title: A PDGFRα-Mediated Switch toward CD9highAdipocyte 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 CD9lowcounterparts, committed to adipogenesis, are almost completely lost in the fibrotic WAT. PDGFRα pathway activation promotes a phenotypic shift toward PDGFRα+CD9highfibrogenic cells, driving pathological remodeling and altering WAT function in obesity. These findings translated to human obesity as the frequency of CD9highprogenitors 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.
authors.affiliation: Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital, F-75013 Paris, France; INSERM, UMRS 1166 (teams 2, 4, and 6 NutriOmics), F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMRS 1166, F-75013 Paris, France. Electronic address: genevieve_marcelin@yahoo.fr.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Marcelin
authors.affiliation: Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital, F-75013 Paris, France; INSERM, UMRS 1166 (teams 2, 4, and 6 NutriOmics), F-75013 Paris, France; Immunometabolism, Department of Nutrition, Nursing School, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil.
authors.forename: Adaliene
authors.initials: A
authors.lastname: Ferreira
authors.affiliation: Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital, F-75013 Paris, France; INSERM, UMRS 1166 (teams 2, 4, and 6 NutriOmics), F-75013 Paris, France; Assistance Publique Hopitaux de Paris, AP-HP, Pitié-Salpêtrière Hospital, Nutrition and Endocrinology Department and Hepato-biliary and Digestive Surgery Department, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMRS 1166, F-75013 Paris, France.
authors.forename: Yuejun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Assistance Publique Hôpitaux de Paris, Aesthetic Plastic Reconstructive Unit, Tenon Hospital, Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, 75020 Paris, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Atlan
authors.affiliation: Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital, F-75013 Paris, France; INSERM, UMRS 1166 (teams 2, 4, and 6 NutriOmics), F-75013 Paris, France; Assistance Publique Hopitaux de Paris, AP-HP, Pitié-Salpêtrière Hospital, Nutrition and Endocrinology Department and Hepato-biliary and Digestive Surgery Department, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMRS 1166, F-75013 Paris, France.
authors.forename: Judith
authors.initials: J
authors.lastname: Aron-Wisnewsky
authors.affiliation: Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital, F-75013 Paris, France; INSERM, UMRS 1166 (teams 2, 4, and 6 NutriOmics), F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMRS 1166, F-75013 Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Pelloux
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Yair
authors.initials: Y
authors.lastname: Botbol
authors.affiliation: Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital, F-75013 Paris, France; INSERM, UMRS 1166 (teams 2, 4, and 6 NutriOmics), F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMRS 1166, F-75013 Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Ambrosini
authors.affiliation: Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital, F-75013 Paris, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Fradet
authors.affiliation: Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital, F-75013 Paris, France; INSERM, UMRS 1166 (teams 2, 4, and 6 NutriOmics), F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMRS 1166, F-75013 Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Rouault
authors.affiliation: HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35806, USA.
authors.forename: Corneliu
authors.initials: C
authors.lastname: Hénégar
authors.affiliation: Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital, F-75013 Paris, France; INSERM, UMRS 1166 (teams 2, 4, and 6 NutriOmics), F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMRS 1166, F-75013 Paris, France.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hulot
authors.affiliation: Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital, F-75013 Paris, France; INSERM, UMRS 1166 (teams 2, 4, and 6 NutriOmics), F-75013 Paris, France; Assistance Publique Hopitaux de Paris, AP-HP, Pitié-Salpêtrière Hospital, Nutrition and Endocrinology Department and Hepato-biliary and Digestive Surgery Department, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMRS 1166, F-75013 Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Poitou
authors.affiliation: Assistance Publique Hopitaux de Paris, AP-HP, Pitié-Salpêtrière Hospital, Nutrition and Endocrinology Department and Hepato-biliary and Digestive Surgery Department, F-75013 Paris, France.
authors.forename: Adriana
authors.initials: A
authors.lastname: Torcivia
authors.affiliation: Assistance Publique Hôpitaux de Paris, Aesthetic Plastic Reconstructive Unit, Tenon Hospital, Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, 75020 Paris, France.
authors.forename: Raphael
authors.initials: R
authors.lastname: Nail-Barthelemy
authors.affiliation: Assistance Publique Hôpitaux de Paris, Plastic Surgery and Mammary Cancer Department, Pitié-Salpêtrière Hospital, F-75013 Paris, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Bichet
authors.affiliation: Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital, F-75013 Paris, France; INSERM, UMRS 1166 (teams 2, 4, and 6 NutriOmics), F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMRS 1166, F-75013 Paris, France.
authors.forename: Emmanuel L
authors.initials: EL
authors.lastname: Gautier
authors.affiliation: Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital, F-75013 Paris, France; INSERM, UMRS 1166 (teams 2, 4, and 6 NutriOmics), F-75013 Paris, France; Assistance Publique Hopitaux de Paris, AP-HP, Pitié-Salpêtrière Hospital, Nutrition and Endocrinology Department and Hepato-biliary and Digestive Surgery Department, F-75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMRS 1166, F-75013 Paris, France. Electronic address: karine.clement2@gmail.com.
authors.forename: Karine
authors.initials: K
authors.lastname: Clément
mesh_terms: D017667:Adipocytes / Q000473:pathology*; D050156:Adipogenesis; D000273:Adipose Tissue / Q000473:pathology*; D052436:Adipose Tissue, White / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000818:Animals; D001835:Body Weight; D004822:Epididymis / Q000378:metabolism; D005355:Fibrosis; D006706:Homeostasis; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D060245:Tetraspanin 29 / Q000378:metabolism*
chemical_list: D010982:Platelet-Derived Growth Factor; D060245:Tetraspanin 29; D020796:Receptor, Platelet-Derived Growth Factor alpha
keywords: adipose tissue; fibrosis; insulin resistance; obesity; progenitors