A PDGFRα-Mediated Switch toward CD9high Adipocyte Progenitors Controls Obesity-Induced Adipose Tissue Fibrosis

Geneviève Marcelin; Adaliene Ferreira; Yuejun Liu; Michael Atlan; Judith Aron-Wisnewsky; Véronique Pelloux; Yair Botbol; Marc Ambrosini; Magali Fradet; Christine Rouault; Corneliu Hénégar; Jean Sébastien Hulot; Christine Poitou; Adriana Torcivia; Raphael Nail-Barthelemy; Jean Christophe Bichet; Emmanuel L. Gautier; Karine Clément

doi:10.1016/j.cmet.2017.01.010

A PDGFRα-Mediated Switch toward CD9^high Adipocyte Progenitors Controls Obesity-Induced Adipose Tissue Fibrosis

Geneviève Marcelin, Adaliene Ferreira, Yuejun Liu, Michael Atlan, Judith Aron-Wisnewsky, Véronique Pelloux, Yair Botbol, Marc Ambrosini, Magali Fradet, Christine Rouault, Corneliu Hénégar, Jean Sébastien Hulot, Christine Poitou, Adriana Torcivia, Raphael Nail-Barthelemy, Jean Christophe Bichet, Emmanuel L. Gautier, Karine Clément

Pathology

Research output: Contribution to journal › Article › peer-review

129 Scopus citations

Abstract

Obesity-induced white adipose tissue (WAT) fibrosis is believed to accelerate WAT dysfunction. However, the cellular origin of WAT fibrosis remains unclear. Here, we show that adipocyte platelet-derived growth factor receptor-α-positive (PDGFRα⁺) progenitors adopt a fibrogenic phenotype in obese mice prone to visceral WAT fibrosis. More specifically, a subset of PDGFRα⁺ cells with high CD9 expression (CD9^high) originates pro-fibrotic cells whereas their CD9^low counterparts, committed to adipogenesis, are almost completely lost in the fibrotic WAT. PDGFRα pathway activation promotes a phenotypic shift toward PDGFRα⁺CD9^high fibrogenic cells, driving pathological remodeling and altering WAT function in obesity. These findings translated to human obesity as the frequency of CD9^high progenitors in omental WAT (oWAT) correlates with oWAT fibrosis level, insulin-resistance severity, and type 2 diabetes. Collectively, our data demonstrate that in addition to representing a WAT adipogenic niche, different PDGFRα⁺ cell subsets modulate obesity-induced WAT fibrogenesis and are associated with loss of metabolic fitness.

Original language	English (US)
Pages (from-to)	673-685
Number of pages	13
Journal	Cell metabolism
Volume	25
Issue number	3
DOIs	https://doi.org/10.1016/j.cmet.2017.01.010
State	Published - Mar 7 2017

Keywords

adipose tissue
fibrosis
insulin resistance
obesity
progenitors

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cmet.2017.01.010

Cite this

Marcelin, G., Ferreira, A., Liu, Y., Atlan, M., Aron-Wisnewsky, J., Pelloux, V., Botbol, Y., Ambrosini, M., Fradet, M., Rouault, C., Hénégar, C., Hulot, J. S., Poitou, C., Torcivia, A., Nail-Barthelemy, R., Bichet, J. C., Gautier, E. L., & Clément, K. (2017). A PDGFRα-Mediated Switch toward CD9^high Adipocyte Progenitors Controls Obesity-Induced Adipose Tissue Fibrosis. Cell metabolism, 25(3), 673-685. https://doi.org/10.1016/j.cmet.2017.01.010

Marcelin, G, Ferreira, A, Liu, Y, Atlan, M, Aron-Wisnewsky, J, Pelloux, V, Botbol, Y, Ambrosini, M, Fradet, M, Rouault, C, Hénégar, C, Hulot, JS, Poitou, C, Torcivia, A, Nail-Barthelemy, R, Bichet, JC, Gautier, EL & Clément, K 2017, 'A PDGFRα-Mediated Switch toward CD9^high Adipocyte Progenitors Controls Obesity-Induced Adipose Tissue Fibrosis', Cell metabolism, vol. 25, no. 3, pp. 673-685. https://doi.org/10.1016/j.cmet.2017.01.010

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title = "A PDGFRα-Mediated Switch toward CD9high Adipocyte Progenitors Controls Obesity-Induced Adipose Tissue Fibrosis",

abstract = "Obesity-induced white adipose tissue (WAT) fibrosis is believed to accelerate WAT dysfunction. However, the cellular origin of WAT fibrosis remains unclear. Here, we show that adipocyte platelet-derived growth factor receptor-α-positive (PDGFRα+) progenitors adopt a fibrogenic phenotype in obese mice prone to visceral WAT fibrosis. More specifically, a subset of PDGFRα+ cells with high CD9 expression (CD9high) originates pro-fibrotic cells whereas their CD9low counterparts, committed to adipogenesis, are almost completely lost in the fibrotic WAT. PDGFRα pathway activation promotes a phenotypic shift toward PDGFRα+CD9high fibrogenic cells, driving pathological remodeling and altering WAT function in obesity. These findings translated to human obesity as the frequency of CD9high progenitors in omental WAT (oWAT) correlates with oWAT fibrosis level, insulin-resistance severity, and type 2 diabetes. Collectively, our data demonstrate that in addition to representing a WAT adipogenic niche, different PDGFRα+ cell subsets modulate obesity-induced WAT fibrogenesis and are associated with loss of metabolic fitness.",

