Sexual dimorphism in activation of placental autophagy in obese women with evidence for fetal programming from a placenta-specific mouse model

The incidence of maternal obesity and its co-morbidities (diabetes, cardiovascular disease) continues to increase at an alarming rate, with major public health implications. In utero exposure to maternal obesity has been associated with development of cardiovascular and metabolic diseases in the offspring as a result of developmental programming. The placenta regulates maternal-fetal metabolism and shows significant changes in its function with maternal obesity. Autophagy is a cell-survival process, which is responsible for the degradation of damaged organelles and misfolded proteins. Here we show an activation of autophagosomal formation and autophagosome-lysosome fusion in placentas of males but not females from overweight (OW) and obese (OB) women vs. normal weight (NW) women. However, total autophagic activity in these placentas appeared to be decreased as it showed an increase in SQSTM1/p62 and a decrease in lysosomal biogenesis. A mouse model with a targeted deletion of the essential autophagy gene Atg7 in placental tissue showed significant placental abnormalities comparable to those seen in human placenta with maternal obesity. These included a decrease in expression of mitochondrial genes and antioxidants, and decreased lysosomal biogenesis. Strikingly, the knockout mice were developmentally programmed as they showed an increased sensitivity to high-fat diet-induced obesity, hyperglycemia, hyperinsulinemia, increased adiposity, and cardiac remodeling. In summary, our results indicate a sexual dimorphism in placental autophagy in response to maternal obesity. We also show that autophagy plays an important role in placental function and that inhibition of placental autophagy programs the offspring to obesity, and to metabolic and cardiovascular diseases.

母体肥胖及其并发症（如糖尿病、心血管疾病）的发病率正以令人担忧的速度持续上升，对公共卫生产生重大影响。母体肥胖在子宫内的暴露与后代心血管和代谢性疾病的发展编程相关。胎盘调节母体-胎儿代谢，并在母体肥胖的情况下显示出其功能的显著变化。自噬是一种细胞存活过程，负责降解受损的细胞器和错误折叠的蛋白质。在本研究中，我们展示了来自超重（OW）和肥胖（OB）女性的胎盘在雄性而非雌性中自噬小体形成和自噬小体-溶酶体融合的激活，而正常体重（NW）女性的胎盘则没有这种现象。然而，这些胎盘中的总自噬活性似乎有所下降，表现为SQSTM1/p62的增加和溶酶体生物合成的减少。一个在胎盘组织中特异性敲除必需自噬基因Atg7的小鼠模型显示出与人类母体肥胖胎盘相似的显著胎盘异常。这包括线粒体基因和抗氧化剂的减少表达，以及溶酶体生物合成的减少。令人震惊的是，敲除小鼠表现出发育编程，它们对高脂饮食诱导的肥胖、高血糖、高胰岛素血症、增加的脂肪沉积和心脏重塑的敏感性增加。总之，我们的结果表明，母体肥胖对胎盘自噬的反应存在性别差异。我们还表明，自噬在胎盘功能中起着重要作用，且胎盘自噬的抑制将后代编程为肥胖，以及代谢和心血管疾病。