Paracrine stimulation of brown adipose tissue vascularization by adipocyte O-GlcNAc signaling

Brown adipose tissue (BAT) is extensively vascularized, which is essential for its physiological activities. The molecular mechanism that underpins BAT vascularization, however, remains poorly understood. This study presents evidence that acute cold exposure induces an elevation in total protein O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) in BAT. Ablation of O-GlcNAc transferase in brown adipocytes drastically impairs BAT vascularization. Mechanistic studies demonstrate that O-GlcNAcylation of specificity protein 1 in brown adipocytes enhances its transcriptional activity toward kielin/chordin-like protein (Kcp). Secreted KCP subsequently promotes BAT angiogenesis by paracrine activation of bone morphogenetic protein signaling. Furthermore, boosting O-GlcNAc signaling with glucosamine supplementation effectively augments BAT vascularization and thermogenesis. These findings thus uncover a previously unrecognized role of adipocyte O-GlcNAc signaling in the metabolism-driven regulation of BAT vascularization and function.