Myeloid MMP14 Couples Extracellular Proteolysis to Inflammatory and Metabolic Remodeling During Obesity

Macrophages orchestrate tissue remodeling, inflammation, and metabolic dysfunction in obesity, yet how macrophage-intrinsic extracellular proteolysis integrates with immunometabolic reprogramming remains poorly defined. Matrix metalloproteinase-14 (MMP14), a membrane-anchored protease with broad matrix-remodeling capacity, is markedly induced during monocyte-to-macrophage differentiation and further upregulated in adipose tissue macrophages from high-fat diet (HFD)-fed mice. Pharmacologic inhibition or myeloid-specific deletion of Mmp14 impaired macrophage differentiation, proliferation, migration, and phagocytosis, and blunted pro-inflammatory activation in response to obese adipose tissue–derived cues. Mechanistically, MMP14 enhanced inflammatory programming in part by promoting endotrophin generation and amplifying TLR4-NF-κB signaling. In parallel, MMP14 reshaped macrophage lipid metabolism by suppressing lipolysis and fostering lipid accumulation, thereby modifying macrophage-derived metabolic signals to neighboring cells. In vivo, myeloid-specific Mmp14 deletion protected mice from HFD-induced insulin resistance, dyslipidemia, hepatic steatosis, and adipose tissue inflammation and fibrosis, while increasing energy expenditure and fatty acid utilization. Collectively, these findings identify macrophage MMP14 as a central node linking extracellular matrix remodeling to inflammatory and metabolic dysfunction in obesity.