17β-estradiol promotes acute refeeding in hungry mice via membrane-initiated ERα signaling

Abstract

Objective 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. Methods 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 0 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. Results 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 0 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. Conclusion 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.

Effects of maternal nutrient restriction during the periconceptional period on placental development in the mouse

“…Very little is known about the dynamics of refeeding after nutrient restriction in pregnant mice, and here food consumption was not determined after the resumption of ad libitum feeding in the calorie restricted mice. However, it is known that caloric restriction can induce later hyperphagia in non-pregnant mice, and that estrogen plays a role in acute refeeding after fasting [ 73 , 74 ]. Thus, it is possible that after the food restricted mice were returned to ad libitum feeding at day 11.5, that they consumed more calories than the control mice.…”

Hypothalamic Perineuronal Nets Are Regulated by Sex and Dietary Interventions

“…Notably, abundant ERα is expressed by POMC neurons in the ARH ( Miller et al, 1995 ; Attia, 2010 ; de Souza et al, 2011 ), to a less extent by AgRP neurons ( Olofsson et al, 2009 ; Roepke et al, 2011 ), while ERβ expression in the ARH is minimal ( Merchenthaler et al, 2004 ). We recently showed that intact ERα signals are required for the glucose-sensing functions of ARH neurons ( Yu et al, 2020 ). Further, estrogen can enhance glutamatergic synapses onto POMC neurons ( Gao et al, 2007 ), and increase their excitability ( Malyala et al, 2008 ; Saito et al, 2015 ).…”

Defining vitamin D receptor expression in the brain using a novel VDRCre mouse

“…This rapid induction of neuronal activity is faster than other reports of vitamin D action (Biswas & Zanello, 2009; Gooch et al, 2019), although these are in different cell types and utilize different doses and experimental paradigms. However, these rapid effects are in line with effects of agonists of other classic nuclear receptors such as ERα (C. Wang et al, 2018; Yu et al, 2020). Thus, these results give additional support to our mouse model as being a reliable indicator of VDR expression in the brain.…”