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

Abstract

Brain astrocytes generate free glucose at the conclusion of glycogenolysis or gluconeogenesis by glucose-6-phosphatase-beta (Glc-6-Pase-β) 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-β gene-knockdown. Gene-silencing caused reductions in VMN astrocyte Glc-6-Pase-β protein expression and tissue glycogen and glucose content. Hypoglycemic suppression (dorsomedial VMN; VMNdm) or augmentation (ventrolateral VMN; VMNvl) of glycogen involves Glc-6-Pase-β -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-β gene-knockdown correspondingly suppressed or enhanced baseline expression of glutamate decarboxylase_65/67 (GAD) and neuronal nitric oxide synthase (nNOS), protein markers for the counterregulation-inhibiting or -enhancing neurochemicals γ-aminobutyric acid and nitric oxide. Glc-6-Pase-β siRNA pretreatment did not alter hypoglycemic suppression of VMN GAD protein but reversed (VMNdm) or amplified (VMNvl) nNOS up-regulation. VMN Glc-6-Pase-β gene-silencing attenuated hypoglycemic patterns of corticosterone and growth hormone secretion and enhanced glucagon release. In summary, data provide unique evidence that VMN Glc-6-Pase-β activity affects glucose counterregulation. Outcomes document astrocyte Glc-6-Pase-β control of VMN glucose and glycogen accumulation as well as VMN neuron counterregulatory neurotransmission. Further research is warranted to identify Glc-6-Pase-β - mediated adjustments in astrocyte glucose metabolism that affect VMN GABAergic and/or nitrergic signaling within the brain glucostatic circuitry.

Keywords: Glucose-6-phosphatase-beta; Glutamate decarboxylase(65/67); Insulin-induced hypoglycemia; Laser-catapult-microdissection; Ventromedial hypothalamic nucleus.