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<p>Maternal exercise can improve the metabolic health of the offspring. However, the molecular mechanisms underlying the beneficial effects of maternal exercise on the offspring remain unclear. Here, we show that maternal exercise during pregnancy alleviates high-fat diet (HFD)-induced adipose inflammation and glucose intolerance in offspring mice, accompanied by upregulation of the adipokine serine protease inhibitor A3C (SERPINA3C) both in maternal adipose tissues and the fetal circulation. Adipose SERPINA3C knockdown impairs, but its overexpression in dams mimics, maternal exercise-mediated metabolic benefits in HFD-fed offspring. Maternal SERPINA3C is transported into the fetal circulation and promotes Krüppel-like factor 4 (<i>Klf4</i>) gene promoter demethylation in fetal preadipocytes to increase KLF4 expression, which inhibits adipose inflammation in HFD-fed offspring mice. The SERPINA3C–cathepsin G–integrin β1 axis activates phosphatidylinositol 3-kinase signalling in preadipocytes. This promotes nuclear translocation of the p110β subunit to generate phosphatidylinositol 3,4,5-trisphosphate (PIP<sub>3</sub>) in the nucleus. O-linked β-<i>N</i>-acetylglucosamine (<i>O</i>-GlcNAc) transferase then binds to PIP<sub>3</sub> to promote ten–eleven translocation methylcytosine dioxygenase 1 (TET1) <i>O</i>-GlcNAcylation, thereby enhancing TET1 activity to facilitate <i>Klf4</i> gene promoter demethylation. These results provide mechanistic insights into maternal exercise-mediated improvement of offspring metabolism.</p>

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Maternal exercise prevents metabolic disorders in offspring mice through SERPINA3C

  • 期刊论文

  • 发表日期：

    2025年1月31日

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  • Yang Li,
  • Ruo-Ying Li,
  • Jie-Ying Zhu,
  • Min Chen,
  • Wang-Jing Mu,
  • Hong-Yang Luo,
  • Shan Li,
  • Lin-Jing Yan,
  • Meng-Ting Yin,
  • Xin Li,
  • Hu-Min Chen,
  • Liang Guo

摘要

Maternal exercise can improve the metabolic health of the offspring. However, the molecular mechanisms underlying the beneficial effects of maternal exercise on the offspring remain unclear. Here, we show that maternal exercise during pregnancy alleviates high-fat diet (HFD)-induced adipose inflammation and glucose intolerance in offspring mice, accompanied by upregulation of the adipokine serine protease inhibitor A3C (SERPINA3C) both in maternal adipose tissues and the fetal circulation. Adipose SERPINA3C knockdown impairs, but its overexpression in dams mimics, maternal exercise-mediated metabolic benefits in HFD-fed offspring. Maternal SERPINA3C is transported into the fetal circulation and promotes Krüppel-like factor 4 (Klf4) gene promoter demethylation in fetal preadipocytes to increase KLF4 expression, which inhibits adipose inflammation in HFD-fed offspring mice. The SERPINA3C–cathepsin G–integrin β1 axis activates phosphatidylinositol 3-kinase signalling in preadipocytes. This promotes nuclear translocation of the p110β subunit to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the nucleus. O-linked β-N-acetylglucosamine (O-GlcNAc) transferase then binds to PIP3 to promote ten–eleven translocation methylcytosine dioxygenase 1 (TET1) O-GlcNAcylation, thereby enhancing TET1 activity to facilitate Klf4 gene promoter demethylation. These results provide mechanistic insights into maternal exercise-mediated improvement of offspring metabolism.