Defective extracellular matrix remodeling in brown adipose tissue is associated with fibro-inflammation and reduced diet-induced thermogenesis

Cell Rep. 2023 Jun 27;42(6):112640. doi: 10.1016/j.celrep.2023.112640. Epub 2023 Jun 13.

Abstract

The relevance of extracellular matrix (ECM) remodeling is reported in white adipose tissue (AT) and obesity-related dysfunctions, but little is known about the importance of ECM remodeling in brown AT (BAT) function. Here, we show that a time course of high-fat diet (HFD) feeding progressively impairs diet-induced thermogenesis concomitantly with the development of fibro-inflammation in BAT. Higher markers of fibro-inflammation are associated with lower cold-induced BAT activity in humans. Similarly, when mice are housed at thermoneutrality, inactivated BAT features fibro-inflammation. We validate the pathophysiological relevance of BAT ECM remodeling in response to temperature challenges and HFD using a model of a primary defect in the collagen turnover mediated by partial ablation of the Pepd prolidase. Pepd-heterozygous mice display exacerbated dysfunction and BAT fibro-inflammation at thermoneutrality and in HFD. Our findings show the relevance of ECM remodeling in BAT activation and provide a mechanism for BAT dysfunction in obesity.

Keywords: CP: Metabolism; PEPD; brown adipose tissue; extracellular matrix; fibrosis; obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, Brown* / metabolism
  • Adipose Tissue, White / metabolism
  • Animals
  • Diet, High-Fat
  • Energy Metabolism
  • Extracellular Matrix
  • Humans
  • Inflammation / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Obesity* / metabolism
  • Thermogenesis