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Brain glucose-sensing neurons detect glucose fluctuations and prevent severe hypoglycemia, but mechanisms mediating functions of these glucose-sensing neurons are unclear. Here we report that estrogen receptor-α (ERα)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH) can sense glucose fluctuations, being glucose-inhibited neurons (GI-ERα vlVMH ) or glucose-excited neurons (GE-ERα vlVMH ). Hypoglycemia activates GI-ERα vlVMH  neurons via the anoctamin 4 channel, and inhibits GE-ERα vlVMH  neurons through opening the ATP-sensitive potassium channel. Further, we show that GI-ERα vlVMH  neurons preferentially project to the medioposterior arcuate nucleus of the hypothalamus (mpARH) and GE-ERα vlVMH  neurons preferentially project to the dorsal Raphe nuclei (DRN). Activation of ERα vlVMH  to mpARH circuit and inhibition of ERα vlVMH  to DRN circuit both increase blood glucose. Thus, our results indicate that ERα vlVMH  neurons detect glucose fluctuations and prevent severe hypoglycemia in mice.

Estrogen receptor-α expressing neurons in the ventrolateral VMH regulate glucose balance