Inhibition of a Novel CLK1-THRAP3-PPARγ Axis Improves Insulin Sensitivity.
CLK1
PPARγ
THRAP3
browning
insulin sensitivity
Journal
Frontiers in physiology
ISSN: 1664-042X
Titre abrégé: Front Physiol
Pays: Switzerland
ID NLM: 101549006
Informations de publication
Date de publication:
2021
2021
Historique:
received:
23
04
2021
accepted:
09
08
2021
entrez:
16
9
2021
pubmed:
17
9
2021
medline:
17
9
2021
Statut:
epublish
Résumé
Increasing energy expenditure by promoting "browning" in adipose tissues is a promising strategy to prevent obesity and associated diabetes. To uncover potential targets of cold exposure, which induces energy expenditure, we performed phosphoproteomics profiling in brown adipose tissue of mice housed in mild cold environment at 16°C. We identified CDC2-like kinase 1 (CLK1) as one of the kinases that were significantly downregulated by mild cold exposure. In addition, genetic knockout of CLK1 or chemical inhibition in mice ameliorated diet-induced obesity and insulin resistance at 22°C. Through proteomics, we uncovered thyroid hormone receptor-associated protein 3 (THRAP3) as an interacting partner of CLK1, further confirmed by co-immunoprecipitation assays. We further demonstrated that CLK1 phosphorylates THRAP3 at Ser243, which is required for its regulatory interaction with phosphorylated peroxisome proliferator-activated receptor gamma (PPARγ), resulting in impaired adipose tissue browning and insulin sensitivity. These data suggest that CLK1 plays a critical role in controlling energy expenditure through the CLK1-THRAP3-PPARγ axis.
Identifiants
pubmed: 34526909
doi: 10.3389/fphys.2021.699578
pmc: PMC8435799
doi:
Types de publication
Journal Article
Langues
eng
Pagination
699578Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK020572
Pays : United States
Informations de copyright
Copyright © 2021 Wang, Gao, Li, Zhu, Zhao, Garcia-Barrio, Zhang, Guo, Chen, Zeng, Wu and Chang.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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