Dey Soumyadeep, Lee Jeeyoung, Noguchi Constance T
Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States.
Front Pharmacol. 2021 Sep 15;12:725734. doi: 10.3389/fphar.2021.725734. eCollection 2021.
Erythropoietin (EPO) receptor (EPOR) determines EPO response. High level EPOR on erythroid progenitor cells gives rise to EPO regulated production of red blood cells. Animal models provide evidence for EPO activity in non-hematopoietic tissue mediated by EPOR expression. Beyond erythropoiesis, EPO activity includes neuroprotection in brain ischemia and trauma, endothelial nitric oxide production and cardioprotection, skeletal muscle wound healing, and context dependent bone remodeling affecting bone repair or bone loss. This review highlights examples of EPO protective activity in select non-hematopoietic tissue with emphasis on metabolic response mediated by EPOR expression in fat and brain and sex-specific regulation of fat mass and inflammation associated with diet induced obesity. Endogenous EPO maintains glucose and insulin tolerance and protects against fat mass accumulation and inflammation. Accompanying the increase in erythropoiesis with EPO treatment is improved glucose tolerance and insulin response. During high fat diet feeding, EPO also decreases fat mass accumulation in male mice. The increased white adipose tissue inflammation and macrophage infiltration associated with diet induced obesity are also reduced with EPO treatment with a shift toward an anti-inflammatory state and decreased inflammatory cytokine production. In female mice the protective effect of estrogen against obesity supersedes EPO regulation of fat mass and inflammation, and requires estrogen receptor alpha activity. In brain, EPOR expression in the hypothalamus localizes to proopiomelanocortin neurons in the arcuate nucleus that promotes a lean phenotype. EPO stimulation of proopiomelanocortin neurons increases STAT3 signaling and production of proopiomelanocortin. Cerebral EPO contributes to metabolic response, and elevated brain EPO reduces fat mass and hypothalamus inflammation during diet induced obesity in male mice without affecting EPO stimulated erythropoiesis. Ovariectomy abrogates the sex-specific metabolic response of brain EPO. The sex-dimorphic EPO metabolic response associated with fat mass accumulation and inflammation during diet induced obesity provide evidence for crosstalk between estrogen and EPO in their anti-obesity potential in female mice mediated in part via tissue specific response in brain and white adipose tissue. Endogenous and exogenous EPO response in non-hematopoietic tissue demonstrated in animal models suggests additional activity by which EPO treatment may affect human health beyond increased erythropoiesis.
促红细胞生成素（EPO）受体（EPOR）决定了对EPO的反应。红系祖细胞上高水平的EPOR会引发EPO调节的红细胞生成。动物模型为EPOR表达介导的非造血组织中的EPO活性提供了证据。除了红细胞生成外，EPO活性还包括脑缺血和创伤中的神经保护、内皮一氧化氮生成和心脏保护、骨骼肌伤口愈合以及影响骨修复或骨质流失的依赖于环境的骨重塑。本综述重点介绍了EPO在特定非造血组织中的保护活性实例，重点关注脂肪和大脑中由EPOR表达介导的代谢反应以及与饮食诱导肥胖相关的脂肪量和炎症的性别特异性调节。内源性EPO维持葡萄糖和胰岛素耐受性，并防止脂肪量积累和炎症。随着EPO治疗导致红细胞生成增加，葡萄糖耐受性和胰岛素反应也会改善。在高脂饮食喂养期间，EPO还会减少雄性小鼠的脂肪量积累。与饮食诱导肥胖相关的白色脂肪组织炎症增加和巨噬细胞浸润也会因EPO治疗而减少，炎症状态向抗炎转变，炎症细胞因子产生减少。在雌性小鼠中，雌激素对肥胖的保护作用取代了EPO对脂肪量和炎症的调节，并且需要雌激素受体α活性。在大脑中，下丘脑的EPOR表达定位于弓状核中促阿黑皮素原神经元，该神经元促进瘦体型。EPO刺激促阿黑皮素原神经元会增加STAT3信号传导和促阿黑皮素原的产生。脑源性EPO有助于代谢反应，在雄性小鼠饮食诱导肥胖期间，脑内EPO水平升高可减少脂肪量和下丘脑炎症，而不影响EPO刺激的红细胞生成。卵巢切除术消除了脑源性EPO的性别特异性代谢反应。饮食诱导肥胖期间与脂肪量积累和炎症相关的性别二态性EPO代谢反应为雌激素和EPO在雌性小鼠抗肥胖潜力方面的相互作用提供了证据，这种相互作用部分通过大脑和白色脂肪组织中的组织特异性反应介导。动物模型中显示的非造血组织中的内源性和外源性EPO反应表明，EPO治疗除了增加红细胞生成外，还可能通过其他活性影响人类健康。
