Background. Combined aerobic and resistance training has been demonstrated to benefit glycemic control and reverse nonalcoholic fatty liver disease in childhood obesity. General control nonderepressible 2 (GCN2) deficiency has been reported to attenuate hepatic steatosis and insulin resistance. However, whether GCN2 impacts the positive effects of combined aerobic and resistance exercise remains unknown. Objectives. To investigate whether combined aerobic and resistance exercise improves hepatic steatosis and glucose intolerance and the role GCN2 plays in mediating the metabolic regulation of exercise. Methods. Wild-type (WT) and GCN2 knockout (GCN2KO) mice were fed a high-fat diet (HFD) for 25 weeks. The WT and GCN2KO mice performed exercise (treadmill running + ladder climbing) during the last eight weeks. Their body and liver weights, their triglyceride content, and their levels of aspartate transaminase (AST), alanine transaminase (ALT), and blood glucose were measured, and the expressions of proteins involved in the GCN2/eIF2α/ATF4 pathway and the glucolipid metabolism-related proteins (e.g., p-AMPK, SIRT1, PPARα, PGC-1α, GLUT4, and p-GSK-3β) were determined. Results. The body weight of WT and GCN2KO mice continued to increase until the end of the experiment. The liver weights, hepatic triglyceride content, and AST and ALT levels of the exercised mice were significantly reduced compared to those of the sedentary mice. Exercise improved blood glucose levels and glucose clearance ability in the WT mice, but the glucose intolerance of GCN2KO mice was not improved. Exercise increased PGC-1α, GLUT4, and p-GSK-3β expressions in the WT rather than the GCN2KO mice. Interestingly however, exercise-trained GCN2KO mice were better protected against hepatic steatosis with downregulated expressions of p-eIF2α and ATF4, upregulated expressions of p-AMPK and SIRT1, and the presence of PPARα in the liver, compared to the exercised WT mice. Conclusion. Combined aerobic and resistance exercise had positive effects on hepatic steatosis and the control of glucose intolerance. GCN2 was found to be necessary for exercise-induced improved glucose intolerance. However, the better efficacy in improving hepatic steatosis by exercise in the GCN2-deficient mice enhanced liver lipid metabolism, at least partially, via the AMPK/SIRT1/PPARα pathway.

中文翻译：

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GCN2缺乏增强运动对肝脂肪变性的保护作用

背景。有氧和阻力训练相结合已被证明有利于儿童肥胖症的血糖控制和逆转非酒精性脂肪肝。据报道，一般控制非抑制性 2 (GCN2) 缺乏可减轻肝脂肪变性和胰岛素抵抗。然而，GCN2 是否会影响有氧运动和抗阻运动相结合的积极作用仍然未知。目标。研究有氧运动和抗阻运动相结合是否能改善肝脏脂肪变性和葡萄糖耐受不良，以及 GCN2 在调节运动代谢调节中的作用。方法。野生型 (WT) 和GCN2基因敲除 (GCN2KO) 小鼠被喂食高脂肪饮食 (HFD) 25 周。WT 和 GCN2KO 小鼠在过去八周内进行了锻炼（跑步机跑步 + 爬梯）。测量他们的体重和肝脏重量、甘油三酯含量、天冬氨酸转氨酶 (AST)、丙氨酸转氨酶 (ALT) 和血糖水平，以及参与 GCN2/eIF2 α /ATF4 通路的蛋白质和糖脂的表达测定了代谢相关蛋白（例如，p-AMPK、SIRT1、PPAR α、PGC-1 α、GLUT4 和 p-GSK-3 β）。结果. WT和GCN2KO小鼠的体重持续增加直到实验结束。与久坐的小鼠相比，运动小鼠的肝脏重量、肝脏甘油三酯含量以及 AST 和 ALT 水平显着降低。运动改善了 WT 小鼠的血糖水平和葡萄糖清除能力，但 GCN2KO 小鼠的葡萄糖耐受性没有得到改善。运动增加了 WT 而不是 GCN2KO 小鼠中 PGC-1 α、 GLUT4 和 p-GSK-3 β的表达。然而有趣的是，运动训练的 GCN2KO 小鼠通过下调 p-eIF2 α和 ATF4 的表达、上调 p-AMPK 和 SIRT1 的表达以及 PPAR α的存在，可以更好地防止肝脂肪变性在肝脏中，与运动的 WT 小鼠相比。结论。有氧运动和抗阻运动相结合对肝脏脂肪变性和葡萄糖耐受不良的控制有积极作用。GCN2 被发现是运动引起的葡萄糖耐受不良改善所必需的。然而，在GCN2缺陷小鼠中，通过运动改善肝脏脂肪变性的效果更好，至少部分通过 AMPK/SIRT1/PPAR α途径增强了肝脏脂质代谢。