Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
Mol Metab. 2020 Feb;32:56-68. doi: 10.1016/j.molmet.2019.12.001. Epub 2019 Dec 6.
The glycoprotein hormone erythropoietin (EPO) is required for erythropoiesis, and the kidney is the primary site of adult EPO synthesis. Limited evidence has suggested that EPO could be detectable in the brain under certain conditions, but it remains unknown if the brain might have its own EPO system for biological functions that are independent of peripheral EPO production and action. We performed this study to address this question using mice under normal conditions versus pathophysiological conditions including aging and dietary obesity.
EPO expression was measured in different brain regions as well as in the cerebrospinal fluid. Hypothalamic ventricular EPO was administered to physiologically examine possible therapeutic effects on the conditions of aging and dietary obesity. Body weight, body composition, insulin tolerance, and glucose tolerance were measured to assess the central effects of EPO on metabolic physiology, and muscle strength and histology were analyzed to assess the central effects of EPO on muscle function. In addition, β2-adrenergic receptor knockout bone marrow transplant was employed to determine the potential role of bone marrow in linking the brain to some of these peripheral functions.
This study revealed that EPO is expressed in the ventromedial hypothalamus in addition to a few other brain regions and is present in the cerebrospinal fluid. Unlike blood EPO concentration, which increased with aging and dietary obesity, hypothalamic EPO decreased in these disease conditions. Therapeutically, aged mice were chronically treated with EPO in the hypothalamic ventricle, showing an increase in lean mass, while body weight and fat mass decreased as a result of a moderate reduction of food intake. Both muscle and metabolic functions were improved by this central treatment, and mechanistically, adrenergic signals to the bone marrow played a role in conveying hypothalamic EPO to these peripheral actions. Dietary obesity was also studied, showing that hypothalamic EPO treatment caused a reduction in food intake and obesity, leading to improved metabolic functions related to decreased fat as well as increased lean mass.
Hypothalamic EPO plays a role in the central regulation of muscle and metabolic physiology, while its decline contributes to aging and obesity physiology in a manner that is independent of peripheral EPO.
糖蛋白激素促红细胞生成素（EPO）是红细胞生成所必需的，肾脏是成人 EPO 合成的主要部位。有限的证据表明，在某些情况下，EPO 可以在大脑中被检测到，但目前尚不清楚大脑是否具有自身的 EPO 系统，用于与外周 EPO 产生和作用无关的生物学功能。我们进行了这项研究，以在正常条件下和包括衰老和饮食肥胖在内的病理生理条件下使用小鼠来解决这个问题。
测量不同脑区以及脑脊液中的 EPO 表达。向脑室内给予促红细胞生成素，以对衰老和饮食肥胖的情况进行生理检查，观察可能的治疗效果。测量体重、身体成分、胰岛素耐量和葡萄糖耐量，以评估 EPO 对代谢生理学的中枢作用，并分析肌肉力量和组织学，以评估 EPO 对肌肉功能的中枢作用。此外，采用β2-肾上腺素能受体敲除骨髓移植来确定骨髓在将大脑与这些外周功能联系起来方面的潜在作用。
这项研究表明，EPO 除了在少数其他脑区表达外，还在室旁下丘脑表达，并存在于脑脊液中。与随衰老和饮食肥胖而增加的血液 EPO 浓度不同，这些疾病状态下下丘脑的 EPO 减少。在治疗上，衰老的小鼠在室旁脑室内接受 EPO 的慢性治疗，表现出瘦体重增加，而由于食物摄入量适度减少，体重和脂肪量减少。这种中枢治疗改善了肌肉和代谢功能，并且从机制上讲，向骨髓传递的肾上腺素能信号在将下丘脑 EPO 传递到这些外周作用中发挥了作用。还研究了饮食肥胖，发现促红细胞生成素治疗导致食物摄入量和肥胖减少，从而改善与脂肪减少和瘦体重增加相关的代谢功能。
下丘脑 EPO 在肌肉和代谢生理学的中枢调节中发挥作用，而其下降以与外周 EPO 无关的方式导致衰老和肥胖生理学的发生。
