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.

中文翻译：

---

肥胖症中基质金属蛋白酶14在脂肪组织重塑中的关键作用。

纤维化被认为是肥胖症发展过程中脂肪组织的主要病理变化。但是，控制纤维化成分及其修饰剂之间相互作用的详细机制仍不清楚。在这里，我们报告说，基质金属蛋白酶14（MMP14），一种关键的细胞周围胶原酶，在肥胖的脂肪组织中显着上调。我们生成了强力霉素诱导的脂肪组织特异性MMP14过表达模型，以研究其调节功能。我们发现，在已建立的肥胖脂肪组织中，MMP14的过度表达导致转基因小鼠脂肪细胞增大和体重增加。此外，小鼠表现出减少的能量消耗，脂质代谢受损和胰岛素抵抗。从机理上讲，我们发现MMP14消化6α3胶原蛋白以产生内啡肽，一种有效的纤维化和炎症共刺激剂。出乎意料的是，当在肥胖的早期肥胖组织中过表达MMP14时，转基因小鼠显示出更健康的代谢特征，包括改善的纤维化和炎症，以及改善的脂质和葡萄糖代谢。这种独特的代谢表型可能是由于MMP14对致密脂肪组织细胞外基质的消化/修饰，从而释放了机械应力以使其健康扩张。理解MMP14的这些二元影响，为治疗与肥胖相关的代谢性疾病的策略提供了新颖的见解。包括改善的纤维化和炎症，以及改善的脂质和葡萄糖代谢。这种独特的代谢表型可能是由于MMP14对致密脂肪组织细胞外基质的消化/修饰，从而释放了机械应力以使其健康扩张。理解MMP14的这些二元影响，为治疗与肥胖相关的代谢性疾病的策略提供了新颖的见解。包括改善的纤维化和炎症，以及改善的脂质和葡萄糖代谢。这种独特的代谢表型可能是由于MMP14对致密脂肪组织细胞外基质的消化/修饰，从而释放了机械应力以使其健康扩张。理解MMP14的这些二元影响，为治疗与肥胖相关的代谢性疾病的策略提供了新颖的见解。