Sex-specific effect of estrogen sulfotransferase on mouse models of type 2 diabetes.
Sex-specific effect of estrogen sulfotransferase on mouse models of type 2 diabetes.
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作者：
Gao J;He J;Shi X;Stefanovic-Racic M;Xu M;O'Doherty RM;Garcia-Ocana A;Xie W
雌激素磺基转移酶（estrogen sulfotransferase，EST）是雌激素的磺化和失活酶，在雌激素稳态中起重要作用。在这项研究中，我们表明肝Est的诱导是2型糖尿病的共同特征。雌性小鼠Est的缺失改善了ob/ob、地塞米松和高脂饮食诱导的2型糖尿病小鼠模型的代谢功能。Est消融的代谢益处包括改善身体组成、增加能量消耗和胰岛素敏感性以及减少肝脏糖异生和脂肪生成。这种代谢益处似乎是由于减少雌激素剥夺和增加肝脏中的雌激素活性，而这种益处在卵巢切除小鼠中被消除。有趣的是，Est的作用是性别特异性的，因为ob/ob雄性中的Est消融加剧了糖尿病表型，这是由胰岛β细胞质量减少和体内葡萄糖刺激的胰岛素分泌失败引起的。缺乏Est的ob/ob雄性中β细胞质量的损失与白色脂肪组织中巨噬细胞浸润和炎症增加相关。我们的研究结果揭示了EST在能量代谢和2型糖尿病发病机制中的重要作用。抑制EST，至少在女性中，可能代表一种新的方法来管理2型糖尿病。
Estrogen sulfotransferase (EST), the enzyme responsible for the sulfonation and inactivation of estrogens, plays an important role in estrogen homeostasis. In this study, we showed that induction of hepatic Est is a common feature of type 2 diabetes. Loss of Est in female mice improved metabolic function in ob/ob, dexamethasone-, and high-fat diet–induced mouse models of type 2 diabetes. The metabolic benefit of Est ablation included improved body composition, increased energy expenditure and insulin sensitivity, and decreased hepatic gluconeogenesis and lipogenesis. This metabolic benefit appeared to have resulted from decreased estrogen deprivation and increased estrogenic activity in the liver, whereas such benefit was abolished in ovariectomized mice. Interestingly, the effect of Est was sex-specific, as Est ablation in ob/ob males exacerbated the diabetic phenotype, which was accounted for by the decreased islet β-cell mass and failure of glucose-stimulated insulin secretion in vivo. The loss of β-cell mass in ob/ob males deficient in Est was associated with increased macrophage infiltration and inflammation in white adipose tissue. Our results revealed an essential role of EST in energy metabolism and the pathogenesis of type 2 diabetes. Inhibition of EST, at least in females, may represent a novel approach to manage type 2 diabetes.
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