Estrogens prevent obesity primarily through actions on estrogen receptor-alpha (ERalpha).However, ERalpha-expressing cells mediating these effects are not identified.To address this issue, we have used the Cre-loxP strategy to generate a number of mouse models with ERalpha deleted in several brain regions.First, we demonstrate that deletion of ERalpha in the entire brain causes abdominal obesity stemming from both hyperphagia and decreased energy expenditure.The decreased energy expenditure and abdominal obesity, but not hyperphagia, are recapitulated in female mice lacking ERalpha in hypothalamic steroidogenic factor-1 (SF 1) neurons.In contrast, deletion of ERalpha in hypothalamic pro opiomelanocortin (POMC) neurons in females leads to hyperphagia, without directly influencing energy expenditure or fat distribution.Further, simultaneous deletion of ERalpha from both SF 1 and POMC neurons in females causes hyperphagia, decreased energy expenditure and increased visceral adiposity.Interestingly, while brain-specific deletion of ERalpha also leads to obesity in male mice, neither the SF1/POMC single deletion nor the double deletion of ERalpha affects body weight in males.Notably, deletion of ERalpha in a subset of amygdalar neurons causes increased body weight gain only in males, but not in females.In summary, the comprehensive metabolic analyses of these models have provided evidence to support a segregation model for ERalpha functions in male and female brains.In females, SF 1 neurons expressing ERalpha are the key mediator for estrogenic actions on energy expenditure and fat distribution, while ERalpha in POMC neurons is mainly responsible for regulating food intake.In male brains, on the other hand, distinct ERalpha populations, e.g.those in the amygdala, are required to mediate effects of estrogens on body weight control.