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

Pellegrinelli, V (author)
Univ Cambridge, Wellcome MRC Inst Metab Sci, Cambridge, England.;Univ Cambridge, MRC Metab Dis Unit, Cambridge, England.
Rodriguez-Cuenca, S. (author)
Univ Cambridge, Wellcome MRC Inst Metab Sci, Cambridge, England.;Univ Cambridge, MRC Metab Dis Unit, Cambridge, England.;Univ Cambridge, Nanjing Ctr Technol & Innovat, Nanjing, Peoples R China.
Rouault, C. (author)
Sorbonne Univ, NutriOm Res Unit, INSERM, Paris, France.
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Figueroa-Juarez, E. (author)
Univ Cambridge, Wellcome MRC Inst Metab Sci, Cambridge, England.;Univ Cambridge, MRC Metab Dis Unit, Cambridge, England.
Schilbert, H. (author)
Bielefeld Univ, Ctr Biotechnol CeBiTec, Genet & Genom Plants, Bielefeld, Germany.;Bielefeld Univ, Fac Biol, Bielefeld, Germany.
Virtue, S. (author)
Univ Cambridge, Wellcome MRC Inst Metab Sci, Cambridge, England.;Univ Cambridge, MRC Metab Dis Unit, Cambridge, England.
Moreno-Navarrete, J. M. (author)
Univ Hosp Girona Dr Josep Trueta, Girona Biomed Res Inst IDIBGI, Dept Diabet Endocrinol & Nutr, Girona, Germany.;Univ Girona, Dept Med, Girona, Spain.;Inst Salud Carlos III, CIBERobn Pathophysiol Obes & Nutr, Madrid, Spain.
Bidault, G. (author)
Univ Cambridge, Wellcome MRC Inst Metab Sci, Cambridge, England.;Univ Cambridge, MRC Metab Dis Unit, Cambridge, England.
Vazquez-Borrego, M. C. (author)
Univ Cambridge, Wellcome MRC Inst Metab Sci, Cambridge, England.;Univ Cambridge, MRC Metab Dis Unit, Cambridge, England.;Maimonides Inst Biomed Res Cordoba IMIBIC, Cordoba, Spain.
Dias, A. R. (author)
Univ Cambridge, Wellcome MRC Inst Metab Sci, Cambridge, England.;Univ Cambridge, MRC Metab Dis Unit, Cambridge, England.
Pucker, B. (author)
Bielefeld Univ, Ctr Biotechnol CeBiTec, Genet & Genom Plants, Bielefeld, Germany.;Bielefeld Univ, Fac Biol, Bielefeld, Germany.;Univ Cambridge, Dept Plant Sci, Evolut & Divers, Cambridge, England.
Dale, M. (author)
Univ Cambridge, Wellcome MRC Inst Metab Sci, Cambridge, England.;Univ Cambridge, MRC Metab Dis Unit, Cambridge, England.
Campbell, M. (author)
Univ Cambridge, Wellcome MRC Inst Metab Sci, Cambridge, England.;Univ Cambridge, MRC Metab Dis Unit, Cambridge, England.;Univ Cambridge, Nanjing Ctr Technol & Innovat, Nanjing, Peoples R China.
Carobbio, S. (author)
Univ Cambridge, Wellcome MRC Inst Metab Sci, Cambridge, England.;Univ Cambridge, MRC Metab Dis Unit, Cambridge, England.;Ctr Invest Principe Felipe, Valencia, Spain.
Lin, Y. H. (author)
Univ Cambridge, Wellcome MRC Inst Metab Sci, Cambridge, England.;Univ Cambridge, MRC Metab Dis Unit, Cambridge, England.;Kaohsiung Chang Gung Mem Hosp, Dept Surg, Kaohsiung, Taiwan.;Chang Gung Univ, Coll Med, Kaohsiung, Taiwan.
Vacca, M. (author)
Univ Cambridge, Wellcome MRC Inst Metab Sci, Cambridge, England.;Univ Cambridge, MRC Metab Dis Unit, Cambridge, England.;Univ Bari Aldo Moro, Insterdisciplinary Dept Med, Bari, Italy.
Aron-Wisnewsky, J. (author)
Sorbonne Univ, NutriOm Res Unit, INSERM, Paris, France.;Hop La Pitie Salpetriere, AP HP, Nutr Dept, Paris, France.
Mora, S. (author)
Univ Barcelona, Fac Biol, Dept Biochem & Mol Biomed, Barcelona, Spain.;Univ Barcelona IBUB, Inst Biomed, Barcelona, Spain.
Masiero, M. M. (author)
Uppsala universitet,Science for Life Laboratory, SciLifeLab,Uppsala Univ, Beijer Lab, Uppsala, Sweden.;Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden.
Emmanouilidou, Anastasia (author)
Uppsala universitet,Medicinsk genetik och genomik,Science for Life Laboratory, SciLifeLab
Mukhopadhyay, S. (author)
Kings Coll London, Sch Immunol & Microbial Sci, Dept Immunobiol, VIRC Ctr Transplantat Peter Gorer, London, England.
Dougan, G. (author)
Univ Cambridge, Jeffrey Cheah Biomed Ctr, Cambridge Inst Therapeut Immunol & Infect Dis, Cambridge, England.;Univ Cambridge, Dept Med, Div Infect Dis, Cambridge, England.
den Hoed, Marcel, 1980- (author)
Uppsala universitet,Science for Life Laboratory, SciLifeLab,Molekylär epidemiologi,Medicinsk genetik och genomik
Loos, R. J. F. (author)
Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA.;Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, Copenhagen, Denmark.
Fernandez-Real, J. M. (author)
Univ Hosp Girona Dr Josep Trueta, Girona Biomed Res Inst IDIBGI, Dept Diabet Endocrinol & Nutr, Girona, Germany.;Univ Girona, Dept Med, Girona, Spain.;Inst Salud Carlos III, CIBERobn Pathophysiol Obes & Nutr, Madrid, Spain.
Chiarugi, D. (author)
Univ Cambridge, Wellcome MRC Inst Metab Sci, Cambridge, England.;Univ Cambridge, MRC Metab Dis Unit, Cambridge, England.
Clement, K. (author)
Sorbonne Univ, NutriOm Res Unit, INSERM, Paris, France.;Hop La Pitie Salpetriere, AP HP, Nutr Dept, Paris, France.
Vidal-Puig, A. (author)
Univ Cambridge, Wellcome MRC Inst Metab Sci, Cambridge, England.;Univ Cambridge, MRC Metab Dis Unit, Cambridge, England.;Univ Cambridge, Nanjing Ctr Technol & Innovat, Nanjing, Peoples R China.;Ctr Invest Principe Felipe, Valencia, Spain.
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Univ Cambridge, Wellcome MRC Inst Metab Sci, Cambridge, England;Univ Cambridge, MRC Metab Dis Unit, Cambridge, England. Univ Cambridge, Wellcome MRC Inst Metab Sci, Cambridge, England.;Univ Cambridge, MRC Metab Dis Unit, Cambridge, England.;Univ Cambridge, Nanjing Ctr Technol & Innovat, Nanjing, Peoples R China. (creator_code:org_t)
2022-04-25
2022
English.
In: Nature Metabolism. - : Springer Nature. - 2522-5812. ; 4:4, s. 476-
Related links:
https://urn.kb.se/re...
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https://doi.org/10.1...
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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. Obesity-associated AT fibro-inflammation and metabolic disturbances are linked to PEPD activity and PEPD extracellular levels.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

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ref (subject category)
art (subject category)

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