CLCF1 signaling restrains thermogenesis and disrupts metabolic homeostasis by inhibiting mitochondrial biogenesis in brown adipocytes
CLCF1 signaling restrains thermogenesis and disrupts metabolic homeostasis by inhibiting mitochondrial biogenesis in brown adipocytes
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DOI：
10.1073/pnas.2305717120
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发表时间：
2023-08
影响因子：
11.1
通讯作者：
Meng Ding;Hong Xu;Wei-Yu Zhou;Yi-Fan Xia;Bai-Yu Li;YiJun Shi;Xin Dou;Qiqi Yang;S. Qian-S.-Qi
中科院分区：
文献类型：
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作者：
Meng Ding;Hong Xu;Wei-Yu Zhou;Yi-Fan Xia;Bai-Yu Li;YiJun Shi;Xin Dou;Qiqi Yang;S. Qian-S.-Qi
棕色脂肪细胞是一种特殊的产热细胞，能够以热的形式耗散营养能量，有利于代谢稳态。由于未知的褐色脂肪抑制信号，肥胖限制了产热。在这里，我们发现CLCF1信号是产热的一个刹车信号，它在肥胖时被激活，在产热过程中被抑制。CLCF1激活CNTFR-STAT3信号通路；此后，STAT3转录抑制PGC-1α和PGC-1β的表达，从而抑制棕色脂肪细胞线粒体的生物发生。因此，CLCF1转基因小鼠表现出能量消耗和产热能力受损，并在没有外部代谢应激的情况下自发发生代谢异常。我们的发现将CLCF1信号定义为肥胖相关的棕色脂肪细胞变性的一种解释，这可能是干预代谢紊乱的一个目标。
Significance Brown adipocytes are specialized thermogenic cells able to dissipate nutritional energy in the form of heat, which is conducive to metabolic homeostasis. Obesity limits thermogenesis due to unknown inhibitory signals for brown fat. Here, we identify CLCF1 signaling as a brake signal on thermogenesis, which is activated in obesity and inhibited during thermogenesis. CLCF1 activates CNTFR-STAT3 signaling pathway; thereafter, STAT3 transcriptionally inhibits PGC-1α and PGC-1β expression, thus restraining mitochondrial biogenesis in brown adipocytes. Consequently, CLCF1 transgenic mice exhibit impaired energy expenditure and thermogenic capacity and spontaneously develop metabolic abnormalities without external metabolic stress. Our finding defines CLCF1 signaling as an explanation for obesity-related brown adipocyte degeneration, which may be a target for intervention in metabolic disorders.