Estrogen-Responsive Neurons in the Ventrolateral VMH Regulate Glucose Balance

Abstract

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-ERαvlVMH) or glucose-excited neurons (GE-ERαvlVMH). In particular, hypoglycemia inhibits GE-ERαvlVMH neurons through opening the KATP channel, and activates GI-ERαvlVMH neurons via enhanced t-type voltage-gated calcium currents. 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); selective activation of the ERαvlVMH◊mpARH circuit and inhibition of the ERαvlVMH◊DRN circuit both increase blood glucose. Importantly, loss of estrogen-ERα signals impairs glucose-sensing properties of ERαvlVMH 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 ERαvlVMH neurons; enhanced AMP kinase activity selectively in ERαvlVMH restores the glucose response in female mice depleted of estrogen. Thus, our results indicate that estrogen-ERα-AMP kinase signals in ERαvlVMH neurons are required for these neurons to detect hypoglycemia and therefore are indispensable for defending against severe hypoglycemia in female mice. Disclosure Y. He: None. P. Xu: None. Y. Xia: None. Y. Yang: None. X. Cai: None. I. Hyseni: None. Y. Xu: None.