Choi Jin Woo, Ohn Jung Hun, Jung Hye Seung, Park Young Joo, Jang Hak Chul, Chung Sung Soo, Park Kyong Soo
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea.
Metabolism. 2018 Jan;78:43-51. doi: 10.1016/j.metabol.2017.09.005. Epub 2017 Sep 28.
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 carnitine treatment is well known to improve insulin resistance by promoting mitochondrial function, we investigated if carnitine affects autophagy in the skeletal muscle of a high-fat diet-induced rodent model of obesity.
After 6weeks on a high-fat diet (48kcal% fat), mice developed glucose intolerance, and the gastrocnemius muscle showed a decrease in insulin signaling and mitochondrial function, which was reversed after carnitine (100mg/kg/day) treatment by oral gavage for 2weeks. Swollen mitochondria with destroyed cristae were observed in the skeletal muscle of high-fat diet-fed mice but were not there after carnitine treatment. High-fat diet decreased LC3B-II, a marker of autophagosome formation, and increased sequestosome 1 (SQSTM1), expression of which was reversed after carnitine treatment. In C2C12 myotubes, prolonged treatment with palmitate suppressed autophagy, which was relieved by carnitine treatment. However, the induction of autophagy by carnitine in C2C12 myotubes was not observed after knock-down of peroxisome proliferator-activated receptor γ (PPARγ), which is known to regulate autophagy.
We conclude that the removal of dysfunctional mitochondria by induction of autophagy through PPARγ may be a novel mechanism by which carnitine improves insulin resistance and mitochondrial dysfunction in obesity.
在高脂饮食诱导胰岛素抵抗的情况下，骨骼肌和肝脏中的自噬受到抑制。自噬对于维持线粒体功能至关重要，而功能失调的线粒体与胰岛素抵抗相关。由于众所周知肉碱治疗可通过促进线粒体功能来改善胰岛素抵抗，我们研究了肉碱是否会影响高脂饮食诱导的肥胖啮齿动物模型骨骼肌中的自噬。
在高脂饮食（脂肪含量48千卡%）喂养6周后，小鼠出现葡萄糖不耐受，腓肠肌的胰岛素信号传导和线粒体功能降低，经口灌胃给予肉碱（100毫克/千克/天）治疗2周后这些情况得到逆转。在高脂饮食喂养小鼠的骨骼肌中观察到线粒体肿胀且嵴被破坏，但肉碱治疗后不再出现这种情况。高脂饮食降低了自噬体形成的标志物LC3B-II，并增加了聚集体蛋白1（SQSTM1），肉碱治疗后其表达得到逆转。在C2C12肌管中，棕榈酸酯长时间处理会抑制自噬，而肉碱治疗可缓解这种抑制。然而，在敲低已知可调节自噬的过氧化物酶体增殖物激活受体γ（PPARγ）后，未观察到肉碱在C2C12肌管中诱导自噬。
我们得出结论，通过PPARγ诱导自噬来清除功能失调的线粒体可能是肉碱改善肥胖中胰岛素抵抗和线粒体功能障碍的一种新机制。
