Critical Role of Matrix Metalloproteinase 14 in Adipose Tissue Remodeling during Obesity

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.

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“…Preparation of tissue samples has been described previously 40 . The protein samples were separated by SDS‐gel, transferred onto methanol pre‐wet‐PVDF membranes.…”

Vesicles Shed by Pathological Murine Adipocytes Spread Pathology: Characterization and Functional Role of Insulin Resistant/Hypertrophied Adiposomes

“…DJ-1 protein is implicated in oxidative stress regulation among other functions, but has been also described as participating in adipogenesis and in obesity-induced inflammation [47]. Furthermore, MMP-14 was found to be overexpressed in obese adipose participating in abnormal lipid metabolism and insulin resistance [28]. Finally, it is also interesting to mention those proteins whose presence was elevated in EVs from non-differentiated adipocytes compared to those from mature cells, which may parallel those mesenchymal stem cells (MSCs) embedded in adipose tissue.…”

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“…Recently, we have demonstrated that the matrix metalloproteinase MMP14 expression levels are strongly increased in the AT of obese mice ( Li and Zhao, 2020 ). Application of LPS substantially reduced the expression level of MMP14 in lungs; moreover, MMP14 -/- mice receiving LPS demonstrated 100% mortality connected with severe lung injury ( Aguirre et al, 2017 ).…”