Erythropoietin reduces fat mass in female mice lacking estrogen receptor alpha,Molecular Metabolism

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Erythropoietin reduces fat mass in female mice lacking estrogen receptor alpha
Molecular Metabolism ( IF 7.0 ) Pub Date : 2020-12-10 , DOI: 10.1016/j.molmet.2020.101142
Jeeyoung Lee ₁ , Mary F Walter ₂ , Kenneth S Korach ₃ , Constance Tom Noguchi ₁

Affiliation

Objective

Erythropoietin (EPO), the cytokine required for erythropoiesis, contributes to metabolic regulation of fat mass and glycemic control. EPO treatment in mice on high-fat diets (HFD) improved glucose tolerance and decreased body weight gain via reduced fat mass in males and ovariectomized females. The decreased fat accumulation with EPO treatment during HFD in ovariectomized females was abrogated with estradiol supplementation, providing evidence for estrogen-related gender-specific EPO action in metabolic regulation. In this study, we examined the cross-talk between estrogen mediated through estrogen receptor α (ERα) and EPO for the regulation of glucose metabolism and fat mass accumulation.

Methods

Wild-type (WT) mice and mouse models with ERα knockout (ERα−/−) and targeted deletion of ERα in adipose tissue (ERα^adipoKO) were used to examine EPO treatment during high-fat diet feeding and after diet-induced obesity.

Results

ERα−/− mice on HFD exhibited increased fat mass and glucose intolerance. EPO treatment on HFD reduced fat accumulation in male WT and ERα−/− mice and female ERα−/− mice but not female WT mice. EPO reduced HFD increase in adipocyte size in WT mice but not in mice with deletion of ERα independent of EPO-stimulated reduction in fat mass. EPO treatment also improved glucose and insulin tolerance significantly greater in female ERα−/− mice and female ERα^adipoKO compared with WT controls. Increased metabolic activity by EPO was associated with browning of white adipocytes as shown by reductions in white fat-associated genes and induction of brown fat-specific uncoupling protein 1 (UCP1).

Conclusions

This study clearly identified the role of estrogen signaling in modifying EPO regulation of glucose metabolism and the sex-differential EPO effect on fat mass regulation. Cross-talk between EPO and estrogen was implicated for metabolic homeostasis and regulation of body mass in female mice.

中文翻译：

促红细胞生成素减少缺乏雌激素受体α的雌性小鼠的脂肪量

客观的

红细胞生成素 (EPO) 是红细胞生成所需的细胞因子，有助于脂肪量的代谢调节和血糖控制。高脂肪饮食 (HFD) 小鼠的 EPO 治疗通过减少雄性和切除卵巢的雌性的脂肪量来改善葡萄糖耐量并减少体重增加。卵巢切除女性在 HFD 期间通过 EPO 治疗减少的脂肪积累被补充雌二醇取消，为雌激素相关的性别特异性 EPO 在代谢调节中的作用提供证据。在这项研究中，我们检查了通过雌激素受体 α (ERα) 和 EPO 介导的雌激素之间的串扰，以调节葡萄糖代谢和脂肪堆积。

方法

使用野生型 (WT) 小鼠和具有 ERα 敲除 (ERα-/-) 和脂肪组织中 ERα 靶向缺失 (ERα ^adipoKO ) 的小鼠模型来检查高脂饮食喂养期间和饮食诱导肥胖后的 EPO 治疗。

结果

使用 HFD 的 ERα-/- 小鼠表现出增加的脂肪量和葡萄糖耐受不良。EPO 对 HFD 的处理减少了雄性 WT 和 ERα-/- 小鼠以及雌性 ERα-/- 小鼠的脂肪积累，但不会减少雌性 WT 小鼠的脂肪积累。EPO 减少了 WT 小鼠脂肪细胞大小的 HFD 增加，但不影响 ERα 缺失的小鼠，这与 EPO 刺激的脂肪量减少无关。与 WT 对照相比，EPO 治疗还显着改善了雌性 ERα-/- 小鼠和雌性 ERα ^{adipoKO 的}葡萄糖和胰岛素耐受性。EPO 增加的代谢活性与白色脂肪细胞的褐变有关，如白色脂肪相关基因的减少和棕色脂肪特异性解偶联蛋白 1 (UCP1) 的诱导所示。