Estrogen-Responsive Neurons in the Ventrolateral VMH Regulate Glucose Balance

Brain glucose-sensing neurons can detect glucose fluctuations and prevent severe hypoglycemia. We observed that estrogen receptor-α (ERα)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH) are all glucose-sensing neurons, being either glucose-inhibited neurons (GI-ERα^vlVMH) or glucose-excited neurons (GE-ERα^vlVMH). In particular, hypoglycemia inhibits GE-ERα^vlVMH neurons through opening the K_ATP channel, and activates GI-ERα^vlVMH neurons via enhanced t-type voltage-gated calcium currents. 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); selective activation of the ERα^vlVMH◊mpARH circuit and inhibition of the ERα^vlVMH◊DRN circuit both increase blood glucose. Importantly, loss of estrogen-ERα signals impairs glucose-sensing properties of ERα^vlVMH neurons and attenuates hyperglycemic response to the central glucopenia in female mice. Depletion of estrogen impairs the AMP kinase pathway which accounts for the reduced glucose-sensing capability of these ERα^vlVMH neurons; enhanced AMP kinase activity selectively in ERα^vlVMH restores the glucose response in female mice depleted of estrogen. Thus, our results indicate that estrogen-ERα-AMP kinase signals in ERα^vlVMH neurons are required for these neurons to detect hypoglycemia and therefore are indispensable for defending against severe hypoglycemia in female mice.