Brown adipose tissue (BAT) activity contributes to cardiovascular health by its energy-dissipating capacity but how BAT modulates vascular function and atherosclerosis through endocrine mechanisms remains poorly understood. Here we show that BAT-derived neuregulin-4 (Nrg4) ameliorates atherosclerosis in mice. BAT-specific Nrg4 deficiency accelerates vascular inflammation and adhesion responses, endothelial dysfunction and apoptosis and atherosclerosis in male mice. BAT-specific Nrg4 restoration alleviates vascular inflammation and adhesion responses, attenuates leukocyte homing and reduces endothelial injury and atherosclerosis in male mice. In endothelial cells, Nrg4 decreases apoptosis, inflammation and adhesion responses induced by oxidized low-density lipoprotein. Mechanistically, protein kinase B (Akt)–nuclear factor-κB signaling is involved in the beneficial effects of Nrg4 on the endothelium. Taken together, the results reveal Nrg4 as a potential cross-talk factor between BAT and arteries that may serve as a target for atherosclerosis.

棕色脂肪组织 (BAT) 活动通过其能量耗散能力促进心血管健康，但 BAT 如何通过内分泌机制调节血管功能和动脉粥样硬化仍知之甚少。在这里，我们表明 BAT 衍生的神经调节蛋白 4 (Nrg4) 可改善小鼠的动脉粥样硬化。BAT 特异性 Nrg4 缺乏会加速雄性小鼠的血管炎症和粘附反应、内皮功能障碍和细胞凋亡以及动脉粥样硬化。BAT 特异性 Nrg4 修复可减轻雄性小鼠的血管炎症和粘附反应，减弱白细胞归巢并减少内皮损伤和动脉粥样硬化。在内皮细胞中，Nrg4 减少氧化低密度脂蛋白诱导的细胞凋亡、炎症和粘附反应。从机械上讲，蛋白激酶 B (Akt)–核因子-κB 信号转导参与 Nrg4 对内皮细胞的有益作用。总之，结果表明 Nrg4 是 BAT 和动脉之间潜在的串扰因子，可以作为动脉粥样硬化的靶标。