DataSheet1_Maternal obesity alters the placental transcriptome in a fetal sex-dependent manner.PDF

Infants born to obese mothers have an increased risk of developing obesity and metabolic diseases in childhood and adulthood. Although the molecular mechanisms linking maternal obesity during pregnancy to the development of metabolic diseases in offspring are poorly understood, evidence suggests that changes in the placental function may play a role. Using a mouse model of diet-induced obesity with fetal overgrowth, we performed RNA-seq analysis at embryonic day 18.5 to identify genes differentially expressed in the placentas of obese and normal-weight dams (controls). In male placentas, 511 genes were upregulated and 791 genes were downregulated in response to maternal obesity. In female placentas, 722 genes were downregulated and 474 genes were upregulated in response to maternal obesity. The top canonical pathway downregulated in maternal obesity in male placentas was oxidative phosphorylation. In contrast, sirtuin signaling, NF-kB signaling, phosphatidylinositol, and fatty acid degradation were upregulated. In female placentas, the top canonical pathways downregulated in maternal obesity were triacylglycerol biosynthesis, glycerophospholipid metabolism, and endocytosis. In contrast, bone morphogenetic protein, TNF, and MAPK signaling were upregulated in the female placentas of the obese group. In agreement with RNA-seq data, the expression of proteins associated with oxidative phosphorylation was downregulated in male but not female placentas of obese mice. Similarly, sex-specific changes in the protein expression of mitochondrial complexes were found in placentas collected from obese women delivering large-for-gestational-age (LGA) babies. In conclusion, maternal obesity with fetal overgrowth differentially regulates the placental transcriptome in male and female placentas, including genes involved in oxidative phosphorylation.

母亲肥胖所诞下的婴儿，在儿童期及成年期罹患肥胖与代谢性疾病的风险显著升高。尽管目前学界对妊娠期母亲肥胖与子代代谢疾病发生之间的分子机制尚不完全明确，但已有研究提示胎盘功能改变可能参与其中。本研究借助饮食诱导肥胖且伴随胎儿过度生长的小鼠模型，于胚胎第18.5天（E18.5）开展RNA测序（RNA-seq）分析，以鉴定肥胖母鼠与正常体重母鼠（对照组）胎盘中的差异表达基因。在雄性胎盘中，母体肥胖可导致511个基因上调、791个基因下调；而在雌性胎盘中，母体肥胖则使722个基因下调、474个基因上调。雄性胎盘中，母体肥胖诱导下调的经典通路以氧化磷酸化（oxidative phosphorylation）最为显著；与之相反，去乙酰化酶（sirtuin）信号通路、核因子κB（NF-κB）信号通路、磷脂酰肌醇（phosphatidylinositol）及脂肪酸降解通路均出现上调。雌性胎盘中，母体肥胖诱导下调的经典通路包括甘油三酯生物合成、甘油磷脂代谢及胞吞作用；与之相对，肥胖母鼠的雌性胎盘中，骨形态发生蛋白（bone morphogenetic protein）、肿瘤坏死因子（TNF）及丝裂原活化蛋白激酶（MAPK）信号通路均出现上调。与RNA-seq测序结果一致，肥胖小鼠的雄性胎盘组织中，与氧化磷酸化相关的蛋白表达水平显著下调，而雌性胎盘则无此变化。类似地，在肥胖女性所诞下大于胎龄儿（large-for-gestational-age, LGA）的胎盘样本中，同样观察到线粒体复合物蛋白表达存在性别特异性改变。综上，伴随胎儿过度生长的母体肥胖，可对雌雄胎盘中的胎盘转录组产生性别差异性调控，其中包括氧化磷酸化相关基因。