A G-protein-coupled estrogen receptor is involved in hypothalamic control of energy homeostasis
A G-protein-coupled estrogen receptor is involved in hypothalamic control of energy homeostasis
复制标题
DOI：
10.1523/jneurosci.0327-06.2006
复制
发表时间：
2006-05-24
影响因子：
5.3
通讯作者：
Kelly, Martin J.
中科院分区：
文献类型：
--
作者：
Qiu, Jian;Bosch, Martha A.;Kelly, Martin J.
雌激素参与下丘脑对多种稳态功能的控制，包括生殖、应激反应、能量代谢、睡眠周期、温度调节和动机行为。 17 SS-雌二醇（E-2）的关键作用在雌激素低下状态（例如绝经后）中很明显，在这种情况下，许多功能都会出现问题。 E-2 在大脑中的作用归因于通过核、细胞质或膜作用激活雌激素受体 α 和 ss。然而，我们已经鉴定出一种假定的膜相关雌激素受体，该受体与豚鼠和小鼠下丘脑原阿黑皮素神经元中 GABAB 和 mu-阿片受体的脱敏相关。我们合成了一种新的非甾体化合物 STX，它选择性地靶向 G α q 偶联磷脂酶 C 蛋白激酶 C 蛋白激酶 A 通路，并确定 STX 在豚鼠和小鼠神经元中以 ICI 182、780 敏感方式介导这种脱敏作用比 E2 更有效。 E-2 和 STX 对雌激素受体 α、ss 敲除小鼠均完全有效。此外，与 E-2 类似，STX 体内治疗可减弱雌激素水平低的雌性豚鼠的体重增加。因此，这种膜界定的信号通路在能量稳态的控制中发挥着关键作用，并可能为女性绝经后症状和饮食失调的治疗提供新的治疗靶点。
Estrogens are involved in the hypothalamic control of multiple homeostatic functions including reproduction, stress responses, energy metabolism, sleep cycles, temperature regulation, and motivated behaviors. The critical role of 17 ss-estradiol (E-2) is evident in hypoestrogenic states ( e. g.,postmenopause) in which many of these functions go awry. The actions of E-2 in the brain have been attributed to the activation of estrogen receptors alpha and ss through nuclear, cytoplasmic, or membrane actions. However, we have identified a putative membrane- associated estrogen receptor that is coupled to desensitization of GABAB and mu-opioid receptors in guinea pig and mouse hypothalamic proopiomelanocortin neurons. We have synthesized a new nonsteroidal compound, STX, which selectively targets the G alpha q-coupled phospholipase C-protein kinase C-protein kinase A pathway, and have established that STX is more potent than E2 in mediating this desensitization in an ICI 182, 780-sensitive manner in both guinea pig and mouse neurons. Both E-2 and STX were fully efficacious in estrogen receptor alpha, ss knock-out mice. Moreover, in vivo treatment with STX, similar to E-2, attenuated the weight gain in hypoestrogenic female guinea pigs. Therefore, this membrane- delimited signaling pathway plays a critical role in the control of energy homeostasis and may provide a novel therapeutic target for treatment of postmenopausal symptoms and eating disorders in females.