1663-P: Estrogenic Regulation of Energy Balance in the Medial Amygdala

Compelling evidence has demonstrated that estradiol (E2) and estrogen receptors α/β (ERα/β) play critical roles in the central regulation of energy balance and glucose homeostasis. Our previous research proved that ERα in the medial amygdala (ERαMeA) mediates estrogenic actions to stimulate physical activity, promote energy expenditure, and prevent diet-induced obesity (DIO). Interestingly, ERβ is also highly expressed in the MeA neurons. To explore the metabolic functions of ERβMeA, we generated a mouse model with ERβ selectively deleted in the MeA (ERβKOMeA) during adulthood by using AAV virus-mediated Cre-Lox site-specific recombination. When fed on a high-fat diet (HFD) but not a standard chow diet, both male and female ERβKOMeA mice showed decreased body weight gain and fat deposition, associated with a decrease in ambulatory activity. Consistently, we also observed an increase in energy expenditure of female ERβKOMeA mice during diet switching from chow to HFD, suggesting a diet-dependent regulatory role of ERβMeA in body weight control. In addition, both electrophysiology and immunohistochemistry staining results indicated that half of the ERαMeA 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. Further, we found that the chemogenetic activation of ERαMeA neurons promotes physical activity and stimulates body thermogenesis, while the inhibition of ERβMeA neurons downregulates physical activity and body thermogenesis. In line with this, inhibition of ERβMeA neurons impaired cold-induced brown adipose tissue thermogenesis, resulting in lower rectal temperature during acute cold exposure. Collectively, our results support a model that E2 acts on ERα/βMeA neurons to provide bidirectional regulation of body weight and resistance to DIO. Disclosure H.Ye: None. M.Mun: None. Y.He: None. P.Xu: None. B.Feng: None. P.Luo: None. L.Carrillo-sáenz: None. V.C.Torres irizarry: None. L.Ibrahimi: None. N.Antony: None. M.Kota: None. D.Dixit: None. Funding National Institutes of Health (R01DK123098, P30DK020595, P20GM135002, R01DK129548, T32AA026577, K01DK119471); U.S. Department of Agriculture (3092-51000-062-04(B)S); American Heart Association (915789, 19CDA34660335, 20POST35120600); U.S. Department of Defense (W81XWH-20-1-0075)