Singular versus combinatory glucose-sensitive signal control of metabolic sensor protein profiles in hypothalamic astrocyte cultures from each sex

Abstract

Brain metabolic-sensory targets for modulatory glucose-sensitive endocrine and neurochemical signals remain unidentified. A hypothalamic astrocyte primary culture model was here used to investigate whether glucocorticoid receptor (GR) and noradrenergic signals regulate astrocyte glucose (glucose transporter-2 [GLUT2], glucokinase) and/or energy (5′-AMP-activated protein kinase [AMPK]) sensor reactivity to glucoprivation by sex. Glucose-supplied astrocytes of each sex showed increased GLUT2 expression after incubation with the GR agonist dexamethasone (DEX) or norepinephrine (NE); DEX plus NE (DEX/NE) augmented GLUT2 in the female, but not in male. Glucoprivation did not alter GLUT2 expression, but eliminated NE regulation of this protein in both sexes. Male and female astrocyte glucokinase profiles were refractory to all drug treatments, but were down-regulated by glucoprivation. Glucoprivation altered AMPK expression in male only, and caused divergent sex-specific changes in activated, i.e., phosphoAMPK (pAMPK) levels. DEX or DEX/NE inhibited (male) or stimulated (female) AMPK and pAMPK proteins in both glucose-supplied and -deprived astrocytes. In male, NE coincidently up-regulated AMPK and inhibited pAMPK profiles in glucose-supplied astrocytes; these effects were abolished by glucoprivation. In female, AMPK profiles were unaffected by NE irrespective of glucose status, whereas pAMPK expression was up-regulated by NE only during glucoprivation. Present outcomes document, for each sex, effects of glucose status on hypothalamic astrocyte glucokinase, AMPK, and pAMPK protein expression and on noradrenergic control of these profiles. Data also show that DEX and NE regulation of GLUT2 is sex-monomorphic, but both stimuli impose divergent sex-specific effects on AMPK and pAMPK. Further effort is warranted to characterize mechanisms responsible for sex-dimorphic GR and noradrenergic governance of hypothalamic astrocyte energy sensory function.

Keywords

• dexamethasone
• norepinephrine
• glut2
• glucokinase
• ampk
• glucocorticoid receptor