Mitophagy Directs Muscle-Adipose Crosstalk to Alleviate Dietary Obesity
Mitophagy Directs Muscle-Adipose Crosstalk to Alleviate Dietary Obesity
复制标题
线粒体自噬引导肌肉-脂肪相互作用以减轻饮食性肥胖
DOI：
10.1016/j.celrep.2018.03.127
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发表时间：
2018-05-01
期刊：
影响因子：
8.8
通讯作者：
Gan, Zhenji
中科院分区：
文献类型：
--
作者：
Fu, Tingting;Xu, Zhisheng;Gan, Zhenji
在适应性应激反应中，骨骼肌线粒体的质量对于维持代谢稳态至关重要。然而，肌肉线粒体质量的精确控制机制及其生理影响尚不清楚。在这里，我们证明了FUNDC1，一个线粒体自噬的介质，在控制肌肉线粒体质量和代谢稳态中起着关键作用。小鼠骨骼肌特异性消融FUNDC1导致lc3介导的线粒体自噬缺陷，导致线粒体能量学受损。这导致运动时肌肉脂肪利用率和耐力下降。有趣的是，缺乏肌肉FUNDC1的小鼠免受高脂肪饮食引起的肥胖，全身胰岛素敏感性和葡萄糖耐量得到改善，尽管肌肉线粒体能量减少。从机制上讲，FUNDC1缺乏引起肌肉的逆行反应，上调FGF21的表达，从而促进脂肪组织的热性重塑。因此，这些发现揭示了fundc1依赖的线粒体质量控制在调节肌肉脂肪对话以调节全身代谢中的关键作用。
The quality of mitochondria in skeletal muscle is essential for maintaining metabolic homeostasis during adaptive stress responses. However, the precise control mechanism of muscle mitochondrial quality and its physiological impacts remain unclear. Here, we demonstrate that FUNDC1, a mediator of mitophagy, plays a critical role in controlling muscle mitochondrial quality as well as metabolic homeostasis. Skeletal-muscle-specific ablation of FUNDC1 in mice resulted in LC3-mediated mitophagy defect, leading to impaired mitochondrial energetics. This caused decreased muscle fat utilization and endurance capacity during exercise. Interestingly, mice lacking muscle FUNDC1 were protected against high-fat-diet-induced obesity with improved systemic insulin sensitivity and glucose tolerance despite reduced muscle mitochondrial energetics. Mechanistically, FUNDC1 deficiency elicited a retrograde response in muscle that upregulated FGF21 expression, thereby promoting the thermogenic remodeling of adipose tissue. Thus, these findings reveal a pivotal role of FUNDC1-dependent mitochondrial quality control in mediating the muscleadipose dialog to regulate systemic metabolism.