Estrogen receptor activation reduces lipid synthesis in pancreatic islets and prevents β cell failure in rodent models of type 2 diabetes
Estrogen receptor activation reduces lipid synthesis in pancreatic islets and prevents β cell failure in rodent models of type 2 diabetes
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DOI：
10.1172/jci44564
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发表时间：
2011-08-01
影响因子：
15.9
通讯作者：
Mauvais-Jarvis, Franck
中科院分区：
文献类型：
--
作者：
Tiano, Joseph P.;Delghingaro-Augusto, Viviane;Mauvais-Jarvis, Franck
胰腺β细胞未能适应日益增长的胰岛素需求是患者从胰岛素抵抗进展为2型糖尿病(T2D)的主要机制，并且被认为与这些细胞内的脂质稳态功能失调有关。在多种糖尿病动物模型中，雌性动物表现出对β细胞衰竭的相对保护作用。我们之前发现激素 17 β-雌二醇 (E2) 在一定程度上介导了这种益处。在这里，我们发现用 E2 治疗雄性 Zucker 糖尿病脂肪 (ZDF) 大鼠可抑制胰岛中脂肪酸和甘油脂的合成和积累，并防止 β 细胞衰竭。 E2 的抗脂肪生成作用通过在大鼠 β 细胞系以及培养的 ZDF 大鼠、小鼠和人胰岛中雌激素受体 α (ERa α) 或 ER β 的药理激活来概括。小鼠胰腺特异性 ER α 缺失 (PER α(-/-)) 通过直接作用于胰岛，阻止了 E2 脂质合成的减少，而 PER α(-/-) 小鼠因高脂肪饮食喂养而容易出现胰岛脂质积累和 β 细胞功能障碍。 ER 激活通过依赖于激活的 Stat3 的非经典途径抑制脂肪酸合酶的表达（和活性），从而抑制 β 细胞脂质合成。因此，小鼠胰腺特异性删除 Stat3 可减少内质网介导的脂质合成抑制。这些数据表明，核外 ER 可能是预防 T2D β 细胞衰竭的有希望的治疗靶点。
The failure of pancreatic beta cells to adapt to an increasing demand for insulin is the major mechanism by which patients progress from insulin resistance to type 2 diabetes (T2D) and is thought to be related to dysfunctional lipid homeostasis within those cells. In multiple animal models of diabetes, females demonstrate relative protection from beta cell failure. We previously found that the hormone 17 beta-estradiol (E2) in part mediates this benefit. Here, we show that treating male Zucker diabetic fatty (ZDF) rats with E2 suppressed synthesis and accumulation of fatty acids and glycerolipids in islets and protected against beta cell failure. The antilipogenic actions of E2 were recapitulated by pharmacological activation of estrogen receptor alpha (ERa alpha) or ER beta in a rat beta cell line and in cultured ZDF rat, mouse, and human islets. Pancreas-specific null deletion of ER alpha in mice (PER alpha(-/-)) prevented reduction of lipid synthesis by E2 via a direct action in islets, and PER alpha(-/-) mice were predisposed to islet lipid accumulation and beta cell dysfunction in response to feeding with a high-fat diet. ER activation inhibited beta cell lipid synthesis by suppressing the expression (and activity) of fatty acid synthase via a nonclassical pathway dependent on activated Stat3. Accordingly, pancreas-specific deletion of Stat3 in mice curtailed ER-mediated suppression of lipid synthesis. These data suggest that extranuclear ERs may be promising therapeutic targets to prevent beta cell failure in T2D.