Pharmacological inhibition of dynamin-related protein 1 attenuates skeletal muscle insulin resistance in obesity.
Pharmacological inhibition of dynamin-related protein 1 attenuates skeletal muscle insulin resistance in obesity.
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DOI：
10.14814/phy2.14808
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发表时间：
2021-04
影响因子：
2.5
通讯作者：
Zou K
中科院分区：
文献类型：
--
作者：
Kugler BA;Deng W;Duguay AL;Garcia JP;Anderson MC;Nguyen PD;Houmard JA;Zou K
动力蛋白相关蛋白-1（Drp 1）是线粒体分裂的关键调节因子。在肥胖条件下，骨骼肌中过量的Drp 1介导的线粒体分裂与胰岛素作用受损相关。然而，目前尚不清楚使用Drp 1特异性抑制剂线粒体分裂抑制剂1（Mdivi‐1）对Drp 1的药理学抑制是否能有效缓解骨骼肌胰岛素抵抗并改善肥胖和胰岛素抵抗条件下的全身代谢健康。我们对C57 BL/6 J小鼠进行了为期5周的高脂饮食（HFD）或低脂饮食（LFD）。HFD喂养的小鼠在饮食干预的最后一周接受Mdivi-1或盐水注射。此外，用Mdivi-1或生理盐水处理来自肥胖胰岛素抵抗人类的肌管12小时。我们测量了葡萄糖耐量试验（GTT）的葡萄糖曲线下面积（AUC）、骨骼肌胰岛素作用、线粒体动力学、呼吸和H2 O2含量。我们发现Mdivi-1减弱了HFD喂养诱导的GTT的骨骼肌胰岛素信号传导和血糖AUC的损伤（p < 0.05）。HFD组骨骼肌中H2 O2含量升高（与LFD相比，p < 0.05），但Mdivi-1治疗降低，这可能部分解释了骨骼肌胰岛素作用的改善。类似地，Mdivi-1增强了线粒体网络结构，减少了活性氧，并改善了肥胖人肌管中的胰岛素作用（与盐水相比，p < 0.05）。总之，在肥胖诱导的胰岛素抵抗的情况下，短期给予Mdivi‐1抑制Drp 1可减弱骨骼肌胰岛素信号传导的损伤，并改善全身葡萄糖耐量。靶向Drp 1可能是治疗肥胖诱导的胰岛素抵抗的可行方法。我们发现，在肥胖诱导的胰岛素抵抗的情况下，抑制Drp 1可以减弱骨骼肌胰岛素信号传导的损伤，并改善全身葡萄糖耐量。靶向Drp 1可能是治疗肥胖诱导的胰岛素抵抗的可行方法。
Dynamin‐related protein‐1 (Drp1) is a key regulator in mitochondrial fission. Excessive Drp1‐mediated mitochondrial fission in skeletal muscle under the obese condition is associated with impaired insulin action. However, it remains unknown whether pharmacological inhibition of Drp1, using the Drp1‐specific inhibitor Mitochondrial Division Inhibitor 1 (Mdivi‐1), is effective in alleviating skeletal muscle insulin resistance and improving whole‐body metabolic health under the obese and insulin‐resistant condition. We subjected C57BL/6J mice to a high‐fat diet (HFD) or low‐fat diet (LFD) for 5‐weeks. HFD‐fed mice received Mdivi‐1 or saline injections for the last week of the diet intervention. Additionally, myotubes derived from obese insulin‐resistant humans were treated with Mdivi‐1 or saline for 12 h. We measured glucose area under the curve (AUC) from a glucose tolerance test (GTT), skeletal muscle insulin action, mitochondrial dynamics, respiration, and H2O2 content. We found that Mdivi‐1 attenuated impairments in skeletal muscle insulin signaling and blood glucose AUC from a GTT induced by HFD feeding (p < 0.05). H2O2 content was elevated in skeletal muscle from the HFD group (vs. LFD, p < 0.05), but was reduced with Mdivi‐1 treatment, which may partially explain the improvement in skeletal muscle insulin action. Similarly, Mdivi‐1 enhanced the mitochondrial network structure, reduced reactive oxygen species, and improved insulin action in myotubes from obese humans (vs. saline, p < 0.05). In conclusion, inhibiting Drp1 with short‐term Mdivi‐1 administration attenuates the impairment in skeletal muscle insulin signaling and improves whole‐body glucose tolerance in the setting of obesity‐induced insulin resistance. Targeting Drp1 may be a viable approach to treat obesity‐induced insulin resistance. We found that inhibiting Drp1 attenuates the impairment in skeletal muscle insulin signaling and improves whole‐body glucose tolerance in the setting of obesity‐induced insulin resistance. Targeting Drp1 may be a viable approach to treat obesity‐induced insulin resistance.
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影响因子：
8.1
作者：
Moore, Timothy M.;Zhou, Zhenqi;Hevener, Andrea L.
通讯作者：
Hevener, Andrea L.
影响因子：
7.4
作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Danesh, Farhad R.