Central Type II Glucocorticoid Receptor Regulation of Ventromedial Hypothalamic Nucleus Glycogen Metabolic Enzyme and Glucoregulatory Neurotransmitter Marker Protein Expression in the Male Rat.

The ventromedial hypothalamic nucleus (VMN) glucoregulatory neurotransmitters γ-aminobutyric acid (GABA) and nitric oxide (NO) signal adjustments in glycogen mobilization. Glucocorticoids control astrocyte glycogen metabolism in vitro. The classical (type II) glucocorticoid receptor (GR) is expressed in key brain structures that govern glucostasis, including the VMN. Current research addressed the hypothesis that forebrain GR regulation of VMN glycogen synthase (GS) and phosphorylase (GP) protein expression correlates with control of glucoregulatory transmission. Groups of male rats were pretreated by intracerebroventricular (icv) delivery of the GR antagonist RU486 or vehicle prior to insulin-induced hypoglycemia (IIH), or were pretreated icv with dexamethasone (DEX) or vehicle before subcutaneous insulin diluent injection. DEX increased VMN GS and norepinephrine-sensitive GP-muscle type (GPmm), but did not alter metabolic deficit-sensitive GP-brain type (GPbb) expression. RU486 enhanced GS and GPbb profiles during IIH. VMN astrocyte (MCT1) and neuronal (MCT2) monocarboxylate transporter profiles were up-regulated in euglycemic and hypoglycemic animals by DEX or RU486, respectively. Glutamate decarboxylase65/67 and neuronal nitric oxide synthase (nNOS) proteins were both increased by DEX, yet RU486 augmented hypoglycemic nNOS expression patterns. Results show that GR exert divergent effects on VMN GS, MCT1/2, and nNOS proteins during eu- (stimulatory) versus hypoglycemia (inhibitory); these findings imply that up-regulated NO transmission may reflect, in part, augmented glucose incorporation into glycogen and/or increased tissue lactate requirements. Data also provide novel evidence for metabolic state-dependent GR regulation of VMN GPmm and GPbb profiles; thus, GABA signaling of metabolic stability may reflect, in part, stimulus-specific glycogen breakdown during eu- versus hypoglycemia.