TY - JOUR
T1 - Dysregulation of amyloid precursor protein impairs adipose tissue mitochondrial function and promotes obesity
AU - An, Yu A.
AU - Crewe, Clair
AU - Asterholm, Ingrid Wernstedt
AU - Sun, Kai
AU - Chen, Shiuhwei
AU - Zhang, Fang
AU - Shao, Mengle
AU - Funcke, Jan Bernd
AU - Zhang, Zhuzhen
AU - Straub, Leon
AU - Yoshino, Jun
AU - Klein, Samuel
AU - Kusminski, Christine M.
AU - Scherer, Philipp E.
N1 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85076265656&partnerID=8YFLogxK
U2 - 10.1038/s42255-019-0149-1
DO - 10.1038/s42255-019-0149-1
M3 - Article
C2 - 31984308
AN - SCOPUS:85076265656
SN - 2522-5812
VL - 1
SP - 1243
EP - 1257
JO - Nature Metabolism
JF - Nature Metabolism
IS - 12
ER -