Zhang Li, Yu Xinyang, Wu Yue, Fu Huijia, Xu Ping, Zheng Yangxi, Wen Li, Yang Xiaotao, Zhang Fumei, Hu Mingyu, Wang Hao, Liu Xiyao, Qiao Juan, Peng Chuan, Gao Rufei, Saffery Richard, Fu Yong, Qi Hongbo, Tong Chao, Kilby Mark D, Baker Philip N
Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing, China.
Front Cell Dev Biol. 2021 Nov 2;9:722024. doi: 10.3389/fcell.2021.722024. eCollection 2021.
AMP-activated protein kinase (AMPK) is an important regulator of glucose metabolism, and glucose transporter 3 (GLUT3) is an efficient glucose transporter in trophoblasts. Whether placental AMPK and GLUT3 respond accordingly to gestational diabetes mellitus (GDM) remains uncertain. Here, we explored the regulatory role of AMPK in the GLUT3-dependent uptake of glucose by placental trophoblasts and the viability of the cells. In this study, the level of glycolysis in normal and GDM-complicated placentas was assessed by LC-MS/MS. The trophoblast hyperglycemia model was induced by the incubation of HTR8/SVneo cells with a high glucose concentration. GDM animal models were generated with db/ + mice and C57BL/6J mice fed a high-fat diet, and AMPK was manipulated by the oral administration of metformin. The uptake of glucose by trophoblasts was assessed using 2-NBDG or 2-deoxy-D-[H] glucose. The results showed that GDM is associated with impaired glycolysis, AMPK activity, GLUT3 expression in the plasma membrane (PM) and cell survival in the placenta. Hyperglycemia induced similar changes in trophoblasts, and these changes were rescued by AMPK activation. Both hyperglycemic db/ + and high-fat diet-induced GDM mice exhibited a compromised AMPK-GLUT3 axis and suppressed cell viability in the placenta as well as excessive fetal growth, and all of these effects were partially alleviated by metformin. Taken together, our findings support the notion that AMPK activation upregulates trophoblast glucose uptake by stimulating GLUT3 translocation, which is beneficial for viability. Thus, the modulation of glucose metabolism in trophoblasts by targeting AMPK might ameliorate the adverse intrauterine environment caused by GDM.
腺苷酸活化蛋白激酶（AMPK）是葡萄糖代谢的重要调节因子，而葡萄糖转运蛋白3（GLUT3）是滋养层细胞中一种高效的葡萄糖转运蛋白。胎盘AMPK和GLUT3是否会对妊娠期糖尿病（GDM）做出相应反应仍不确定。在此，我们探讨了AMPK在胎盘滋养层细胞依赖GLUT3的葡萄糖摄取及细胞活力方面的调节作用。在本研究中，通过液相色谱-串联质谱法（LC-MS/MS）评估正常胎盘和GDM合并胎盘的糖酵解水平。通过用高糖浓度孵育HTR8/SVneo细胞诱导滋养层高血糖模型。用db/+小鼠和喂食高脂饮食的C57BL/6J小鼠建立GDM动物模型，并通过口服二甲双胍来调控AMPK。使用2-NBDG或2-脱氧-D-[H]葡萄糖评估滋养层细胞对葡萄糖的摄取。结果表明，GDM与胎盘糖酵解受损、AMPK活性、质膜（PM）中GLUT3表达及细胞存活有关。高血糖在滋养层细胞中诱导了类似变化，而这些变化通过AMPK激活得以挽救。高血糖的db/+小鼠和高脂饮食诱导的GDM小鼠均表现出AMPK-GLUT3轴受损、胎盘细胞活力受抑制以及胎儿过度生长，而二甲双胍部分缓解了所有这些影响。综上所述，我们的研究结果支持以下观点：AMPK激活通过刺激GLUT3易位上调滋养层细胞对葡萄糖的摄取，这对细胞活力有益。因此，通过靶向AMPK调节滋养层细胞中的葡萄糖代谢可能会改善GDM引起的不良宫内环境。
