Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance.
Journal
Nature metabolism
ISSN: 2522-5812
Titre abrégé: Nat Metab
Pays: Germany
ID NLM: 101736592
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
received:
11
08
2020
accepted:
18
03
2022
entrez:
28
4
2022
pubmed:
29
4
2022
medline:
30
4
2022
Statut:
ppublish
Résumé
Resulting from impaired collagen turnover, fibrosis is a hallmark of adipose tissue (AT) dysfunction and obesity-associated insulin resistance (IR). Prolidase, also known as peptidase D (PEPD), plays a vital role in collagen turnover by degrading proline-containing dipeptides but its specific functional relevance in AT is unknown. Here we show that in human and mouse obesity, PEPD expression and activity decrease in AT, and PEPD is released into the systemic circulation, which promotes fibrosis and AT IR. Loss of the enzymatic function of PEPD by genetic ablation or pharmacological inhibition causes AT fibrosis in mice. In addition to its intracellular enzymatic role, secreted extracellular PEPD protein enhances macrophage and adipocyte fibro-inflammatory responses via EGFR signalling, thereby promoting AT fibrosis and IR. We further show that decreased prolidase activity is coupled with increased systemic levels of PEPD that act as a pathogenic trigger of AT fibrosis and IR. Thus, PEPD produced by macrophages might serve as a biomarker of AT fibro-inflammation and could represent a therapeutic target for AT fibrosis and obesity-associated IR and type 2 diabetes.
Identifiants
pubmed: 35478031
doi: 10.1038/s42255-022-00561-5
pii: 10.1038/s42255-022-00561-5
doi:
Substances chimiques
Dipeptidases
EC 3.4.13.-
proline dipeptidase
EC 3.4.13.9
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
476-494Subventions
Organisme : Medical Research Council
ID : MC_UU_12012/4
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00014/2
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 208363/Z/17/Z
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/12/13/29853
Pays : United Kingdom
Organisme : Wellcome Trust
ID : #098051
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12012/2
Pays : United Kingdom
Organisme : Medical Research Council
ID : MRC_MC_UU_12012/4
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 100574/Z/12/Z
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK107786
Pays : United States
Organisme : British Heart Foundation
ID : RG/18/7/33636
Pays : United Kingdom
Organisme : Medical Research Council
ID : MRC_MC_UU_12012/5
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12012/5
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00014/5
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12012/3
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0000872
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
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