Sex-specific estrogen regulation of hypothalamic astrocyte estrogen receptor expression and glycogen metabolism in rats

Brain astrocytes are implicated in estrogenic neuroprotection against bio-energetic insults, which may involve their glycogen energy reserve. Forebrain estrogen receptors (ER)-alpha (ERa) and -beta (ER beta) exert differential control of glycogen metabolic enzyme [glycogen synthase (GS); phosphorylase (GP)] expression in hypoglycemic male versus female rats. Studies were conducted using a rat hypothalamic astrocyte primary culture model along with selective ER agonists to investigate the premise that estradiol (E-2) exerts sex-dimorphic control over astrocyte glycogen mass and metabolism. Female astrocyte GS and GP profiles are more sensitive to E-2 stimulation than the male. E-2 did not regulate expression of phospho-GS (inactive enzyme form) in either sex. Data also show that transmembrane G protein-coupled ER-1 (GPER) signaling is implicated in E-2 control of GS profiles in each sex and alongside ER alpha, GP expression in females. E-2 increases total 5'-AMP-activated protein kinase (AMPK) protein in female astrocytes, but stimulated pAMPK (active form) expression with equivalent potency via GPER in females and ER alpha in males. In female astrocytes, ER alpha protein was up-regulated at a lower E-2 concentration and over a broader dosage range compared to males, whereas ER beta was increased after exposure to 1-10 nM versus 100 pM E-2 levels in females and males, respectively. GPER profiles were stimulated by E-2 in female, but not male astrocytes. E-2 increased astrocyte glycogen content in female, but not male astrocytes; selective ER beta or ER alpha stimulation elevated glycogen levels in the female and male, respectively. Outcomes imply that dimorphic astrocyte ER and glycogen metabolic responses to E-2 may reflect, in part, differential steroid induction of ER variant expression and/or regulation of post-receptor signaling in each sex.