These findings suggest that MO disrupts trophoblast differentiation and placental metabolic function during midgestation, which may contribute to placental vulnerability later in pregnancy.NEW & NOTEWORTHY Using placental single-cell RNA sequencing at embryonic day (E) 13.5, we found that maternal obesity (MO) was associated with a lower observed trophoblast proportion and downregulation of placental-development and oxidative-phosphorylation programs. These changes occurred alongside reduced peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) protein and activated JAK-STAT signaling. At embryonic day 17.5, female placentas from obese dams showed reduced weight and labyrinth area, revealing sex-dependent placental vulnerability.