keywords = "adipose tissue, fibrosis, insulin resistance, obesity, progenitors",

author = "Genevi{\`e}ve Marcelin and Adaliene Ferreira and Yuejun Liu and Michael Atlan and Judith Aron-Wisnewsky and V{\'e}ronique Pelloux and Yair Botbol and Marc Ambrosini and Magali Fradet and Christine Rouault and Corneliu H{\'e}n{\'e}gar and Hulot, {Jean S{\'e}bastien} and Christine Poitou and Adriana Torcivia and Raphael Nail-Barthelemy and Bichet, {Jean Christophe} and Gautier, {Emmanuel L.} and Karine Cl{\'e}ment",

note = "Funding Information: We thank the Institute of Cardiometabolism and Nutrition Core Facility Preclin-ICAN mouse phenotyping core (Amelie Lacombe and Thierry Huby). We thank Nicolas Philibert and Sonia Mutel for their technical help and Sophie Nadaud for sharing the PDGFRα-CreERT2 and PDGFRα+/D842V mouse lines. We acknowledge Rachel Peat for her critical editing of the manuscript. The clinical work was partly supported by clinical research contracts (FibroTA to J.A.-W. and K.C.). Funding was obtained from the Fondation pour la Recherche M{\'e}dicale (DEQ20120323701), the French National Agency of Research (ANR), Adipofib program, the national program “Investissement d'Avenir” ANR-10-IAHU-05, and as part of the second “Investissements d'Avenir” Carmma program ANR-15-RHUS-0003. E.L.G. was supported by ANR Lipocamd program ANR-14-CE12-0017-03, ANR Maclear program ANR-15-CE14-0015-02, and the Fondation de France (00056835). A.F. was supported by Coordena{\c c}{\~a}o de Aperfei{\c c}oamento de Pessoal de N{\'i}vel Superior (CAPES). We thank patients and nurses, as well as Valentine Lemoine and Dr Marchelli for patient recruitment and data management aspects. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

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AU - Marcelin, Geneviève

AU - Ferreira, Adaliene

AU - Liu, Yuejun

AU - Atlan, Michael

AU - Aron-Wisnewsky, Judith

AU - Pelloux, Véronique

AU - Botbol, Yair

AU - Ambrosini, Marc

AU - Fradet, Magali

AU - Rouault, Christine

AU - Hénégar, Corneliu

AU - Hulot, Jean Sébastien

AU - Poitou, Christine

AU - Torcivia, Adriana

AU - Nail-Barthelemy, Raphael

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AU - Clément, Karine

N1 - Funding Information: We thank the Institute of Cardiometabolism and Nutrition Core Facility Preclin-ICAN mouse phenotyping core (Amelie Lacombe and Thierry Huby). We thank Nicolas Philibert and Sonia Mutel for their technical help and Sophie Nadaud for sharing the PDGFRα-CreERT2 and PDGFRα+/D842V mouse lines. We acknowledge Rachel Peat for her critical editing of the manuscript. The clinical work was partly supported by clinical research contracts (FibroTA to J.A.-W. and K.C.). Funding was obtained from the Fondation pour la Recherche Médicale (DEQ20120323701), the French National Agency of Research (ANR), Adipofib program, the national program “Investissement d'Avenir” ANR-10-IAHU-05, and as part of the second “Investissements d'Avenir” Carmma program ANR-15-RHUS-0003. E.L.G. was supported by ANR Lipocamd program ANR-14-CE12-0017-03, ANR Maclear program ANR-15-CE14-0015-02, and the Fondation de France (00056835). A.F. was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). We thank patients and nurses, as well as Valentine Lemoine and Dr Marchelli for patient recruitment and data management aspects. Publisher Copyright: © 2017 Elsevier Inc.

PY - 2017/3/7

Y1 - 2017/3/7

N2 - Obesity-induced white adipose tissue (WAT) fibrosis is believed to accelerate WAT dysfunction. However, the cellular origin of WAT fibrosis remains unclear. Here, we show that adipocyte platelet-derived growth factor receptor-α-positive (PDGFRα+) progenitors adopt a fibrogenic phenotype in obese mice prone to visceral WAT fibrosis. More specifically, a subset of PDGFRα+ cells with high CD9 expression (CD9high) originates pro-fibrotic cells whereas their CD9low counterparts, committed to adipogenesis, are almost completely lost in the fibrotic WAT. PDGFRα pathway activation promotes a phenotypic shift toward PDGFRα+CD9high fibrogenic cells, driving pathological remodeling and altering WAT function in obesity. These findings translated to human obesity as the frequency of CD9high progenitors in omental WAT (oWAT) correlates with oWAT fibrosis level, insulin-resistance severity, and type 2 diabetes. Collectively, our data demonstrate that in addition to representing a WAT adipogenic niche, different PDGFRα+ cell subsets modulate obesity-induced WAT fibrogenesis and are associated with loss of metabolic fitness.

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KW - adipose tissue

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KW - insulin resistance

KW - obesity

KW - progenitors

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