Critical role of matrix metalloproteinase 14 in adipose tissue remodeling during obesity

Xin Li, Yueshui Zhao, Chuan Chen, Li Yang, Hyun Ho Lee, Zening Wang, Ningyan Zhang, Mikhail G. Kolonin, Zhiqiang An, Xin Ge, Philipp E. Scherer, Kai Sun

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Fibrosis is recognized as the major pathological change in adipose tissue during the development of obesity. However, the detailed mechanisms governing the interactions between the fibrotic components and their modifiers remain largely unclear. Here, we reported that matrix metalloproteinase 14 (MMP14), a key pericellular collagenase, is dramatically upregulated in obese adipose tissue. We generated a doxycycline-inducible adipose tissue-specific MMP14 overexpression model to study its regulatory function. We found that overexpression of MMP14 in the established obese adipose tissue leads to enlarged adipocytes and increased body weights in transgenic mice. Furthermore, the mice exhibited decreased energy expenditure, impaired lipid metabolism, and insulin resistance. Mechanistically, we found that MMP14 digests collagen 6α3 to produce endotrophin, a potent costimulator of fibrosis and inflammation. Unexpectedly, when overexpressing MMP14 in the early-stage obese adipose tissue, the transgenic mice showed a healthier metabolic profile, including ameliorated fibrosis and inflammation, as well as improved lipid and glucose metabolism. This unique metabolic phenotype is likely due to digestion/ modification of the dense adipose tissue extracellular matrix by MMP14, thereby releasing the mechanical stress to allow for its healthy expansion. Understanding these dichotomous impacts of MMP14 provides novel insights into strategies to treat obesity-related metabolic disorders.

Original languageEnglish (US)
Article numbere00564-19
JournalMolecular and cellular biology
Volume40
Issue number8
DOIs
StatePublished - Mar 1 2020

Keywords

  • Adipose tissue
  • Collagen 6
  • ECM
  • Endotrophin
  • Fibrosis
  • HIF1
  • Inflammation
  • Lipid metabolism
  • MMP14
  • Obesity

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Li, X., Zhao, Y., Chen, C., Yang, L., Lee, H. H., Wang, Z., Zhang, N., Kolonin, M. G., An, Z., Ge, X., Scherer, P. E., & Sun, K. (2020). Critical role of matrix metalloproteinase 14 in adipose tissue remodeling during obesity. Molecular and cellular biology, 40(8), [e00564-19]. https://doi.org/10.1128/MCB.00564-19