Evidence suggests that maternal obesity (MO) can aggravate placental function causing severe pathologies during the perinatal window. However, molecular changes and mechanisms of placental dysfunction remain largely unknown. This work aimed to decipher structural and molecular alterations of the placental transfer zone associated with MO. To this end, mice were fed a high fat diet (HFD) to induce obesity before mating, and pregnant dams were sacrificed at E15.5 to receive placentas for molecular, histological, and ultrastructural analysis and to assess unidirectional materno-fetal transfer capacity. Laser-capture microdissection was used to collect specifically placental cells of the labyrinth zone for proteomics profiling. Using BeWo cells, fatty acid-mediated mechanisms of adherens junction stability, cell layer permeability, and lipid accumulation were deciphered. Proteomics profiling revealed downregulation of cell adhesion markers in the labyrinth zone of obese dams, and disturbed syncytial fusion and detachment of the basement membrane (BM) within this zone was observed, next to an increase in materno-fetal transfer in vivo across the placenta. We found that fetuses of obese dams develop a growth restriction and in those placentas, labyrinth zone volume-fraction was significantly reduced. Linoleic acid was shown to mediate beta-catenin level and increase cell layer permeability in vitro. Thus, MO causes fetal growth restriction, molecular and structural changes in the transfer zone leading to impaired trophoblast differentiation, BM disruption, and placental dysfunction despite increased materno-fetal transfer capacity. These adverse effects are probably mediated by fatty acids found in HFD demonstrating the need for obesity treatment to mitigate placental dysfunction and prevent offspring pathologies.

中文翻译：

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母体高脂肪饮食诱导的肥胖影响小鼠的滋养细胞分化和胎盘功能。

有证据表明，孕产妇肥胖 (MO) 会加重胎盘功能，导致围产期出现严重病变。然而，胎盘功能障碍的分子变化和机制在很大程度上仍然未知。这项工作旨在破译与 MO 相关的胎盘转移区的结构和分子改变。为此，小鼠在交配前被喂食高脂肪饮食 (HFD) 以诱导肥胖，并在 E15.5 处死怀孕的水坝以接受胎盘进行分子、组织学和超微结构分析，并评估单向母胎转移能力。激光捕获显微切割用于收集迷路区的特定胎盘细胞，用于蛋白质组学分析。使用 BeWo 细胞，脂肪酸介导的粘附连接稳定性机制，细胞层渗透性，和脂质积累被破译。蛋白质组学分析显示，肥胖大坝迷宫区的细胞粘附标记物下调，并观察到该区域内基底膜 (BM) 的合胞体融合和分离受到干扰，同时体内跨胎盘的母胎转移增加。我们发现肥胖水坝的胎儿会出现生长受限，并且在这些胎盘中，迷宫区体积分数显着降低。亚油酸在体外可调节 β-连环蛋白水平并增加细胞层通透性。因此，尽管母胎转移能力增加，但 MO 会导致胎儿生长受限、转移区的分子和结构变化，导致滋养细胞分化受损、BM 破坏和胎盘功能障碍。