Prevention of Obesity and Insulin Resistance by Estrogens Requires ERa Activation Function-2 ( ERαAF-2), Whereas ERαAF-1 Is Dispensable
Prevention of Obesity and Insulin Resistance by Estrogens Requires ERa Activation Function-2 ( ERαAF-2), Whereas ERαAF-1 Is Dispensable
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DOI：
10.2337/db13-0282
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发表时间：
2013-12-01
期刊：
影响因子：
7.7
通讯作者：
Gourdy, Pierre
中科院分区：
文献类型：
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作者：
Handgraaf, Sandra;Riant, Elodie;Gourdy, Pierre
基于雌激素的疗法的有益代谢作用主要由雌激素受体 (ER) 介导，雌激素受体是一种核受体，通过两种激活功能 (AF) 调节基因转录：AF-1 和 AF-2。使用选择性删除 ERAF-1（ERAF-1 度）或 ERAF-2（ERAF-2 度）的小鼠模型，我们确定了它们在雌激素对身体成分和葡萄糖稳态的作用中各自的作用，以响应正常饮食或高脂肪饮食（HFD）。 ERAF-2 度的雄性和雌性出现体重加速增加、大量肥胖、严重的胰岛素抵抗和葡萄糖不耐症，这很容易让人想起在删除整个 ER 蛋白 (ER-/-) 的小鼠中观察到的表型。与此形成鲜明对比的是，ERAF-1 度小鼠和野生型 (wt) 小鼠具有相似的代谢表型。因此，17-雌二醇的施用调节了胰岛素敏感组织中的关键代谢基因，并为wt和ERAF-1度卵巢切除小鼠提供了针对HFD诱导的代谢紊乱的强大保护作用，而这些作用在ERAF-2度和ER-/-小鼠中完全消除了。因此，虽然这两种 AF 先前已被证明有助于子宫内膜和乳腺癌细胞增殖，但雌激素对肥胖和胰岛素抵抗的保护作用取决于 ERAF-2 而不是 ERAF-1，从而为选择性调节 ER 提供了新的选择。
The beneficial metabolic actions of estrogen-based therapies are mainly mediated by estrogen receptor (ER), a nuclear receptor that regulates gene transcription through two activation functions (AFs): AF-1 and AF-2. Using mouse models deleted electively for ERAF-1 (ERAF-1 degrees) or ERAF-2 (ERAF-2 degrees), we determined their respective roles in the actions of estrogens on body composition and glucose homeostasis in response to either a normal diet or a high-fat diet (HFD). ERAF-2 degrees males and females developed accelerated weight gain, massive adiposity, severe insulin resistance, and glucose intolerancequite reminiscent of the phenotype observed in mice deleted for the entire ER protein (ER-/-). In striking contrast, ERAF-1 degrees and wild-type (wt) mice shared a similar metabolic phenotype. Accordingly, 17-estradiol administration regulated key metabolic genes in insulin-sensitive tissues and conferred a strong protection against HFD-induced metabolic disturbances in wt and ERAF-1 degrees ovariectomized mice, whereas these actions were totally abrogated in ERAF-2 degrees and ER-/- mice. Thus, whereas both AFs have been previously shown to contribute to endometrial and breast cancer cell proliferation, the protective effect of estrogens against obesity and insulin resistance depends on ERAF-2 but not ERAF-1, thereby delineating new options for selective modulation of ER.