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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 (ERαMeA) 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 ERβMeA, we generated a mouse model with ERβ selectively deleted in the MeA (ERβKOMeA) 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 ERβKOMeA mice showed decreased body weight gain and fat deposition, which were associated with increased energy expenditure. We further showed 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. Finally, we showed that chemogenetic activation of ERαMeA or ERβMeA neurons induces a similar increase in energy expenditure. Collectively, our results support a model that, estrogen acts on ERα/βMeA neurons to provide bidirectional regulation of body weight and resistance to DIO, whereas activating ERαMeA decreases and activating ERβMeA increases body weight. Disclosure: H. Ye: None. Y. He: None. L. Ibrahimi: None. S. Schaul: None. P. Luo: None. L. Carrillo-Sáenz: None. P. Lai: None. N. Patel: None. M. Kota: None. D. Dixit: None. P. Xu: None. Funding: National Institutes of Health (5R00DK107008-04) [ABSTRACT FROM AUTHOR]