title: Human adipocyte function is impacted by mechanical cues.
abstract: Fibrosis is a hallmark of human white adipose tissue (WAT) during obesity-induced chronic inflammation. The functional impact of increased interstitial fibrosis (peri-adipocyte fibrosis) on adjacent adipocytes remains unknown. Here we developed a novel in vitro 3D culture system in which human adipocytes and decellularized material of adipose tissue (dMAT) from obese subjects are embedded in a peptide hydrogel. When cultured with dMAT, adipocytes showed decreased lipolysis and adipokine secretion and increased expression/production of cytokines (IL-6, G-CSF) and fibrotic mediators (LOXL2 and the matricellular proteins THSB2 and CTGF). Moreover, some alterations including lipolytic activity and fibro-inflammation also occurred when the adipocyte/hydrogel culture was mechanically compressed. Notably, CTGF expression levels correlated with the amount of peri-adipocyte fibrosis in WAT from obese individuals. Moreover, dMAT-dependent CTGF promoter activity, which depends on β1-integrin/cytoskeleton pathways, was enhanced in the presence of YAP, a mechanosensitive co-activator of TEAD transcription factors. Mutation of TEAD binding sites abolished the dMAT-induced promoter activity. In conclusion, fibrosis may negatively affect human adipocyte function via mechanosensitive molecules, in part stimulated by cell deformation.
authors.affiliation: INSERM, UMR S 1166, Nutriomics Team, Paris, France; Sorbonne Universités, UPMC University of Paris 06, UMR S 1166, ICAN, Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Pellegrinelli
authors.forename: J
authors.initials: J
authors.lastname: Heuvingh
authors.forename: O
authors.initials: O
authors.lastname: du Roure
authors.forename: C
authors.initials: C
authors.lastname: Rouault
authors.forename: A
authors.initials: A
authors.lastname: Devulder
authors.forename: C
authors.initials: C
authors.lastname: Klein
authors.forename: M
authors.initials: M
authors.lastname: Lacasa
authors.forename: E
authors.initials: E
authors.lastname: Clément
authors.forename: D
authors.initials: D
authors.lastname: Lacasa
authors.forename: K
authors.initials: K
authors.lastname: Clément
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D052438:Adipocytes, White / Q000378:metabolism* / Q000473:pathology; D054392:Adipokines / Q000235:genetics / Q000378:metabolism; D000594:Amino Acid Oxidoreductases / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D048430:Cell Shape; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008066:Lipolysis; D040542:Mechanotransduction, Cellular; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D013997:Time Factors; D014157:Transcription Factors; D014162:Transfection; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D054392:Adipokines; C526317:CCN2 protein, human; C508600:IL6 protein, human; D019012:Integrin beta1; D015850:Interleukin-6; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D055513:Connective Tissue Growth Factor; D016179:Granulocyte Colony-Stimulating Factor; D003094:Collagen; D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human
keywords: 3D culture; adipocytes; fibrosis; human obesity