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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 …