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^vlVMH) 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^vlVMH neurons. We found that selective activation of ERα^vlVMH neurons stimulated brown adipose tissue (BAT) thermogenesis, physical activity, and core temperature and that ERα^vlVMH neurons provide monosynaptic glutamatergic inputs to 5-hydroxytryptamine (5-HT) neurons in the dorsal raphe nucleus (DRN). Notably, the ERα^vlVMH → DRN circuit responds to changes in ambient temperature and nutritional states. We further showed that 5-HT^DRN neurons mediate the stimulatory effects of ERα^vlVMH neurons on BAT thermogenesis and physical activity and that ERα expressed by DRN-projecting ERα^vlVMH neurons is required for the maintenance of energy balance. Together, these findings support a model that ERα^vlVMH neurons activate BAT thermogenesis and physical activity through stimulating 5-HT^DRN neurons.