Dysregulation of Amyloid Precursor Protein Impairs Adipose Tissue Mitochondrial Function and Promotes Obesity.
Adipocytes
/ metabolism
Adipose Tissue
/ metabolism
Adipose Tissue, White
/ metabolism
Adult
Amyloid beta-Protein Precursor
/ biosynthesis
Animals
Body Weight
Cell Size
Diet, High-Fat
Fatty Liver
/ metabolism
Female
HEK293 Cells
Humans
Insulin Resistance
/ genetics
Lipolysis
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria
/ metabolism
Obesity
/ genetics
Weight Gain
Journal
Nature metabolism
ISSN: 2522-5812
Titre abrégé: Nat Metab
Pays: Germany
ID NLM: 101736592
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
entrez:
28
1
2020
pubmed:
28
1
2020
medline:
28
1
2020
Statut:
ppublish
Résumé
Mitochondrial function in white adipose tissue (WAT) is an important yet understudied aspect in 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 significantly induce APP production in WAT and its enrichment in mitochondria. Mechanistically, a 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. Adipocyte-specific and mitochondria-targeted APP overexpressing mice display increased body mass and reduced insulin sensitivity, along with dysfunctional WAT due to a dramatic hypertrophic program in adipocytes. Elimination of adipocyte APP rescues HFD-impaired mitochondrial function with significant protection from weight gain and systemic metabolic deficiency. Our data highlights an important role of APP in modulating WAT mitochondrial function and obesity-associated metabolic dysfunction.
Identifiants
pubmed: 31984308
doi: 10.1038/s42255-019-0149-1
pmc: PMC6980705
mid: NIHMS1541985
pii: 10.1038/s42255-019-0149-1
doi:
Substances chimiques
APP protein, human
0
APP protein, mouse
0
Amyloid beta-Protein Precursor
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
1243-1257Subventions
Organisme : NIDDK NIH HHS
ID : P01 DK088761
Pays : United States
Organisme : NIH HHS
ID : S10 OD021685
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK056341
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000448
Pays : United States
Organisme : NIDDK NIH HHS
ID : RC2 DK118620
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK099110
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002345
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK055758
Pays : United States
Déclaration de conflit d'intérêts
Competing interests All the authors declare no competing interests.
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