Shryack Grace E, Krause Alexa A, Hernandez Ruano Simone, Schulz Laura C, Pennington Kathleen A, Rector R Scott
Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, MO, United States.
NextGen Precision Health, University of Missouri, Columbia, MO, United States.
Front Endocrinol (Lausanne). 2025 Jun 25;16:1498764. doi: 10.3389/fendo.2025.1498764. eCollection 2025.
Gestational Diabetes Mellitus (GDM) impacts roughly 1 in 7 pregnancies and results in metabolic dysfunction-associated steatotic liver disease (MASLD) in 30% of these women. Nonetheless, there exists a dearth of investigation into the relationship between GDM and MASLD. Here, we sought to investigate the potential role of hepatic mitochondrial function in GDM and MASLD.
One week prior to conception and throughout pregnancy, mice were fed either a low-fat control diet (CD) or a high-fat, high-sucrose (HFHS) diet to induce an established model of GDM. Maternal livers were collected at day 0, 6.5, 13.5 and 17.5 of pregnancy. Hepatic markers (via mRNA and western blot analyses) of mitochondrial biogenesis, autophagy, mitophagy, activity, and function were assessed, as well as markers of inflammation and antioxidant status were evaluated.
Progressing gestation in both CD and GDM dams significantly decreased protein and mRNA markers of hepatic mitochondrial biogenesis (), autophagy (), mitophagy () and lipid handling (, pAMPK/AMPK, FAS, ACC, pACC, ) with a main effect for time (P<0.05). HFHS-induced model of GDM lead to significant elevations in liver triglycerides and NAFLD Activity Score (NAS) (P<0.0001, P<0.0001) independent of body weight gain during gestation. MASLD development in the GDM mice occurred in conjunction with significant reductions in hepatic mitochondrial activity at day 6.5 (citrate synthase, p<0.01) and day 17.5 (β-HAD, citrate synthase, P<0.001) compared to CD mice. However, GDM lead to elevated protein and/or mRNA markers of mitochondrial biogenesis (), mitophagy (BNIP3, ), lipid handling (), inflammation ( and antioxidant defense () (P<0.05).
Pregnancy, independent of diet, decreased markers of liver mitochondrial biogenesis, autophagy, and mitophagy in dams. The GDM mouse model exhibited elevated hepatic TG and NAS, as well as decreased liver mitochondrial activity. These findings demonstrate that pregnancy and GDM significantly impact maternal liver mitochondrial metabolism and unveil new insight on the potential relationship between MASLD and GDM.
妊娠期糖尿病（GDM）影响约七分之一的妊娠，并导致其中30%的女性出现代谢功能障碍相关脂肪性肝病（MASLD）。尽管如此，对于GDM与MASLD之间的关系仍缺乏研究。在此，我们试图探究肝脏线粒体功能在GDM和MASLD中的潜在作用。
在受孕前一周及整个孕期，给小鼠喂食低脂对照饮食（CD）或高脂高糖（HFHS）饮食，以诱导建立GDM模型。在妊娠第0、6.5、13.5和17.5天收集母鼠肝脏。评估线粒体生物发生、自噬、线粒体自噬、活性和功能的肝脏标志物（通过mRNA和蛋白质印迹分析），以及炎症和抗氧化状态的标志物。
CD组和GDM组母鼠在妊娠过程中，肝脏线粒体生物发生（）、自噬（）、线粒体自噬（）和脂质处理（pAMPK/AMPK、FAS、ACC、pACC、）的蛋白质和mRNA标志物均显著降低，时间有主要影响（P<0.05）。HFHS诱导的GDM模型导致肝脏甘油三酯和非酒精性脂肪性肝病活动评分（NAS）显著升高（P<0.0001，P<0.0001），与妊娠期体重增加无关。与CD组小鼠相比，GDM小鼠在妊娠第6.5天（柠檬酸合酶，p<0.01）和第17.5天（β-羟酰基辅酶A脱氢酶、柠檬酸合酶，P<0.001）时，MASLD的发展伴随着肝脏线粒体活性的显著降低。然而，GDM导致线粒体生物发生（）、线粒体自噬（BNIP3，）、脂质处理（）、炎症（和抗氧化防御（）的蛋白质和/或mRNA标志物升高（P<0.05）。
妊娠，与饮食无关，降低了母鼠肝脏线粒体生物发生、自噬和线粒体自噬的标志物。GDM小鼠模型表现出肝脏甘油三酯和NAS升高，以及肝脏线粒体活性降低。这些发现表明，妊娠和GDM显著影响母鼠肝脏线粒体代谢，并揭示了MASLD与GDM之间潜在关系的新见解。
