Food Biochemistry Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan.
Food Biochemistry Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan.
J Biol Chem. 2021 Jan-Jun;296:100131. doi: 10.1074/jbc.RA120.016203. Epub 2020 Dec 4.
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 capillary electrophoresis time-of-flight mass spectrometry 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 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 the 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.
TGR5 是一种 G 蛋白偶联胆酸受体，在各种组织中表达，调节多种生理过程。在骨骼肌中，已知 TGR5 的激活可诱导肌肉肥大；然而，尽管骨骼肌在能量代谢中起主要作用，但它对葡萄糖和脂质代谢的影响仍不清楚。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。毛细管电泳飞行时间质谱的代谢物分析表明，Tg 小鼠骨骼肌中的糖酵解通量被激活，导致葡萄糖利用增加。在长期高脂肪饮食挑战下，Tg 小鼠的血糖清除率得到改善，而骨骼肌胰岛素敏感性没有提高，体重也没有减轻。此外，Tg 小鼠表现出年龄相关性葡萄糖不耐受的改善。这些结果强烈表明，TGR5 通过增强骨骼肌的葡萄糖代谢能力，改善了由饮食诱导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 TGR5 的激活可有效改善葡萄糖代谢，可能有助于开发预防或治疗高血糖的新策略。
