Endothelial ADGRF5(GPR116) governs vascular adaptation required for sustained thermogenic remodeling of brown adipose tissue.

OBJECTIVES: Brown adipose tissue (BAT) dissipates energy via non-shivering thermogenesis, but durable thermogenic benefit requires sustained cold remodeling that stabilizes a cold-adapted tissue state. While most studies have focused on adipocyte-intrinsic pathways that drive acute activation, how stromal niche cells-particularly the vasculature-sense and coordinate long-term adaptation remains poorly defined. Because GPCRs are key sensors of extracellular and neurohumoral cues, we mapped GPCR expression across mouse and human BAT at single-nucleus resolution and identified adhesion GPCRs as a prominent family enriched in vascular cells, with endothelial ADGRF5(GPR116) emerging as a leading candidate regulator. METHODS: Single-nucleus RNA sequencing of mouse and human BAT was used to map GPCR expression across cell types. Global, inducible endothelial-specific, and adipocyte-specific ADGRF5(GPR116) knockout mouse models were each challenged with acute and prolonged cold exposure. Endothelial and adipocyte states were analyzed using single-nucleus RNA sequencing transcriptional profiling, functional vascular assays, and cell-cell communication modeling. RESULTS: Endothelial deletion of ADGRF5(GPR116) impaired the ability of mice to sustain thermogenesis during prolonged cold exposure, whereas adipocyte-specific deletion did not affect thermogenic capacity in vivo. Loss of endothelial ADGRF5(GPR116) did not alter endothelial cell abundance, but induced endothelial transcriptional reprogramming characterized by disrupted quiescent remodeling programs, shifts in endothelial state with EndMT-like features, and context-dependent alterations in barrier-associated pathways, occurring in the absence of immune cell infiltration or overt fibrosis. Adipocyte reclustering revealed a failure to acquire a fully cold-adapted thermogenic state, with thermogenically inefficient programs and adrenergic hyporesponsiveness, despite preserved sympathetic input. CellChat and NicheNet analyses predicted altered endothelial-derived paracrine signaling capable of reshaping adipocyte identity. CONCLUSIONS: Endothelial ADGRF5(GPR116) is a critical regulator of vascular adaptation during sustained cold exposure and supports full acquisition of the thermogenic adipocyte state through endothelial identity and paracrine signaling.