期刊
NATURE METABOLISM
卷 1, 期 12, 页码 1243-+出版社
NATURE RESEARCH
DOI: 10.1038/s42255-019-0149-1
关键词
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资金
- US National Institutes of Health [P01-DK088761, R01-DK55758, R01-DK56341, RC2-118620, R01-DK099110]
- Novo Nordisk Foundation [NNF19OC0056601]
- Pershing Square Foundation
- Swedish Research Council [2017-00792, 2013-7107]
- Swedish Diabetes Foundation
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [414232833]
- [RR024992]
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.
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