Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance. / Pellegrinelli, V.; Rodriguez-Cuenca, S.; Rouault, C.; Figueroa-Juarez, E.; Schilbert, H.; Virtue, S.; Moreno-Navarrete, J. M.; Bidault, G.; Vázquez-Borrego, M. C.; Dias, A. R.; Pucker, B.; Dale, M.; Campbell, M.; Carobbio, S.; Lin, Y. H.; Vacca, M.; Aron-Wisnewsky, J.; Mora, S.; Masiero, M. M.; Emmanouilidou, A.; Mukhopadhyay, S.; Dougan, G.; den Hoed, M.; Loos, R. J.F.; Fernández-Real, J. M.; Chiarugi, D.; Clément, K.; Vidal-Puig, A.

In: Nature Metabolism, Vol. 4, No. 4, 2022, p. 476-494.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Pellegrinelli, V, Rodriguez-Cuenca, S, Rouault, C, Figueroa-Juarez, E, Schilbert, H, Virtue, S, Moreno-Navarrete, JM, Bidault, G, Vázquez-Borrego, MC, Dias, AR, Pucker, B, Dale, M, Campbell, M, Carobbio, S, Lin, YH, Vacca, M, Aron-Wisnewsky, J, Mora, S, Masiero, MM, Emmanouilidou, A, Mukhopadhyay, S, Dougan, G, den Hoed, M, Loos, RJF, Fernández-Real, JM, Chiarugi, D, Clément, K & Vidal-Puig, A 2022, 'Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance', Nature Metabolism, vol. 4, no. 4, pp. 476-494. https://doi.org/10.1038/s42255-022-00561-5

APA

Pellegrinelli, V., Rodriguez-Cuenca, S., Rouault, C., Figueroa-Juarez, E., Schilbert, H., Virtue, S., Moreno-Navarrete, J. M., Bidault, G., Vázquez-Borrego, M. C., Dias, A. R., Pucker, B., Dale, M., Campbell, M., Carobbio, S., Lin, Y. H., Vacca, M., Aron-Wisnewsky, J., Mora, S., Masiero, M. M., ... Vidal-Puig, A. (2022). Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance. Nature Metabolism, 4(4), 476-494. https://doi.org/10.1038/s42255-022-00561-5

Vancouver

Pellegrinelli V, Rodriguez-Cuenca S, Rouault C, Figueroa-Juarez E, Schilbert H, Virtue S et al. Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance. Nature Metabolism. 2022;4(4):476-494. https://doi.org/10.1038/s42255-022-00561-5

Author

Pellegrinelli, V. ; Rodriguez-Cuenca, S. ; Rouault, C. ; Figueroa-Juarez, E. ; Schilbert, H. ; Virtue, S. ; Moreno-Navarrete, J. M. ; Bidault, G. ; Vázquez-Borrego, M. C. ; Dias, A. R. ; Pucker, B. ; Dale, M. ; Campbell, M. ; Carobbio, S. ; Lin, Y. H. ; Vacca, M. ; Aron-Wisnewsky, J. ; Mora, S. ; Masiero, M. M. ; Emmanouilidou, A. ; Mukhopadhyay, S. ; Dougan, G. ; den Hoed, M. ; Loos, R. J.F. ; Fernández-Real, J. M. ; Chiarugi, D. ; Clément, K. ; Vidal-Puig, A. / Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance. In: Nature Metabolism. 2022 ; Vol. 4, No. 4. pp. 476-494.

Bibtex

@article{31fa0692c46148e7ad6bdbbe9886d071,
title = "Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance",
abstract = "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.",
author = "V. Pellegrinelli and S. Rodriguez-Cuenca and C. Rouault and E. Figueroa-Juarez and H. Schilbert and S. Virtue and Moreno-Navarrete, {J. M.} and G. Bidault and V{\'a}zquez-Borrego, {M. C.} and Dias, {A. R.} and B. Pucker and M. Dale and M. Campbell and S. Carobbio and Lin, {Y. H.} and M. Vacca and J. Aron-Wisnewsky and S. Mora and Masiero, {M. M.} and A. Emmanouilidou and S. Mukhopadhyay and G. Dougan and {den Hoed}, M. and Loos, {R. J.F.} and Fern{\'a}ndez-Real, {J. M.} and D. Chiarugi and K. Cl{\'e}ment and A. Vidal-Puig",
note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2022",
doi = "10.1038/s42255-022-00561-5",
language = "English",
volume = "4",
pages = "476--494",
journal = "Nature Metabolism",
issn = "2522-5812",
publisher = "Springer",
number = "4",

}

RIS

TY - JOUR

T1 - Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance

AU - Pellegrinelli, V.

AU - Rodriguez-Cuenca, S.

AU - Rouault, C.

AU - Figueroa-Juarez, E.

AU - Schilbert, H.

AU - Virtue, S.

AU - Moreno-Navarrete, J. M.

AU - Bidault, G.

AU - Vázquez-Borrego, M. C.

AU - Dias, A. R.

AU - Pucker, B.

AU - Dale, M.

AU - Campbell, M.

AU - Carobbio, S.

AU - Lin, Y. H.

AU - Vacca, M.

AU - Aron-Wisnewsky, J.

AU - Mora, S.

AU - Masiero, M. M.

AU - Emmanouilidou, A.

AU - Mukhopadhyay, S.

AU - Dougan, G.

AU - den Hoed, M.

AU - Loos, R. J.F.

AU - Fernández-Real, J. M.

AU - Chiarugi, D.

AU - Clément, K.

AU - Vidal-Puig, A.

N1 - Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

U2 - 10.1038/s42255-022-00561-5

DO - 10.1038/s42255-022-00561-5

M3 - Journal article

C2 - 35478031

AN - SCOPUS:85128937450

VL - 4

SP - 476

EP - 494

JO - Nature Metabolism

JF - Nature Metabolism

SN - 2522-5812

IS - 4

ER -

ID: 305688294