Objective

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.

Methods

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.

Results

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.

Conclusions

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.

中文翻译：

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下丘脑促红细胞生成素对肌肉和代谢生理的调节与其外周作用无关。

客观的

促红细胞生成需要糖蛋白激素促红细胞生成素（EPO），而肾脏是成人EPO合成的主要部位。有限的证据表明，在某些情况下脑中可以检测到EPO，但是大脑是否具有自己的EPO系统来实现生物学功能而又不依赖于外围EPO的产生和作用，这一点仍是未知的。我们进行了这项研究，以在正常条件下以及病理生理条件下（包括衰老和饮食肥胖）使用小鼠来解决这个问题。

方法

在不同的大脑区域以及脑脊液中测量EPO的表达。下丘脑室EPO被给予以生理检查对衰老和饮食肥胖状况的可能的治疗作用。测量体重，身体组成，胰岛素耐受性和葡萄糖耐受性以评估EPO对代谢生理的中枢作用，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。另外，采用β2-肾上腺素能受体敲除的骨髓移植来确定骨髓在将大脑与这些外周功能中的某些联系起来方面的潜在作用。

结果

这项研究表明，除一些其他大脑区域外，EPO在腹膜下丘脑中表达，并存在于脑脊液中。与血液中的EPO浓度随年龄增长和饮食肥胖而增加不同，下丘脑EPO在这些疾病中会降低。在治疗上，对老年小鼠的下丘脑心室进行EPO长期治疗，显示瘦体重增加，而体重和脂肪量由于适度减少食物摄入而减少。通过这种中央治疗，肌肉和代谢功能均得到改善，并且在机械上，向骨髓的肾上腺素能信号在将下丘脑EPO传递至这些周围动作中发挥了作用。还对饮食肥胖症进行了研究，结果表明，下丘脑EPO治疗可导致食物摄入量和肥胖症减少，

结论

下丘脑EPO在肌肉和代谢生理的中央调节中发挥作用，而其下降以独立于外周EPO的方式促进衰老和肥胖症生理。