An estrogen-sensitive hypothalamus-midbrain neural circuit controls thermogenesis and physical activity.

Estrogen receptor–α (ERα) expressed by neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (ERα) regulates body weight in females, but the downstream neural circuits mediating this biology remain largely unknown. Here we identified a neural circuit mediating the metabolic effects of ERα neurons. We found that selective activation of ERα neurons stimulated brown adipose tissue (BAT) thermogenesis, physical activity, and core temperature and that ERα neurons provide monosynaptic glutamatergic inputs to 5-hydroxytryptamine (5-HT) neurons in the dorsal raphe nucleus (DRN). Notably, the ERα → DRN circuit responds to changes in ambient temperature and nutritional states. We further showed that 5-HT neurons mediate the stimulatory effects of ERα neurons on BAT thermogenesis and physical activity and that ERα expressed by DRN-projecting ERα neurons is required for the maintenance of energy balance. Together, these findings support a model that ERα neurons activate BAT thermogenesis and physical activity through stimulating 5-HT neurons.