USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA; College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, China.
USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA; Pennington Biomedical Research Center, Brain Glycemic and Metabolism Control Department, Louisiana State University, Baton Rouge, LA, 70808, USA.
Mol Metab. 2020 Dec;42:101053. doi: 10.1016/j.molmet.2020.101053. Epub 2020 Jul 23.
Estrogen protects animals from obesity through estrogen receptor α (ERα), partially by inhibiting overeating in animals fed ad libitum. However, the effects of estrogen on feeding behavior in hungry animals remain unclear. In this study, we examined the roles of 17β-estradiol (E2) and ERα in the regulation of feeding in hungry female animals and explored the underlying mechanisms.
Wild-type female mice with surgical depletion of endogenous estrogens were used to examine the effects of E2 supplementation on acute refeeding behavior after starvation. ERα-C451A mutant mice deficient in membrane-bound ERα activity and ERα-AF2 mutant mice lacking ERα transcriptional activity were used to further examine mechanisms underlying acute feeding triggered by either fasting or central glucopenia (induced by intracerebroventricular injections of 2-deoxy-D-glucose). We also used electrophysiology to explore the impact of these ERα mutations on the neural activities of ERα neurons in the hypothalamus.
In the wild-type female mice, ovariectomy reduced fasting-induced refeeding, which was restored by E2 supplementation. The ERα-C451A mutation, but not the ERα-AF2 mutation, attenuated acute feeding induced by either fasting or central glucopenia. The ERα-C451A mutation consistently impaired the neural responses of hypothalamic ERα neurons to hypoglycemia.
In addition to previous evidence that estrogen reduces deviations in energy balance by inhibiting eating at a satiated state, our findings demonstrate the unexpected role of E2 that promotes eating in hungry mice, also contributing to the stability of energy homeostasis. This latter effect specifically requires membrane-bound ERα activity.
雌激素通过雌激素受体α（ERα）保护动物免受肥胖的影响，部分是通过抑制动物自由进食时的暴饮暴食。然而，雌激素对饥饿动物摄食行为的影响仍不清楚。在这项研究中，我们研究了 17β-雌二醇（E2）和 ERα 在调节饥饿雌性动物摄食行为中的作用，并探讨了潜在的机制。
使用经过手术去势的内源性雌激素缺乏的野生型雌性小鼠，来研究 E2 补充对饥饿后急性再进食行为的影响。使用缺乏膜结合 ERα 活性的 ERα-C451A 突变小鼠和缺乏 ERα 转录活性的 ERα-AF2 突变小鼠，进一步研究禁食或中枢性低血糖（通过侧脑室注射 2-脱氧-D-葡萄糖诱导）触发急性进食的潜在机制。我们还使用电生理学方法来研究这些 ERα 突变对下丘脑 ERα 神经元神经活动的影响。
在野生型雌性小鼠中，卵巢切除术减少了禁食引起的再进食，而 E2 补充则恢复了这一过程。与 ERα-AF2 突变不同，ERα-C451A 突变削弱了禁食或中枢性低血糖引起的急性进食。ERα-C451A 突变一致损害了下丘脑 ERα 神经元对低血糖的神经反应。
除了之前的证据表明雌激素通过抑制饱食状态下的进食来减少能量平衡的偏差外，我们的发现还表明 E2 促进饥饿小鼠进食的意外作用，这有助于能量平衡的稳定。这种作用特别需要膜结合的 ERα 活性。
