17B-estradiol promotes acute refeeding in hungry mice via membrane-initiated ERa signaling

Authors: YU, KAIFAN - Children'S Nutrition Research Center (CNRC); HE, YANLIN - Children'S Nutrition Research Center (CNRC); HYSENI, LLIRJANA - Children'S Nutrition Research Center (CNRC); PEI, ZHOU - Children'S Nutrition Research Center (CNRC); YANG, YONGJIE - Children'S Nutrition Research Center (CNRC); XU, PINGWEN - Children'S Nutrition Research Center (CNRC); CAI, XING - Children'S Nutrition Research Center (CNRC); LIU, HESONG - Children'S Nutrition Research Center (CNRC); HE, YANG - Children'S Nutrition Research Center (CNRC); YU, MENG - Children'S Nutrition Research Center (CNRC); LIANG, CHEN - Children'S Nutrition Research Center (CNRC); YANG, TINGTING - Children'S Nutrition Research Center (CNRC); WANG, JULIA - Children'S Nutrition Research Center (CNRC); GOURDY, PIERRE - Universite Paul Sabatier; ARNAL, JEAN-FRANCOIS - Universite Paul Sabatier; LENFANT, FRANCOISE - Universite Paul Sabatier; XU, YONG - Children'S Nutrition Research Center (CNRC); WANG, CHUNMEI - Children'S Nutrition Research Center (CNRC)

Submitted to: Molecular Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/19/2020
Publication Date: 7/23/2020
Citation: Yu, K., He, Y., Hyseni, L., Pei, Z., Yang, Y., Xu, P., Cai, X., Liu, H., He, Y., Yu, M., Liang, C., Yang, T., Wang, J., Gourdy, P., Arnal, J., Lenfant, F., Xu, Y., Wang, C. 2020. 17B-estradiol promotes acute refeeding in hungry mice via membrane-initiated ERa signaling. Molecular Metabolism. 42. Article 101053. https://doi.org/10.1016/j.molmet.2020.101053.
DOI: https://doi.org/10.1016/j.molmet.2020.101053

Interpretive Summary: Sufficient feeding when hungry is essential for survival, but how it is regulated is not fully understood. Here we showed that estrogen, the ovarian hormone, is required for female animals to engage rapid feeding behavior after food deprivation, and we further delineated the molecular mechanisms for this action involves an estrogen receptor on the cell membrane. These findings identify novel mechanisms for the regulation of food intake.

Technical Abstract: Estrogen protects animals from obesity through estrogen receptor a (ERa), 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 17B-estradiol (E2) and ERa 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. ERa-C451A mutant mice deficient in membrane-bound ERa activity and ERa-AF20 mutant mice lacking ERa 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 ERa mutations on the neural activities of ERa neurons in the hypothalamus. In the wild-type female mice, ovariectomy reduced fasting-induced refeeding, which was restored by E2 supplementation. The ERa-C451A mutation, but not the ERa-AF20 mutation, attenuated acute feeding induced by either fasting or central glucopenia. The ERa-C451A mutation consistently impaired the neural responses of hypothalamic ERa 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 ERa activity.