Silencing of estrogen receptor a in the ventromedial nucleus of hypothalamus leads to metabolic syndrome
Silencing of estrogen receptor a in the ventromedial nucleus of hypothalamus leads to metabolic syndrome
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DOI：
10.1073/pnas.0610787104
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发表时间：
2007-02-13
影响因子：
11.1
通讯作者：
Ogawa, Sonoko
中科院分区：
文献类型：
--
作者：
Musatov, Sergei;Chen, Walter;Ogawa, Sonoko
雌激素受体α（ER α）在雌激素调节食物摄入和能量消耗中起着关键作用。尽管有充分的证据表明ER α敲除（ERKO）小鼠中ER α信号传导的破坏导致肥胖表型，但雌激素作用的位点和这种现象背后的机制在很大程度上仍然未知。在本研究中，我们利用腺相关病毒载体介导的RNA干扰来实现下丘脑腹内侧核（能量稳态的关键中心）中ER α的集中沉默。在抑制该核中的ER α表达后，雌性小鼠和大鼠发展出代谢综合征的表型特征，并以肥胖、摄食过多、葡萄糖耐受性受损和能量消耗减少为特征。尽管大脑其他部位的ER α水平正常，但这种表型仍然存在。虽然食物摄入量的增加先于体重增加，但我们的数据表明，该模型中肥胖的主要因素可能是能量消耗的下降，所有三个主要成分都受到影响，包括自愿活动，基础代谢率和饮食诱导的产热。总之，这些发现表明下丘脑腹内侧核神经元中的ER α在控制能量平衡和维持正常体重中起着重要作用。
Estrogen receptor alpha (ER alpha) plays a pivotal role in the regulation of food intake and energy expenditure by estrogens. Although it is well documented that a disruption of ERa signaling in ER alpha knockout (ERKO) mice leads to an obese phenotype, the sites of estrogen action and mechanisms underlying this phenomenon are still largely unknown. In the present study, we exploited RNA interference mediated by adeno-associated viral vectors to achieve focused silencing of ER alpha in the ventromedial nucleus of the hypothalamus, a key center of energy homeostasis. After suppression of ER alpha expression in this nucleus, female mice and rats developed a phenotype characteristic for metabolic syndrome and marked by obesity, hyperphagia, impaired tolerance to glucose, and reduced energy expenditure. This phenotype persisted despite normal ER alpha levels elsewhere in the brain. Although an increase in food intake preceded weight gain, our data suggest that a leading factor of obesity in this model is likely a decline in energy expenditure with all three major constituents being affected, including voluntary activity, basal metabolic rate, and diet-induced thermogenesis. Together, these findings indicate that ER alpha in the ventromedial nucleus of the hypothalamus neurons plays an essential role in the control of energy balance and the maintenance of normal body weight.