Camitine induces autophagy and restores high-fat diet-induced mitochondrial dysfunction
Camitine induces autophagy and restores high-fat diet-induced mitochondrial dysfunction
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DOI：
10.1016/j.metabol.2017.09.005
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发表时间：
2018-01-01
影响因子：
9.8
通讯作者：
Park, Kyong Soo
中科院分区：
文献类型：
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作者：
Choi, Jin Woo;Ohn, Jung Hun;Park, Kyong Soo
Objective.自噬在骨骼肌和肝脏中受到抑制，并伴有高脂饮食诱导的胰岛素抵抗。自噬对于维持线粒体功能是必不可少的，并且功能障碍的线粒体与胰岛素抵抗相关。由于卡米汀治疗是众所周知的，以改善胰岛素抵抗，促进线粒体功能，我们研究了卡米汀是否影响自噬在骨骼肌的高脂肪饮食诱导的啮齿动物模型的肥胖。高脂饮食（48 kcal%脂肪）6周后，小鼠出现葡萄糖耐受不良，腓肠肌显示胰岛素信号传导和线粒体功能降低，经口灌胃给予卡米汀（100 mg/kg/天）2周后逆转。在高脂饮食喂养的小鼠的骨骼肌中观察到具有破坏的嵴的Swedish线粒体，但在camitine治疗后没有。高脂饮食降低了自噬体形成的标志物LC 3B-II，并增加了隔离体1（SQSTM 1），其表达在camitine处理后逆转。在C2 C12肌管中，棕榈酸酯的长期治疗抑制了自噬，而camitine治疗则缓解了自噬。然而，在C2 C12肌管中，在过氧化物酶体增殖物激活受体γ（PPARgamma）被敲低后，没有观察到camitine诱导的自噬。我们的结论是，去除功能障碍的线粒体诱导自噬通过过氧化物酶体增殖体激活受体γ可能是一种新的机制，其中camitine改善胰岛素抵抗和线粒体功能障碍的肥胖。(C)2017爱思唯尔公司All rights reserved.
Objective. Autophagy is suppressed in skeletal muscle and the liver with insulin resistance induced by a high-fat diet. Autophagy is essential for maintaining mitochondrial function, and dysfunctional mitochondria are associated with insulin resistance. As camitine treatment is well known to improve insulin resistance by promoting mitochondrial function, we investigated if camitine affects autophagy in the skeletal muscle of a high-fat diet-induced rodent model of obesity.Results. After 6 weeks on a high-fat diet (48 kcal% fat), mice developed glucose intolerance, and the gastrocnemius muscle showed a decrease in insulin signaling and mitochondrial function, which was reversed after camitine (100 mg/kg/day) treatment by oral gavage for 2 weeks. Swollen mitochondria with destroyed cristae were observed in the skeletal muscle of high-fat diet-fed mice but were not there after camitine treatment. High fat diet decreased LC3B-II, a marker of autophagosome formation, and increased sequestosome 1 (SQSTM1), expression of which was reversed after camitine treatment. In C2C12 myotubes, prolonged treatment with palmitate suppressed autophagy, which was relieved by camitine treatment. However, the induction of autophagy by camitine in C2C12 myotubes was not observed after knock-down of peroxisome proliferator-activated receptor gamma (PPAR gamma), which is known to regulate autophagy.Conclusion. We conclude that the removal of dysfunctional mitochondria by induction of autophagy through PPAR gamma may be a novel mechanism by which camitine improves insulin resistance and mitochondrial dysfunction in obesity. (C) 2017 Elsevier Inc. All rights reserved.