Macrophage TFEB knockout promotes white adipose tissue inflammation and fibrosis

The molecular mechanisms coordinating adaptive angiogenesis during this expansion remain poorly understood. Here, we demonstrate that macrophage-specific deletion of Transcription Factor EB (Tfeb) in high-fat diet-fed mice exacerbates epididymal white adipose tissue (eWAT) dysfunction, manifesting as profound hypoxia, fibrosis, and systemic insulin resistance.

Mechanistically, single-cell RNA sequencing and chromatin immunoprecipitation assays reveal a novel TFEB-VEGFA axis: TFEB directly activates Vegfa transcription in macrophages, and its absence impairs angiogenic compensation under hypoxic stress. These findings establish macrophage TFEB as a critical regulator of healthy adipose remodeling and validate the TFEB-VEGFA axis as a therapeutic target for metabolic diseases.