1997-P: Bidirectional Regulation of Energy Homeostasis Mediated by Estrogen Receptor a and ß in the Medial Amygdala

Abstract

Compelling evidence has demonstrated that estradiol and estrogen receptor α/β (ERα/β) play key roles in the central regulation of energy balance and glucose homeostasis. Our previous research showed that ERα in the medial amygdala (ERα^MeA) mediates estrogenic actions to stimulate physical activity, therefore promotes energy expenditure and prevents diet-induced obesity (DIO). Interestingly, another estrogen receptor, ERβ, is also highly expressed in the MeA. To test the metabolic functions of ERβ^MeA, we generated a mouse model with ERβ selectively deleted in the MeA (ERβKO^MeA) during adulthood using AAV virus-mediated Cre-Lox site-specific recombination. We found that, when fed on a high-fat diet but not on a normal chow diet, compared to the control mice, both male and female ERβKO^MeA mice showed decreased body weight gain and fat deposition, which were associated with increased energy expenditure. We further showed that half of the ERα^MeA neurons co-express ERβ. In these ERα&β co-expressing MeA neurons, ERα agonist propyl pyrazole trio (PPT) induced ERα-dependent depolarization, while ERβ agonist diarypropionitrile (DPN) induced ERβ-dependent hyperpolarization. Finally, we showed that chemogenetic activation of ERα^MeA or ERβ^MeA neurons induces a similar increase in energy expenditure. Collectively, our results support a model that, estrogen acts on ERα/β^MeA neurons to provide bidirectional regulation of body weight and resistance to DIO, whereas activating ERα^MeA decreases and activating ERβ^MeA increases body weight.