TY - JOUR
T1 - A PDGFRα-Mediated Switch toward CD9high Adipocyte Progenitors Controls Obesity-Induced Adipose Tissue Fibrosis
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
AU - Bichet, Jean Christophe
AU - Gautier, Emmanuel L.
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 PDGFR?-CreERT2 and PDGFR?+/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?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??o de Aperfei?oamento de Pessoal de N?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:
© 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.
AB - 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.
KW - adipose tissue
KW - fibrosis
KW - insulin resistance
KW - obesity
KW - progenitors
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U2 - 10.1016/j.cmet.2017.01.010
DO - 10.1016/j.cmet.2017.01.010
M3 - Article
C2 - 28215843
AN - SCOPUS:85012896702
VL - 25
SP - 673
EP - 685
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 3
ER -