Estrogen protects animals against obesity through estrogen receptor α (ERα), partially by inhibiting overeating in animals fed ad libitum. However, effects of estrogen on feeding behavior in hungry animals remain unclear. Here 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 effects of E2 supplementation on acute refeeding behavior after starvation. ERα-C451A mutant mice deficient in membrane-bound ERα activity and ERα-AF20 mutant mice lacking ERα transcriptional activity were used to further examine mechanisms underlying the 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 wild type female mice, ovariectomy reduced fasting-induced refeeding, which was restored by E2 supplementation. The ERα-C451A mutation, but not the ERα-AF20 mutation, attenuated acute feeding induced by either fasting or by central glucopenia. Consistently, the ERα-C451A mutation impaired the neural responses of hypoglycemic ERα neurons to hypoglycemia.
In addition to previous evidence that estrogen reduces the deviation of the energy balance by inhibiting eating at 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 the membrane-bound ERα activity.