Mitophagy Directs Muscle-Adipose Crosstalk to Alleviate Dietary Obesity

Publication date: 1 May 2018
Source:Cell Reports, Volume 23, Issue 5
Author(s): Tingting Fu, Zhisheng Xu, Lin Liu, Qiqi Guo, Hao Wu, Xijun Liang, Danxia Zhou, Liwei Xiao, Lei Liu, Yong Liu, Min-Sheng Zhu, Quan Chen, Zhenji Gan
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 muscle-adipose dialog to regulate systemic metabolism.

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Teaser

Mitochondrial quality is essential to muscle function. How muscle mitochondrial quality is regulated and its physiological impacts remain unclear. Fu et al. show that loss of FUNDC1-dependent mitochondrial quality control in muscle alleviates high-fat-diet-induced obesity and improves systemic glucose homeostasis through promoting exercise-independent fat burning in adipose tissue.


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