Sex-dimorphic beta(1)-adrenergic receptor regulation of ventromedial hypothalamic nucleus astrocyte glucose sensing and glycogen metabolism.

Ventromedial hypothalamic nucleus (VMN) astrocyte glycogen metabolism shapes glucose counterregulatory neurotransmission. Beta(1)-adrenergic receptor (β1-AR) regulates in vitro cortical astrocyte glycogen turnover. Current studies employed VMN β1-AR gene knockdown tools to investigate whether this receptor controls eu- and/or hypoglycemic patterns of VMN astrocyte glucose handling and glycogen amassment in vivo according to sex. Dorsomedial (VMNdm) and ventrolateral (VMNvl) VMN astrocytes were laser-catapult-microdissected as separate populations for Western blot protein analysis. VMNdm and VMNvl astrocyte glucokinase protein exhibited β1-AR-independent inhibition (female) or opposite adjustments (male) after insulin injection. In males, glucose-6-phosphatase-beta responses to hypoglycemia were exacerbated by β1-AR siRNA, whereas down-regulation in females was averted (VMNdm) or amplified (VMNvl) by this pretreatment. β1-AR siRNA did not affect hypoglycemic suppression of VMNdm glycogen synthase, but amplified VMNvl diminution of this protein in both sexes. Hypoglycemia caused divergent changes in VMNdm versus VMNvl glycogen phosphorylase (GP)-brain type protein; β1-AR gene silencing abolished these division-specific responses in female, not male. Hypoglycemic down-regulation of female astrocyte VMNdm and VMNvl GP-muscle type protein expression was averted or exacerbated, respectively, by β1-AR siRNA. β1-AR gene knockdown exacerbated hypoglycemia-associated reductions in female VMNdm and VMNvl glycogen but amplified (VMNdm) or abolished (VMNvl) glycogen augmentation in males. Gene silencing had opposite effects on hypoglycemia-associated growth hormone, glucagon, and corticosterone secretion in male versus female. Results document sex-contingent β1-AR regulation of glucose sensing, endogenous glucose production, and glycogen metabolism in distinct VMN astrocyte populations. Further work is needed to elucidate if and how such control may affect VMN counterregulatory transmission in each sex.