Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Dokumenter
- Fulltext
Indsendt manuskript, 3,11 MB, PDF-dokument
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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature Metabolism |
| Vol/bind | 4 |
| Udgave nummer | 4 |
| Sider (fra-til) | 476-494 |
| Antal sider | 19 |
| ISSN | 2522-5812 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
This work was funded by a Wellcome Trust strategic award (100574/Z/12/Z), MRC MDU (MC_UU_12012/2), H2020 EPoS (Elucidating Pathways of Steatohepatitis grant agreement 634413) and the British Heart Foundation (RG/18/7/33636). The Disease Model Core, Biochemistry Assay Lab, the Histology Core and the Genomics and Transcriptomics Core are funded by MRC_MC_UU_12012/5 and a Wellcome Trust Strategic Award (208363/Z/17/Z). We thank the Wellcome Trust Sanger Institute Mouse Genetics Project (Sanger MGP) and its funders for providing the mutant mouse line (Pepd). We thank the Disease Model Core from the Wellcome-MRC Institute of Metabolic Science and A. Lukasik for their technical assistance in animal work. All animal work was carried out in the Disease Model Core (MRC Metabolic Diseases Unit (MRC_MC_UU_12012/5); Wellcome Trust Strategic Award (100574/Z/12/Z)). We also thank Genomics and Transcriptomics core, the Histology core and G. Strachan from the Imaging core for their technical assistance. All serum biochemistry was conducted by the Biochemistry Assay Laboratory (MRC Metabolic Diseases Unit (MRC_MC_UU_12012/5)). Clinical studies in France were supported by ‘Contrat de Recherche Clinic’ (CRC APHP, Fibrota to J.A.-W. and K.C.), by the National Agency of Research (ANR-Captor to C.R. and K.C.) and by EFSD (to K.C.). H2020 EPoS funded K.C. (Elucidating Pathways of Steatohepatitis grant agreement 634413). A.R.D., Y.H.L., M.D. and M.C. were funded by MRC MDU (MRC_MC_UU_00014/5). M.D. also receives funding from the National Institute for Health Research (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust). D.C. was supported by MRC MDU (MRC_MC_UU_12012/4). S.C. was supported by the ERC Senior Investigator award (669879). We also thank all the patients and their physicians, L. Genser for the surgical procedures, C. Poitou for patient recruitment and F. Marcheli for data management. R. J. F. Loos is supported by a grant from the National Institutes of Health (NIH R01DK107786). M.d.H. is a fellow of the Swedish Heart-Lung Foundation (20170872), is a Kjell and Märta Beijer Foundation researcher and is supported by project grants from the Swedish Heart-Lung Foundation (20140543, 20170678 and 20180706) and the Swedish Research Council (2015-03657 and 2019-01417). We also acknowledge the FATBANK platform promoted by the CIBEROBN and the IDIBGI Biobank (Biobanc IDIBGI, B.0000872), integrated into the Spanish National Biobanks Network, for their collaboration and coordination. The funders had no role in study design, data collection and interpretation, or submitting the work for publication. The authors’ views are their own and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. tm1a(KOMP)Wtsi
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
ID: 305688294