Journal
JOURNAL OF PATHOLOGY
Volume 233, Issue 2, Pages 183-195Publisher
WILEY-BLACKWELL
DOI: 10.1002/path.4347
Keywords
3D culture; fibrosis; adipocytes; human obesity
Funding
- University Pierre et Marie Curie
- National Agency of Research (ANR Adipofib)
- Fondation pour la Recherche Medicale (FRM team)
- European Community Seventh Framework Programme [201100]
- French government grant (programme 'Investments for the Future') [ANR-10-IAHU]
- Assistance Publique des Hopitaux de Paris [APHP
- Programmes of Clinical Investigation (PHRC)] [0702]
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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 vitro3D 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 1-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. Published by John Wiley & Sons, Ltd
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