Hypoactivity following perturbed estrogen signaling in the medial amygdala.

Activation of estrogen receptor α (ERα) in the brain prevents obesity as the result of increased energy expenditure and decreased food intake. While ERα is present on several neural populations, it is not clear how different regions of the brain mediate the weight-regulating effects of ERα activation. In this issue of the JCI, Xu and colleagues provide extensive evidence that ERα is abundant on neurons expressing single-minded-1 (SIM1) in the medial amygdala (MeA) and that loss of ERα in these cells enhances weight gain in both male and female mice, as the result of reduced physical activity. Moreover, focal deletion of ERα from the MeA recapitulated these alterations in energy homeostasis. Conversely, overexpression of ERα in the MeA partially prevented mice from diet-induced obesity, while chemogenetic activation of SIM1-expressing neurons in the MeA transiently promoted physical activity. The results of this study provide important insight into the regions of the brain that mediate ERα-dependent energy homeostasis.