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Gestational Diabetes Mellitus-Associated Hyperglycemia Impairs Glucose Transporter 3 Trafficking in Trophoblasts Through the Downregulation of AMP-Activated Protein Kinase
journal contributionposted on 2022-12-22, 11:03 authored by Li Zhang, Xinyang Yu, Yue Wu, Huijia Fu, Ping Xu, Yangxi Zheng, Li Wen, Xiaotao Yang, Fumei Zhang, Mingyu Hu, Hao Wang, Xiyao Liu, Juan Qiao, Chuan Peng, Rufei Gao, Richard Saffery, Yong Fu, Hongbo Qi, Chao Tong, Mark D Kilby, Philip N Baker
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-[3H] 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.
This work was supported by the National Natural Science Foundation of China (81671488, 81871189, 82071675, 81771613, and 81901508) and the Chongqing Education Commission (KJZD-K202100404).
CitationZhang L, Yu X, Wu Y, Fu H, Xu P, Zheng Y, Wen L, Yang X, Zhang F, Hu M, Wang H, Liu X, Qiao J, Peng C, Gao R, Saffery R, Fu Y, Qi H, Tong C, Kilby MD, Baker PN. Gestational Diabetes Mellitus-Associated Hyperglycemia Impairs Glucose Transporter 3 Trafficking in Trophoblasts Through the Downregulation of AMP-Activated Protein Kinase. Front Cell Dev Biol. 2021 Nov 2;9:722024. doi: 10.3389/fcell.2021.722024. PMID: 34796169; PMCID: PMC8593042.
Author affiliationCollege of Life Sciences
- VoR (Version of Record)
Published inFrontiers in Cell and Developmental Biology
Science & TechnologyLife Sciences & BiomedicineCell BiologyDevelopmental BiologyAMP-activated protein kinase (AMPK)gestational diabetes mellitus (GDM)glucose transporter 3 (GLUT3)glucose uptaketrophoblastMATERNAL OBESITYGLUT4 TRANSLOCATIONEXPRESSIONMETABOLISMPLACENTAHEARTMOUSEOVEREXPRESSIONMECHANISMSMETFORMIN