In vivo stimulation of oestrogen receptor α increases insulin-stimulated skeletal muscle glucose uptake
In vivo stimulation of oestrogen receptor α increases insulin-stimulated skeletal muscle glucose uptake
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DOI：
10.1113/jphysiol.2010.199018
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发表时间：
2011-04-15
影响因子：
5.5
通讯作者：
Geiger, Paige C.
中科院分区：
文献类型：
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作者：
Gorres, Brittany K.;Bomhoff, Gregory L.;Geiger, Paige C.
非技术性总结 此前的研究表明，雌激素有利于维持血糖水平并帮助身体对胰岛素做出反应。尽管有这些先前的发现，但雌激素的作用机制尚不清楚。我们发现，当存在胰岛素时，雌激素受体α（ERα）的特异性激活会增加骨骼肌对葡萄糖的摄取。单独激活雌激素受体 β (ER β) 或同时激活 ER α 和 ER β 不会增加骨骼肌对葡萄糖的摄取。这表明雌激素的有益作用是通过激活 ER α 来实现的。这些结果对于理解葡萄糖稳态机制具有重要意义，特别是对于雌激素水平较低的绝经后女性。先前的研究表明雌激素受体α（ERα）参与雌激素介导的葡萄糖代谢调节，对于维持全身胰岛素作用至关重要。尽管如此，直接 ER α 调节对胰岛素反应组织的影响尚不清楚。当前研究的目的是确定使用 ER 亚型选择性配体丙基吡唑三基 (PPT) 激活 ER α 对骨骼肌葡萄糖摄取的影响。两个月大的雌性 Sprague-Dawley 大鼠，卵巢切除 1 周，每 24 小时皮下注射 PPT（10 mg kg-1）、苯甲酸雌二醇（EB；20 mu g kg-1）、ER β 激动剂二芳基丙腈（DPN，10 mg kg-1）或载体，持续 3 天。第四天，在体外测量胰岛素刺激的骨骼肌葡萄糖摄取，并通过蛋白质印迹评估胰岛素信号中间体。用 PPT 激活 ER α 会导致慢肌比目鱼肌和快肌指长伸肌 (EDL) 肌肉中胰岛素刺激的葡萄糖摄取增加，胰岛素信号中间体的激活（通过磷酸 Akt (pAkt) 和 pAkt 底物 (PAS) 测量）以及 AMP 激活的蛋白激酶 (AMPK) 的磷酸化。 GLUT4 蛋白仅在 EDL 肌肉中增加。与媒介物治疗的动物相比，用 EB 或 DPN 治疗 3 天的大鼠并没有显示出胰岛素刺激的骨骼肌葡萄糖摄取的增加。这些新发现表明，ER α 的直接激活可积极介导骨骼肌中的葡萄糖摄取和胰岛素作用。雌激素和 ER α 刺激葡萄糖摄取的证据对于理解葡萄糖稳态机制具有重要意义，特别是对于绝经后妇女。
Non-technical summaryPrevious studies show that oestrogen is beneficial for maintaining blood glucose levels and helping the body respond to insulin. Despite these previous findings, the mechanism by which oestrogen acts is unknown. We show that specific activation of oestrogen receptor alpha (ER alpha) increases glucose uptake into skeletal muscle when insulin is present. Activation of oestrogen receptor beta (ER beta) alone or activation of both ER alpha and ER beta together did not increase glucose uptake into skeletal muscle. This suggests that oestrogen's beneficial effect occurs by activating ER alpha. These results have important implications for understanding the mechanisms of glucose homeostasis, particularly in postmenopausal women with low oestrogen levels.Previous studies suggest oestrogen receptor alpha (ER alpha) is involved in oestrogen-mediated regulation of glucose metabolism and is critical for maintenance of whole body insulin action. Despite this, the effect of direct ER alpha modulation in insulin-responsive tissues is unknown. The purpose of the current study was to determine the impact of ER alpha activation, using the ER subtype-selective ligand propylpyrazoletriyl (PPT), on skeletal muscle glucose uptake. Two-month-old female Sprague-Dawley rats, ovariectomized for 1 week, were given subcutaneous injections of PPT (10 mg kg-1), oestradiol benzoate (EB; 20 mu g kg-1), the ER beta agonist diarylpropionitrile (DPN, 10 mg kg-1) or vehicle every 24 h for 3 days. On the fourth day, insulin-stimulated skeletal muscle glucose uptake was measured in vitro and insulin signalling intermediates were assessed via Western blotting. Activation of ER alpha with PPT resulted in increased insulin-stimulated glucose uptake into the slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles, activation of insulin signalling intermediates (as measured by phospho-Akt (pAkt) and pAkt substrate (PAS)) and phosphorylation of AMP-activated protein kinase (AMPK). GLUT4 protein was increased only in the EDL muscle. Rats treated with EB or DPN for 3 days did not show an increase in insulin-stimulated skeletal muscle glucose uptake compared to vehicle-treated animals. These new findings reveal that direct activation of ER alpha positively mediates glucose uptake and insulin action in skeletal muscle. Evidence that oestrogens and ER alpha stimulate glucose uptake has important implications for understanding mechanisms of glucose homeostasis, particularly in postmenopausal women.