Dysregulation of amyloid precursor protein impairs adipose tissue mitochondrial function and promotes obesity
Dysregulation of amyloid precursor protein impairs adipose tissue mitochondrial function and promotes obesity
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DOI：
10.1038/s42255-019-0149-1
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发表时间：
2019-12-01
影响因子：
20.8
通讯作者：
Scherer, Philipp E.
中科院分区：
文献类型：
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作者：
An, Yu A.;Crewe, Clair;Scherer, Philipp E.
白色脂肪组织（WAT）中的线粒体功能是脂肪细胞生物学的一个重要但尚未充分研究的方面。在这里，我们报告了淀粉样前体蛋白（APP）在损害WAT线粒体功能中的作用，通过高脂饮食（HFD）诱导的，非常规的错误定位到线粒体，进一步促进肥胖。在人类和小鼠中，肥胖条件诱导WAT中大量APP产生和线粒体中APP富集。从机制上讲，HFD诱导的信号识别颗粒亚基54 c的失调是APP错误靶向脂肪细胞线粒体的原因。错误定位的APP阻断蛋白质输入机制，导致WAT中的线粒体功能障碍。过表达脂肪细胞特异性APP和靶向APP的小鼠表现出体重增加和胰岛素敏感性降低，沿着WAT功能障碍，这是由于脂肪细胞中的显著肥大程序。脂肪细胞APP的消除挽救了HFD受损的线粒体功能，并对体重增加和全身代谢缺陷提供了相当大的保护。我们的数据强调了APP在调节WAT线粒体功能和肥胖相关代谢功能障碍中的重要作用。
Mitochondrial function in white adipose tissue (WAT) is an important yet understudied aspect of adipocyte biology. Here, we report a role for amyloid precursor protein (APP) in compromising WAT mitochondrial function through a high-fat diet (HFD)-induced, unconventional mis-localization to mitochondria that further promotes obesity. In humans and mice, obese conditions induce substantial APP production in WAT and APP enrichment in mitochondria. Mechanistically, HFD-induced dysregulation of signal recognition particle subunit 54c is responsible for the mis-targeting of APP to adipocyte mitochondria. Mis-localized APP blocks the protein import machinery, leading to mitochondrial dysfunction in WAT. Mice overexpressing adipocyte-specific and mitochondria-targeted APP display increased body mass and reduced insulin sensitivity, along with dysfunctional WAT, owing to a dramatic hypertrophic program in adipocytes. Elimination of adipocyte APP rescues HFD-impaired mitochondrial function with considerable protection from weight gain and systemic metabolic deficiency. Our data highlight an important role for APP in modulating WAT mitochondrial function and obesity-associated metabolic dysfunction.