Multiple estrogen receptor α (ERα) neuron populations in the brain are required to maintain normal body weight. While the metabolic effects of these ERα neuron populations have been investigated, the neural circuit and associated neurotransmitter signaling underlying the regulatory effects of ERα neurons on energy balance are unknown. Here we combined retrograde and anterograde trans-synaptic tracers, chemogenetics, optogenetic circuit mapping, and genetic mouse models to functionally map the downstream neural circuits of ERα neurons. We found that selective activation of ERα neurons in the ventral medial hypothalamus (VMH) stimulated brown adipose tissue (BAT) thermogenesis and physical activity without affecting food intake. We also showed that VMH ERα neurons provide monosynaptic glutamatergic inputs to serotonergic neurons in the dorsal Raphe nuclei (DRN). Inhibition of DRN serotonergic neurons partially attenuated the stimulatory effects of VMH ERα neurons on BAT thermogenesis and physical activity. More intriguingly, specific deletion of ERα or vesicular glutamate transporter 2 (vGluT2) from a subpopulation of VMH neurons projecting to the DRN results in decreased BAT thermogenesis and physical activity with normal food intake. Together, these findings suggest a model that VMH ERα neurons activate BAT thermogenesis and physical activity by stimulating DRN serotonergic neurons.


P. Xu: None. Y. He: None. C. Wang: None. Y. Yang: None. X. Cai: None. Y. Xu: None.


American Diabetes Association (1-17-PDF-138 to Y.H.); National Institutes of Health (R01DK093587), (R01DK101379 to Y.X.); (R00DK107008 to P.X.); U.S. Department of Agriculture (3092-5-001-059 to Y.X.); American Heart Association (17GRNT32960003 to Y.X.)

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