Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
Diabetes. 2014 Jul;63(7):2415-31. doi: 10.2337/db13-0883. Epub 2014 Mar 19.
Obesity-induced white adipose tissue (WAT) inflammation and insulin resistance are associated with macrophage (Mф) infiltration and phenotypic shift from "anti-inflammatory" M2-like to predominantly "proinflammatory" M1-like cells. Erythropoietin (EPO), a glycoprotein hormone indispensable for erythropoiesis, has biological activities that extend to nonerythroid tissues, including antiapoptotic and anti-inflammatory effects. Using comprehensive in vivo and in vitro analyses in mice, EPO treatment inhibited WAT inflammation, normalized insulin sensitivity, and reduced glucose intolerance. We investigated EPO receptor (EPO-R) expression in WAT and characterized the role of its signaling during obesity-induced inflammation. Remarkably, and prior to any detectable changes in body weight or composition, EPO treatment reduced M1-like Mф and increased M2-like Mф in WAT, while decreasing inflammatory monocytes. These anti-inflammatory effects were found to be driven, at least in part, by direct EPO-R response in Mф via Stat3 activation, where EPO effects on M2 but not M1 Mф required interleukin-4 receptor/Stat6. Using obese ∆EpoR mice with EPO-R restricted to erythroid cells, we demonstrated an anti-inflammatory role for endogenous EPO. Collectively, our findings identify EPO-R signaling as a novel regulator of WAT inflammation, extending its nonerythroid activity to encompass effects on both Mф infiltration and subset composition in WAT.
肥胖引起的白色脂肪组织 (WAT) 炎症和胰岛素抵抗与巨噬细胞 (Mф) 浸润以及从“抗炎”M2 样到主要“促炎”M1 样细胞的表型转变有关。促红细胞生成素 (EPO) 是一种对于红细胞生成必不可少的糖蛋白激素，它具有延伸到非红细胞组织的生物学活性，包括抗凋亡和抗炎作用。我们使用小鼠的全面体内和体外分析，发现 EPO 治疗可抑制 WAT 炎症，使胰岛素敏感性正常化，并减少葡萄糖不耐受。我们研究了 WAT 中的 EPO 受体 (EPO-R) 表达，并描述了其在肥胖引起的炎症过程中的信号作用。值得注意的是，在体重或组成发生任何可检测变化之前，EPO 治疗就可减少 WAT 中的 M1 样 Mф并增加 M2 样 Mф，同时减少炎症性单核细胞。这些抗炎作用至少部分是通过 Mф 中的直接 EPO-R 反应通过 Stat3 激活来驱动的，其中 EPO 对 M2 但不是 M1 Mф 的作用需要白细胞介素 4 受体/Stat6。使用 EPO-R 仅限于红细胞细胞的肥胖 ∆EpoR 小鼠，我们证明了内源性 EPO 的抗炎作用。总之，我们的发现确定了 EPO-R 信号作为 WAT 炎症的新型调节剂，将其非红细胞活性扩展到包括对 WAT 中 Mф 浸润和亚群组成的影响。
