Abstract
Aging impairs glucose counterregulatory function by unknown mechanisms. Ventromedial hypothalamic nucleus/dorsomedial division (VMNdm) growth hormone-releasing hormone (Ghrh) neurons control counterregulation through Ghrh-modulated discharge of structurally diverse co-expressed neurochemicals. Current research used gene silencing and single-cell laser-catapult-microdissection/multiplex qPCR tools to investigate whether aging alters eu- and/or hypoglycemic patterns of co-produced counterregulatory-inhibiting (γ-aminobutyric acid) or -stimulating (Ghrh; glutamate; nitric oxide) neurotransmitter marker genes in this cell population. Data document basal Ghrh mRNA diminution in older, i.e., middle-aged rats of each sex and age-specific Ghrh transcriptional responses to hypoglycemia in females. Older rats showed Ghrh repression of glutamate decarboxylase(67) (GAD(67)) and GAD(65) mRNAs, a gain of inhibitory tone in female. In middle-age male rats, both GAD transcripts were refractory to hypoglycemia, an age-related response loss. In older females, hypoglycemia stimulated GAD(65) gene expression, contrary to Ghrh-mediated repression in young adult animals. Ghrh suppressed glutaminase (GLS) mRNA in middle-aged rats of each sex, like young adults. Unlike young adult males, older males showed no GLS transcriptional response to hypoglycemia; older hypoglycemic females exhibited up-regulated GLS mRNA, differing from down-regulated expression in younger animals. Aging reduced neuronal nitric oxide synthase (nNOS) gene profiles in females only; nNOS transcription was increased by hypoglycemia in middle-aged rats irrespective of sex, but was unopposed by Ghrh, indicating loss of this inhibitory tone. Results bolster the notion that by midde-age, aging may adjust, according to sex, multi-modal transmitter signaling by VMNdm Ghrh neurons to the brain glucose-regulatory network. Further research is justified to ascertain consequences of aging-associated patterns of co-expressed transmitter release on counterregulation in each sex.