Lipid-induced monokine cyclophilin-A promotes adipose tissue dysfunction implementing insulin resistance and type 2 diabetes in zebrafish and mice models of obesity.
Adipogenesis
CD147
Cyclophilin-A
Inflammation
Insulin resistance
Monokine
Journal
Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402
Informations de publication
Date de publication:
05 May 2022
05 May 2022
Historique:
received:
21
01
2022
accepted:
11
04
2022
revised:
01
04
2022
entrez:
5
5
2022
pubmed:
6
5
2022
medline:
10
5
2022
Statut:
epublish
Résumé
Several studies have implicated obesity-induced macrophage-adipocyte cross-talk in adipose tissue dysfunction and insulin resistance. However, the molecular cues involved in the cross-talk of macrophage and adipocyte causing insulin resistance are currently unknown. Here, we found that a lipid-induced monokine cyclophilin-A (CyPA) significantly attenuates adipocyte functions and insulin sensitivity. Targeted inhibition of CyPA in diet-induced obese zebrafish notably reduced adipose tissue inflammation and restored adipocyte function resulting in improvement of insulin sensitivity. Silencing of macrophage CyPA or pharmacological inhibition of CyPA by TMN355 effectively restored adipocytes' functions and insulin sensitivity. Interestingly, CyPA incubation markedly increased adipocyte inflammation along with an impairment of adipogenesis, however, mutation of its cognate receptor CD147 at P309A and G310A significantly waived CyPA's effect on adipocyte inflammation and its differentiation. Mechanistically, CyPA-CD147 interaction activates NF-κB signaling which promotes adipocyte inflammation by upregulating various pro-inflammatory cytokines gene expression and attenuates adipocyte differentiation by inhibiting PPARγ and C/EBPβ expression via LZTS2-mediated downregulation of β-catenin. Moreover, inhibition of CyPA or its receptor CD147 notably restored palmitate or CyPA-induced adipose tissue dysfunctions and insulin sensitivity. All these results indicate that obesity-induced macrophage-adipocyte cross-talk involving CyPA-CD147 could be a novel target for the management of insulin resistance and type 2 diabetes.
Identifiants
pubmed: 35511344
doi: 10.1007/s00018-022-04306-1
pii: 10.1007/s00018-022-04306-1
doi:
Substances chimiques
Lipid A
0
Monokines
0
Cyclophilin A
EC 5.2.1.-
Cyclophilins
EC 5.2.1.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
282Subventions
Organisme : Department of Biotechnology , Ministry of Science and Technology
ID : BT/PR24700/NER/95/819/2017
Organisme : Science and Engineering Research Board
ID : ECR/2017/000892
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
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