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

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.