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-a (ERa)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH) can sense glucose fluctuations, being glucose-inhibited neurons (GI-ERavlVMH) or glucose-excited neurons (GE-ERavlVMH). Hypoglycemia activates GI-ERavlVMH neurons via the anoctamin 4 channel, and inhibits GE-ERavlVMH neurons through opening the ATP-sensitive potassium channel. Further, we show that GI-ERavlVMH neurons preferentially project to the medioposterior arcuate nucleus of the hypothalamus (mpARH) and GE-ERavlVMH neurons preferentially project to the dorsal Raphe nuclei (DRN). Activation of ERavlVMH to mpARH circuit and inhibition of ERavlVMH to DRN circuit both increase blood glucose. Thus, our results indicate that ERavlVMH neurons detect glucose fluctuations and prevent severe hypoglycemia in mice.

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