Metabolic effects of skeletal muscle-specific deletion of beta-arrestin-1 and -2 in mice

Type 2 diabetes (T2D) has become a major health problem worldwide. Skeletal muscle (SKM) is the key tissue for whole-body glucose disposal and utilization. New drugs aimed at improving insulin sensitivity of SKM would greatly expand available therapeutic options. β-arrestin-1 and -2 (Barr1 and Barr2, respectively) are two intracellular proteins best known for their ability to mediate the desensitization and internalization of G protein-coupled receptors (GPCRs). Recent studies suggest that Barr1 and Barr2 regulate several important metabolic functions including insulin release and hepatic glucose production. Since SKM expresses many GPCRs, including the metabolically important β2-adrenergic receptor, the goal of this study was to examine the potential roles of Barr1 and Barr2 in regulating SKM and whole-body glucose metabolism. Using SKM-specific knockout (KO) mouse lines, we showed that the loss of SKM Barr2, but not of SKM Barr1, resulted in mild improvements in glucose tolerance in diet-induced obese mice. SKM-specific Barr1- and Barr2-KO mice did not show any significant differences in exercise performance. However, lack of SKM Barr2 led to increased glycogen breakdown following a treadmill exercise challenge. Interestingly, mice that lacked both Barr1 and Barr2 in SKM showed no significant metabolic phenotypes. Thus, somewhat surprisingly, our data indicate that SKM β-arrestins play only rather subtle roles (SKM Barr2) in regulating whole-body glucose homeostasis and SKM insulin sensitivity.2型糖尿病（Type 2 diabetes, T2D）已成为全球范围内的重大公共健康问题。骨骼肌（Skeletal muscle, SKM）是介导全身葡萄糖处置与利用的核心组织。旨在改善骨骼肌胰岛素敏感性的新型药物，将极大扩充现有的临床治疗选择。β抑制蛋白1和2（β-arrestin-1 and -2，简称Barr1、Barr2）是两类最为人熟知的细胞内蛋白，其经典功能是介导G蛋白偶联受体（G protein-coupled receptors, GPCRs）的脱敏与内化。近期研究显示，Barr1与Barr2可调控多项重要代谢过程，包括胰岛素分泌与肝脏葡萄糖生成。由于骨骼肌表达多种GPCRs，其中包括代谢相关的β2肾上腺素能受体，本研究旨在探究Barr1与Barr2在调控骨骼肌及全身葡萄糖代谢中的潜在作用。本研究采用骨骼肌特异性敲除（knockout, KO）小鼠模型，实验结果表明：在饮食诱导肥胖小鼠中，骨骼肌特异性敲除Barr2（而非Barr1）可轻度改善其葡萄糖耐量。骨骼肌特异性敲除Barr1或Barr2的小鼠，其运动能力均未出现显著差异。但骨骼肌缺失Barr2的小鼠，在经受跑台运动负荷后，糖原分解水平有所升高。值得关注的是，骨骼肌同时缺失Barr1与Barr2的小鼠，未表现出显著的代谢表型。综上，本研究数据出人意料地表明，骨骼肌β抑制蛋白在调控全身葡萄糖稳态及骨骼肌胰岛素敏感性方面，仅发挥较为微弱的作用。