TGR5, a G protein-coupled bile acid receptor, is expressed in various tissues and regulates several physiological processes. In the skeletal muscle, TGR5 activation is known to induce muscle hypertrophy; however, the effects on glucose and lipid metabolism are not well understood, despite the fact that the skeletal muscle plays a major role in energy metabolism. Here, we demonstrate that skeletal muscle-specific TGR5 transgenic (Tg) mice exhibit increased glucose utilization, without altering the expression of major genes related to glucose and lipid metabolism. Metabolite profiling analysis by CE-TOF MS showed that glycolytic flux was activated in the skeletal muscle of Tg mice, leading to an increase in glucose utilization. Upon long-term, high-fat diet (HFD) challenge, blood glucose clearance was improved in Tg mice without an accompanying increase in insulin sensitivity in skeletal muscle and a reduction of body weight. Moreover, Tg mice showed improved age-associated glucose intolerance. These results strongly suggest that TGR5 ameliorated glucose metabolism disorder that is caused by diet-induced obesity and aging by enhancing the glucose metabolic capacity of skeletal muscle. Our study demonstrates that TGR5 activation in the skeletal muscle is effective in improving glucose metabolism and may be beneficial in developing a novel strategy for the prevention or treatment of hyperglycemia.

中文翻译：

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肌肉特异性 TGR5 过表达可改善葡萄糖不耐受小鼠的葡萄糖清除率


TGR5 是一种 G 蛋白偶联胆汁酸受体，在多种组织中表达并调节多种生理过程。在骨骼肌中，TGR5 激活已知会诱导肌肉肥大；然而，尽管骨骼肌在能量代谢中发挥着重要作用，但对葡萄糖和脂质代谢的影响尚不清楚。在这里，我们证明骨骼肌特异性 TGR5 转基因 (Tg) 小鼠表现出葡萄糖利用率增加，而不改变与葡萄糖和脂质代谢相关的主要基因的表达。 CE-TOF MS 代谢物分析表明，Tg 小鼠骨骼肌中的糖酵解通量被激活，导致葡萄糖利用率增加。经过长期的高脂肪饮食（HFD）挑战，Tg 小鼠的血糖清除率得到改善，但骨骼肌的胰岛素敏感性并未随之增加，体重也没有减轻。此外，Tg 小鼠表现出与年龄相关的葡萄糖耐受不良的改善。这些结果强烈表明TGR5通过增强骨骼肌的葡萄糖代谢能力来改善由饮食引起的肥胖和衰老引起的葡萄糖代谢紊乱。我们的研究表明，骨骼肌中的 TGR5 激活可有效改善葡萄糖代谢，并可能有利于开发预防或治疗高血糖的新策略。