Endothelial deletion of ADGRF5 (GPR116) promotes fibro-inflammatory EndMT and impairs adaptive thermogenesis in brown adipose tissue

Objective: Brown adipose tissue (BAT) dissipates energy via non-shivering thermogenesis, and it is a promising therapeutic target for metabolic disease. While most research focuses on thermogenic adipocytes, emerging data point to critical contributions from the surrounding stromal niche. Here, we investigated the role of adhesion G protein coupled receptors (aGPCRs) in BAT function, focusing on Adgrf5 (Gpr116), a receptor enriched in endothelial cells. Methods: We used single-nuclei RNA sequencing to map aGPCRs expression across mouse and human BAT. We then examined the consequences of Adgrf5(Gpr116) loss using global, brown adipocyte, and endothelial-specific knockout mouse models under acute and prolonged cold exposure. Results: Inducible endothelial deletion of Adgrf5(Gpr116) impaired the maintenance of thermogenic capacity during prolonged,but not acute cold exposure. This was not associated with defective angiogenesis, but rather with endothelial fibro-inflammatory reprogramming. Single-nuclei RNA sequencing analysis revealed endothelial to mesenchymal transition (EndMT) features, including induction of mesenchymal markers, collagens, and metalloproteinases, and loss of barrier genes. Adgrf5(Gpr116)-deficient endothelial cells also exhibited cytoskeletal remodeling and activation of stress fiber pathways, implicating Adgrf5(Gpr116) as a mechanosensory safeguard of endothelial identity.