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

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