Myeloid MMP14 couples extracellular proteolysis to inflammatory and metabolic remodeling during obesity.

Macrophages orchestrate tissue remodeling, inflammation, and metabolic dysfunction in obesity, but the role of macrophage-intrinsic extracellular proteolysis in immunometabolic regulation remains unclear. Matrix metalloproteinase-14 (MMP14), a membrane-bound protease, is strongly induced during monocyte-to-macrophage differentiation and further elevated in adipose tissue macrophages from high-fat diet (HFD)-fed mice. Pharmacological inhibition or myeloid-specific deletion of Mmp14 impaired macrophage differentiation, proliferation, migration, phagocytosis, and inflammatory activation in response to obesity-associated adipose tissue signals. Mechanistically, MMP14 promoted inflammatory programming by increasing endotrophin generation and enhancing TLR4-NFκB signaling. MMP14 also reprogrammed macrophage lipid metabolism by suppressing lipolysis and promoting lipid accumulation, altering metabolic communication with neighboring cells. In vivo, myeloid-specific Mmp14 deletion protected mice from HFD-induced insulin resistance, dyslipidemia, hepatic steatosis, adipose inflammation, and fibrosis. These findings identify macrophage MMP14 as a key mediator linking extracellular matrix remodeling with inflammatory and metabolic dysfunction in obesity.