Genetic rescue of nonclassical ERα signaling normalizes energy balance in obese Erα-null mutant mice
Genetic rescue of nonclassical ERα signaling normalizes energy balance in obese Erα-null mutant mice
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DOI：
10.1172/jci41702
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发表时间：
2011-02-01
影响因子：
15.9
通讯作者：
Levine, Jon E.
中科院分区：
文献类型：
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作者：
Park, Cheryl J.;Zhao, Zhen;Levine, Jon E.
除了在生殖中的作用外，雌二醇-17 β对调节能量平衡和体重至关重要。雌激素受体α-空（Er α（-/-））突变小鼠发展为肥胖状态，其特征在于能量消耗减少、运动减少、肥胖增加、葡萄糖稳态改变和高瘦素血症。这些特征使人联想到绝经后妇女发展肥胖和2型糖尿病的倾向。然而，ER α信号传导维持正常能量平衡的机制仍不清楚。在这里，我们使用基因敲入小鼠表达突变的ER α，只能通过非经典途径的信号，以评估非经典的ER α信号在能量稳态的作用。在这些小鼠中，我们发现非经典ER α信号恢复ER α（-/-）突变小鼠的代谢参数失调正常或接近正常值。非经典ER α信号对体重和代谢功能的拯救是通过能量消耗的正常化介导的，包括自主运动活动。这些研究结果表明，非经典的ER α信号介导雌二醇-17 β对能量平衡的主要影响，提高了选择性ER α激动剂可能被开发用于降低绝经后妇女肥胖和代谢紊乱风险的可能性。
In addition to its role in reproduction, estradiol-17 beta is critical to the regulation of energy balance and body weight. Estrogen receptor alpha-null (Er alpha(-/-)) mutant mice develop an obese state characterized by decreased energy expenditure, decreased locomotion, increased adiposity, altered glucose homeostasis, and hyperleptinemia. Such features are reminiscent of the propensity of postmenopausal women to develop obesity and type 2 diabetes. The mechanisms by which ER alpha signaling maintains normal energy balance, however, have remained unclear. Here we used knockin mice that express mutant ER alpha that can only signal through the noncanonical pathway to assess the role of nonclassical ER alpha signaling in energy homeostasis. In these mice, we found that nonclassical ER alpha signaling restored metabolic parameters dysregulated in Er alpha(-/-) mutant mice to normal or near-normal values. The rescue of body weight and metabolic function by nonclassical ER alpha signaling was mediated by normalization of energy expenditure, including voluntary locomotor activity. These findings indicate that nonclassical ER alpha signaling mediates major effects of estradiol-17 beta on energy balance, raising the possibility that selective ER alpha agonists may be developed to reduce the risks of obesity and metabolic disturbances in postmenopausal women.