Estrogens can modulate energy balance by regulating food intake and energy expenditure. Hayashi et al. revealed that hypothalamic neuroestrogens, especially E2 from aromatase Cyp19a1, regulate appetite and body weight. In ovariectomized mice, elevated hypothalamic Cyp19a1 and Mc4r expression coincided with reduced food intake and weight loss. Pharmacological or genetic disruption of aromatase in mice lowered Mc4r expression and increased food intake, whereas neuronal Cyp19a1 overexpression enhanced Mc4r expression and suppressed appetite, independent of leptin. Therefore, neuroestrogens critically maintain metabolic equilibrium, positioning aromatase-derived E2 as a promising anti-obesity target.