Astrocyte glucose-6-phosphatase-Beta regulates ventromedial hypothalamic nucleus glucose counterregulatory neurotransmission and systemic hormone profiles

Brain astrocytes generate free glucose at the conclusion of glycogenolysis or gluconeogenesis by glucose-6phosphatase-beta (Glc-6-Pase-J3) hydrolytic action. Astrocytes shape ventromedial hypothalamic nucleus (VMN) control of glucose counterregulation via lactate provision, yet possible effects of astrocyte endogenous glucose production are unknown. Current research investigated eu- and hypoglycemic patterns of VMN neuron counterregulatory neurotransmitter marker protein expression and counterregulatory hormone secretion following in vivo VMN astrocyte Glc-6-Pase-J3 gene-knockdown. Gene-silencing caused reductions in VMN astrocyte Glc-6-Pase-J3 protein expression and tissue glycogen and glucose content. Hypoglycemic suppression (dorsomedial VMN; VMNdm) or augmentation (ventrolateral VMN; VMNvl) of glycogen involves Glc-6-Pase-J3 -independent versus-dependent mechanisms, respectively. siRNA pretreatment reversed hypoglycemic down- regulation of VMNdm glucose levels and intensified up-regulated VMNvl glucose accumulation. Glc-6-Pase-J3 gene-knockdown correspondingly suppressed or enhanced baseline expression of glutamate decarboxylase65/67 (GAD) and neuronal nitric oxide synthase (nNOS), protein markers for the counterregulation-inhibiting or-enhancing neurochemicals gamma-aminobutyric acid and nitric oxide. Glc-6-Pase-J3 siRNA pretreatment did not alter hypoglycemic suppression of VMN GAD protein but reversed (VMNdm) or amplified (VMNvl) nNOS up- regulation. VMN Glc-6-Pase-J3 gene-silencing attenuated hypoglycemic patterns of corticosterone and growth hormone secretion and enhanced glucagon release. In summary, data provide unique evidence that VMN Glc-6Pase-J3 activity affects glucose counterregulation. Outcomes document astrocyte Glc-6-Pase-J3 control of VMN glucose and glycogen accumulation as well as VMN neuron counterregulatory neurotransmission. Further research is warranted to identify Glc-6-Pase-J3 - mediated adjustments in astrocyte glucose metabolism that affect VMN GABAergic and/or nitrergic signaling within the brain glucostatic circuitry.