Hypoglycemic and post-hypoglycemic patterns of glycogen phosphorylase isoform expression in the ventrolateral ventromedial hypothalamic nucleus: impact of sex and estradiol

Abstract

Glycogen metabolism shapes ventromedial hypothalamic nucleus (VMN) control of glucose homeostasis. Brain glycogen mass undergoes compensatory expansion post-recovery from insulin-induced hypoglycemia (IIH). Current research utilized combinatory high-resolution microdissection/high-sensitivity Western blotting to investigate whether IIH causes residual adjustments in glycogen metabolism within the metabolic-sensory ventrolateral VMN (VMNvl). Micropunch-dissected tissue was collected from rostral, middle, and caudal levels of the VMNvl in each sex for analysis of glycogen synthase (GS) and glycogen phosphorylase (GP)-muscle type (GPmm; norepinephrine-sensitive) and GP-brain type (GPbb; glucoprivic-sensitive) isoform expression during and after IIH. Hypoglycemic suppression of VMNvl GS levels in males disappeared or continued after reestablishment of euglycemia, according to sampled segment. Yet, reductions in female VMNvl GS persisted after IIH. Males exhibited reductions in GPmm content in select rostro-caudal VMNvl segments, but this protein declined in each segment post-hypoglycemia. Females, rather, showed augmented or diminished GPmm levels during IIH, but no residual effects of IIH on this protein. In each sex, region-specific up-or down-regulation of VMNvl GPbb profiles during glucose decrements were undetected post-recovery from IIH. Results provide novel proof of estradiol-dependent sex-dimorphic patterns of VMNvl GP variant expression at specific rostro-caudal levels of this critical gluco-regulatory structure. Sex differences in persistence of IIH-associated GS and GPmm patterns of expression after restoration of euglycemia infer that VMNvl recovery from this metabolic stress may involve dissimilar glycogen accumulation in male versus female.