Human adipocyte function is impacted by mechanical cues

J Pathol. 2014 Jun;233(2):183-95. doi: 10.1002/path.4347.

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.

Keywords: 3D culture; adipocytes; fibrosis; human obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adipocytes, White / metabolism*
  • Adipocytes, White / pathology
  • Adipokines / genetics
  • Adipokines / metabolism
  • Amino Acid Oxidoreductases / genetics
  • Amino Acid Oxidoreductases / metabolism
  • Binding Sites
  • Cell Shape*
  • Cells, Cultured
  • Collagen / metabolism
  • Connective Tissue Growth Factor / genetics
  • Connective Tissue Growth Factor / metabolism
  • Fibrosis
  • Gene Expression Regulation
  • Granulocyte Colony-Stimulating Factor / genetics
  • Granulocyte Colony-Stimulating Factor / metabolism
  • Humans
  • Integrin beta1 / genetics
  • Integrin beta1 / metabolism
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Lipolysis
  • Mechanotransduction, Cellular*
  • Obesity / genetics
  • Obesity / metabolism*
  • Obesity / pathology
  • Obesity / physiopathology
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Promoter Regions, Genetic
  • Time Factors
  • Transcription Factors
  • Transfection

Substances

  • Adaptor Proteins, Signal Transducing
  • Adipokines
  • CCN2 protein, human
  • IL6 protein, human
  • Integrin beta1
  • Interleukin-6
  • Phosphoproteins
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • Connective Tissue Growth Factor
  • Granulocyte Colony-Stimulating Factor
  • Collagen
  • Amino Acid Oxidoreductases
  • LOXL2 protein, human