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

Background: Brain glucose-sensing neurons detect glucose fluctuations and prevent severe hypoglycemia, but mechanisms mediating functions of these glucose-sensing neurons are unclear. Methods: We combined mouse genetics, electrophysiology, neural tracing, optogenetics and Patch-RNA-seq to demonstrate how glucose-sensing neurons in the ventrolateral VMH regulate glucose balance. Results: Here we report that estrogen receptor-α (ERα)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH) are glucose-sensing neurons to a 5-1-5mM glucose fluctuation, being glucose-inhibited neurons (GI-ERαvlVMH) or glucose-excited neurons (GE-ERαvlVMH). Hypoglycemia activates GI-ERαvlVMH neurons via the anoctamin 4 channel, and inhibits GE-ERαvlVMH neurons through opening the ATP-sensitive potassium channel. Further, we show that GI-ERαvlVMH neurons preferentially project to the medioposterior arcuate nucleus of the hypothalamus (mpARH) and GE-ERαvlVMH neurons preferentially project to the dorsal Raphe nuclei (DRN). Activation of ERαvlVMH-mpARH circuit and inhibition of ERαvlVMH-DRN circuit both increase blood glucose. Conclusions: Our results indicate that ERαvlVMH neurons detect glucose fluctuations and prevent severe hypoglycemia in mice. Genetically identified single ERα neurons in the vlVMH were first tested for glucoses-sensing features, and then subjected to RNA-seq analyses. Differentially expressed genes were validated through multiple functional assays.