Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Clinical Laboratory Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Mol Metab. 2021 Mar;45:101142. doi: 10.1016/j.molmet.2020.101142. Epub 2020 Dec 10.
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.
Wild-type (WT) mice and mouse models with ERα knockout (ERα-/-) and targeted deletion of ERα in adipose tissue (ERα) were used to examine EPO treatment during high-fat diet feeding and after diet-induced obesity.
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 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).
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.
促红细胞生成素（EPO）是红细胞生成所必需的细胞因子，有助于调节脂肪量和血糖控制的代谢。在高脂肪饮食（HFD）的小鼠中，EPO 治疗可改善葡萄糖耐量，并通过减少雄性和去卵巢雌性小鼠的脂肪量来减轻体重增加。在去卵巢雌性小鼠中，用雌激素补充 EPO 治疗可减少脂肪堆积，这为雌激素相关的性别特异性 EPO 在代谢调节中的作用提供了证据。在这项研究中，我们研究了雌激素通过雌激素受体α（ERα）与 EPO 之间的交叉对话，以调节葡萄糖代谢和脂肪量积累。
使用野生型（WT）小鼠和 ERα 敲除（ERα-/-）和脂肪组织中 ERα 靶向缺失（ERα）的小鼠模型，检查在高脂肪饮食喂养期间和饮食诱导肥胖后 EPO 治疗。
在 HFD 上，ERα-/-小鼠表现出脂肪量增加和葡萄糖耐量降低。EPO 治疗可减少雄性 WT 和 ERα-/-小鼠以及雌性 ERα-/-小鼠的脂肪堆积，但不能减少雌性 WT 小鼠的脂肪堆积。EPO 减少了 WT 小鼠中 HFD 引起的脂肪细胞大小增加，但不能减少独立于 EPO 刺激的脂肪量减少的 ERα 缺失小鼠。EPO 治疗还显著改善了雌性 ERα-/-小鼠和雌性 ERα 与 WT 对照相比的葡萄糖和胰岛素耐量。EPO 增加的代谢活性与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）的诱导有关，表明白色脂肪的棕色化。
这项研究清楚地确定了雌激素信号在调节 EPO 对葡萄糖代谢的调节以及 EPO 对脂肪量调节的性别差异作用中的作用。EPO 和雌激素之间的相互作用对于雌性小鼠的代谢稳态和体重调节很重要。
