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bioRxiv · 10.1101/2025.10.31.683372

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

Merahbi, R. E.·Karagiannakou, V.·Kardinal, R.·Jaecksein, M. Y.·Hildebrand, S.·Hasic, M.·Korkmaz, E.·Kumar, A. J.·Krokidi, A. T.·Dyar, K.·Meissner, F.·Grein, S.·Heeren, J.·Klingenspor, M.·Pfeifer, A.·Hassenauer, J.·Wachten, D.·Herzig, S.·Georgiadi, A.
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Abstract

ObjectiveBrown 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. MethodsWe 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. ResultsInducible 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. ConclusionEndothelial Adgrf5(Gpr116) preserves thermogenic competence in BAT by suppressing EndMT and maladaptive matrix remodeling. Our findings establish vascular mechanosensing as a critical determinant of thermogenic tissue homeostasis. HighlightsO_LIAdhesion GPCRs are the second most abundant GPCR family in mouse and human brown fat C_LIO_LIAdhesion GPCRs are enriched in non-adipocyte cell types in brown fat and participate in cell-cell contact signaling C_LIO_LIEndothelial Adgrf5(Gpr116) is required for thermogenic adaptation during prolonged cold exposure C_LIO_LILoss of Adgrf5(Gpr116) induces fibro-inflammatory reprogramming and endothelial-to-mesenchymal transition (EndMT) C_LI

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Merahbi, R. E., Karagiannakou, V., Kardinal, R., Jaecksein, M. Y., Hildebrand, S., Hasic, M., Korkmaz, E., Kumar, A. J., Krokidi, A. T., Dyar, K., Meissner, F., Grein, S., Heeren, J., Klingenspor, M., Pfeifer, A., Hassenauer, J., Wachten, D., Herzig, S., Georgiadi, A.. 2025-10-31. Endothelial deletion of ADGRF5 (GPR116) promotes fibro-inflammatory EndMT and impairs adaptive thermogenesis in brown adipose tissue. https://doi.org/10.1101/2025.10.31.683372

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