Dysregulation of amyloid precursor protein impairs adipose tissue mitochondrial function and promotes obesity

Yu A. An, Clair Crewe, Ingrid Wernstedt Asterholm, Kai Sun, Shiuhwei Chen, Fang Zhang, Mengle Shao, Jan Bernd Funcke, Zhuzhen Zhang, Leon Straub, Jun Yoshino, Samuel Klein, Christine M. Kusminski, Philipp E. Scherer

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1243-1257
Number of pages15
JournalNature Metabolism
Volume1
Issue number12
DOIs
StatePublished - Dec 1 2019

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    An, Y. A., Crewe, C., Asterholm, I. W., Sun, K., Chen, S., Zhang, F., Shao, M., Funcke, J. B., Zhang, Z., Straub, L., Yoshino, J., Klein, S., Kusminski, C. M., & Scherer, P. E. (2019). Dysregulation of amyloid precursor protein impairs adipose tissue mitochondrial function and promotes obesity. Nature Metabolism, 1(12), 1243-1257. https://doi.org/10.1038/s42255-019-0149-1