Background:The ADRB3 (β3-adrenergic receptors), which is predominantly expressed in brown adipose tissue (BAT), can activate BAT and improve metabolic health. Previous studies indicate that the endocrine function of BAT is associated with cardiac homeostasis and diseases. Here, we investigate the role of ADRB3 activation-mediated BAT function in cardiac remodeling.Methods:BKO (brown adipocyte-specific ADRB3 knockout) and littermate control mice were subjected to Ang II (angiotensin II) for 28 days. Exosomes from ADRB3 antagonist SR59230A (SR-exo) or agonist mirabegron (MR-exo) treated brown adipocytes were intravenously injected to Ang II–infused mice.Results:BKO markedly accelerated cardiac hypertrophy and fibrosis compared with control mice after Ang II infusion. In vitro, ADRB3 KO rather than control brown adipocytes aggravated expression of fibrotic genes in cardiac fibroblasts, and this difference was not detected after exosome inhibitor treatment. Consistently, BKO brown adipocyte-derived exosomes accelerated Ang II–induced cardiac fibroblast dysfunction compared with control exosomes. Furthermore, SR-exo significantly aggravated Ang II–induced cardiac remodeling, whereas MR-exo attenuated cardiac dysfunction. Mechanistically, ADRB3 KO or SR59230A treatment in brown adipocytes resulted an increase of iNOS (inducible nitric oxide synthase) in exosomes. Knockdown of iNOS in brown adipocytes reversed SR-exo-aggravated cardiac remodeling.Conclusions:Our data illustrated a new endocrine pattern of BAT in regulating cardiac remodeling, suggesting that activation of ADRB3 in brown adipocytes offers cardiac protection through suppressing exosomal iNOS.

中文翻译：

---

棕色脂肪细胞 ADRB3 通过抑制外泌体 iNOS 介导心脏保护作用

背景：主要在棕色脂肪组织 (BAT) 中表达的 ADRB3（β3-肾上腺素能受体）可以激活 BAT 并改善代谢健康。先前的研究表明，BAT 的内分泌功能与心脏稳态和疾病有关。在这里，我们研究了 ADRB3 激活介导的 BAT 功能在心脏重塑中的作用。方法：BKO（棕色脂肪细胞特异性 ADRB3 敲除）和同窝对照小鼠接受 Ang II（血管紧张素 II）28 天。将来自 ADRB3 拮抗剂 SR59230A (SR-exo) 或激动剂米拉贝隆 (MR-exo) 处理的棕色脂肪细胞的外泌体静脉注射到注入 Ang II 的小鼠中。结果：与注入 Ang II 的对照小鼠相比，BKO 显着加速心脏肥大和纤维化。体外，ADRB3 KO而不是对照棕色脂肪细胞加重了心脏成纤维细胞中纤维化基因的表达，并且在外泌体抑制剂处理后未检测到这种差异。与对照外泌体相比，BKO 棕色脂肪细胞衍生的外泌体始终加速 Ang II 诱导的心脏成纤维细胞功能障碍。此外，SR-exo 显着加重了 Ang II 诱导的心脏重塑，而 MR-exo 则减轻了心脏功能障碍。从机制上讲，棕色脂肪细胞中的 ADRB3 KO 或 SR59230A 处理导致外泌体中 iNOS（诱导型一氧化氮合酶）的增加。敲除棕色脂肪细胞中的 iNOS 可逆转 SR-exo 加重的心脏重塑。结论：我们的数据说明了 BAT 在调节心脏重塑中的新内分泌模式，