1. Autophagy inhibition blunts PDGFRA adipose progenitors' cell-autonomous fibrogenic response to high-fat diet
- Author
-
Nadine Suffee, Geneviève Marcelin, Emmanuel L. Gautier, Amélie Lacombe, Carla Da Cunha, Isabelle Dugail, Christine Rouault, Nataliya Sokolovska, Karine Clément, Arnaud Leclerc, Camille Gamblin, Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU ICAN], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Dugail, Isabelle, Instituts Hospitalo-Universitaires - Institut de Cardiologie-Métabolisme-Nutrition - - ICAN2010 - ANR-10-IAHU-0005 - IAHU - VALID, Appel à projets générique - LIPA, une nouvelle cible thérapeutique pour le traitement des maladies cardiométaboliques - - LIPOCAMD2014 - ANR-14-CE12-0017 - Appel à projets générique - VALID, Contrôler la fonction des progéniteurs du tissu adipeux pour améliorer les désordres métaboliques de l'obésité - - CAPTOR2017 - ANR-17-CE14-0009 - AAPG2017 - VALID, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Sorbonne Université (SU), Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], Funding from the French National Agency of Research (ANR) is acknowledged and includes support from RHU collaborative grant CARMMA [15-RHUS-0003], from the Institute of Cardiometabolism and Nutrition (reference ANR-10-IAHU-05, to AL), ANR-14-CE12-0017-01 LIPOCAMD and ANR CAPTOR (ANR-17-CE14-0009). GM 615 and KC also received funds from AFERO, EFSD-Novo Nordisk, and SFD to support for salaries and consumables., ANR-10-IAHU-0005,ICAN,Institut de Cardiologie-Métabolisme-Nutrition(2010), ANR-14-CE12-0017,LIPOCAMD,LIPA, une nouvelle cible thérapeutique pour le traitement des maladies cardiométaboliques(2014), ANR-17-CE14-0009,CAPTOR,Contrôler la fonction des progéniteurs du tissu adipeux pour améliorer les désordres métaboliques de l'obésité(2017), Nutrition et obésités: approches systémiques (nutriomics) (UMR-S 1269 INSERM - Sorbonne Université), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de nutrition [CHU Pitié-Salpétrière], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP]
- Subjects
0301 basic medicine ,collagen ,MESH: Signal Transduction ,Male ,obesity ,Receptor, Platelet-Derived Growth Factor alpha ,[SDV.BA] Life Sciences [q-bio]/Animal biology ,MESH: Bone Morphogenetic Proteins ,MESH: Receptor, Platelet-Derived Growth Factor alpha ,[SDV]Life Sciences [q-bio] ,Adipose tissue ,Muscle Proteins ,Autophagy-Related Protein 7 ,Extracellular matrix ,chloroquine ,chemistry.chemical_compound ,Adipose Tissue, Brown ,Fibrosis ,Transforming Growth Factor beta ,Adipocyte ,ScAT: subcutaneous adipose tissue ,MESH: Animals ,OvAT: ovarian adipose tissue ,Promoter Regions, Genetic ,Sex Characteristics ,[SDV.BA]Life Sciences [q-bio]/Animal biology ,Stem Cells ,Cell biology ,Extracellular Matrix ,KO: knockout ,Adipose Tissue ,Adipogenesis ,MESH: Fibrosis ,Bone Morphogenetic Proteins ,HFD: high-fat diet ,Female ,ATG7 ,MESH: Adipose Tissue ,MESH: Sex Characteristics ,Signal Transduction ,Research Paper ,subcutaneous adipose tissue ,TGF-BMP: transforming growth factor-bone morphogenic protein ARTICLE HISTORY KEYWORDS ATG7 ,MESH: Trans-Activators ,MESH: Stem Cells ,Biology ,MESH: Extracellular Matrix ,Diet, High-Fat ,ECM: extracellular matrix ,MESH: Adipose Tissue, Brown ,03 medical and health sciences ,Paracrine signalling ,MESH: Muscle Proteins ,EpiAT: epididymal adipose tissue ,MESH: Mice, Inbred C57BL ,MESH: Promoter Regions, Genetic ,medicine ,Autophagy ,MESH: Autophagy ,Animals ,Abbreviations: CQ: chloroquine ,Heart Atria ,Progenitor cell ,Molecular Biology ,MESH: Transforming Growth Factor beta ,030102 biochemistry & molecular biology ,GTF2IRD1: 25 general transcription factor II I repeat domain-containing 1 ,MESH: Autophagy-Related Protein 7 ,Cell Biology ,medicine.disease ,MESH: Male ,Mice, Inbred C57BL ,MESH: Diet, High-Fat ,MicroRNAs ,030104 developmental biology ,chemistry ,PDGFR: platelet derived growth factor receptor ,Trans-Activators ,MESH: Heart Atria ,MESH: Female ,MESH: MicroRNAs - Abstract
International audience; Adipose tissue (AT) fibrosis in obesity compromises adipocyte functions and responses to intervention-induced weight loss. It is driven by AT progenitors with dual fibro/adipogenic potential, but pro-fibrogenic pathways activated in obesity remain to be deciphered. To investigate the role of macroautophagy/autophagy in AT fibrogenesis, we used Pdgfra-CreErt2 transgenic mice to create conditional deletion of Atg7 alleles in AT progenitor cells (atg7 cKO) and examined sex-dependent, depot-specific AT remodeling in high-fat diet (HFD)-fed mice. Mice with atg7 cKO had markedly decreased extracellular matrix (ECM) gene expression in visceral, subcutaneous, and epicardial adipose depots compared to Atg7lox/lox littermates. ECM gene program regulation by autophagy inhibition occurred independently of changes in the mass of fat tissues or adipocyte numbers of specific depots, and cultured preadipocytes treated with pharmacological or siRNA-mediated autophagy disruptors could mimic these effects. We found that autophagy inhibition promotes global cell-autonomous remodeling of the paracrine TGF-BMP family landscape, whereas ECM gene modulation was independent of the autophagic regulation of GTF2IRD1. The progenitor-specific mouse model of ATG7 inhibition confirms the requirement of autophagy for white/beige adipocyte turnover, and combined to in vitro experiments, reveal progenitor autophagy dependence for AT fibrogenic response to HFD, through the paracrine remodeling of TGF-BMP factors balance. Abbreviations: CQ: chloroquine; ECM: extracellular matrix; EpiAT: epididymal adipose tissue; GTF2IRD1: general transcription factor II I repeat domain-containing 1; HFD: high-fat diet; KO: knockout; OvAT: ovarian adipose tissue; PDGFR: platelet derived growth factor receptor; ScAT: subcutaneous adipose tissue; TGF-BMP: transforming growth factor-bone morphogenic protein.
- Published
- 2020