Ad libitum high-fat diet (HFD) induces obesity and skeletal muscle metabolic dysfunction. Liver kinase B1 (LKB1) regulates skeletal muscle metabolism by controlling the AMP-activated protein kinase family, but its importance in regulating muscle gene expression and glucose tolerance in obese mice has not been established. The purpose of this study was to determine how the lack of LKB1 in skeletal muscle (KO) affects gene expression and glucose tolerance in HFD-fed, obese mice. KO and littermate control wild-type (WT) mice were fed a standard diet or HFD for 14 weeks. RNA sequencing, and subsequent analysis were performed to assess mitochondrial content and respiration, inflammatory status, glucose and insulin tolerance, and muscle anabolic signaling. KO did not affect body weight gain on HFD, but heavily impacted mitochondria-, oxidative stress-, and inflammation-related gene expression. Accordingly, mitochondrial protein content and respiration were suppressed while inflammatory signaling and markers of oxidative stress were elevated in obese KO muscles. KO did not affect glucose or insulin tolerance. However, fasting serum insulin and skeletal muscle insulin signaling were higher in the KO mice. Furthermore, decreased muscle fiber size in skmLKB1-KO mice was associated with increased general protein ubiquitination and increased expression of several ubiquitin ligases, but not muscle ring finger 1 or atrogin-1. Taken together, these data suggest that the lack of LKB1 in skeletal muscle does not exacerbate obesity or insulin resistance in mice on a HFD, despite impaired mitochondrial content and function and elevated inflammatory signaling and oxidative stress.

中文翻译：

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缺乏骨骼肌肝激酶 B1 会改变基因表达、线粒体含量、炎症和氧化应激，而不会影响高脂肪饮食引起的肥胖或胰岛素抵抗。

随意高脂肪饮食 (HFD) 会导致肥胖和骨骼肌代谢功能障碍。肝激酶 B1 (LKB1) 通过控制 AMP 活化蛋白激酶家族来调节骨骼肌代谢，但其在调节肥胖小鼠肌肉基因表达和葡萄糖耐量方面的重要性尚未确定。本研究的目的是确定骨骼肌 (KO) 中 LKB1 的缺乏如何影响 HFD 喂养的肥胖小鼠的基因表达和葡萄糖耐量。KO 和同窝对照野生型 (WT) 小鼠被喂食标准饮食或 HFD 14 周。进行 RNA 测序和随后的分析以评估线粒体含量和呼吸、炎症状态、葡萄糖和胰岛素耐受性以及肌肉合成代谢信号。KO 不影响 HFD 的体重增加，但严重影响线粒体-、氧化应激-、和炎症相关的基因表达。因此，线粒体蛋白含量和呼吸受到抑制，而炎症信号和氧化应激标志物在肥胖 KO 肌肉中升高。KO 不影响葡萄糖或胰岛素耐受性。然而，空腹血清胰岛素和骨骼肌胰岛素信号在 KO 小鼠中更高。此外，skmLKB1-KO 小鼠肌肉纤维大小的减少与一般蛋白质泛素化的增加和几种泛素连接酶的表达增加有关，但与肌肉无名指 1 或 atrogin-1 的表达无关。综上所述，这些数据表明，尽管线粒体含量和功能受损，炎症信号传导和氧化应激升高，但骨骼肌中 LKB1 的缺乏不会加剧 HFD 小鼠的肥胖或胰岛素抵抗。