Male‐Specific Ventromedial Hypothalamic Nucleus Glutamate Decarboxylase ( <scp>GAD</scp> )‐2/ <scp>GAD65</scp> Regulation of Counterregulatory Transmitter Marker Gene Expression and Peripheral Hormone Profiles

The amino acid neurotransmitter gamma-aminobutyric acid (GABA) reportedly acts by unidentified ventromedial hypothalamic mechanisms to suppress hypoglycemia-associated counterregulatory endocrine function in male rats. Present studies addressed the premise that GABAergic transmission of ventromedial hypothalamic nucleus (VMN) origin may regulate dorsomedial VMN (VMNdm) growth hormone-releasing hormone (Ghrh)/steroidogenic factor-1 (SF-1) neuron counterregulatory signaling to control this hormone outflow. VMN glutamate decarboxylase-2 (GAD2/GAD₆₅) gene knockdown increased basal but inhibited insulin-induced hypoglycemia (IIH)-associated augmentation of corticosterone and glucagon secretion, while suppressing growth hormone secretion regardless of glucose status. Multiplex qPCR analysis of laser-catapult-microdissected VMNdm Ghrh-immunoreactive neurons showed that GAD2 siRNA pretreatment intensified IIH-associated upregulation of mRNAs that encode the counterregulatory-enhancing neurochemicals nitric oxide and glutamate, and exacerbated hypoglycemic downregulation of GAD1, GAD2, and SF-1 transcription. VMN GAD2 gene silencing augmented hypoglycemic enhancement of Ghrh neuron 5'-AMP-activated protein kinase alpha-1 and alpha-2 gene expression. VMN GAD2 gene knockdown exacerbated both positive lactate receptor and negative estrogen receptor transcriptional reactivity to IIH. Study outcomes provide novel evidence for bidirectional, glucose status-specific VMN GABAergic control of corticosterone and glucagon secretion in male rats, which is not documented in the other sex. Data verify GABA regulation of VMN dorsomedial Ghrh neuron metabolic and hormonal signal reception, energy screening, and counterregulatory neurochemical release. Further effort is needed to characterize the impact of GABA-dependent neurotransmission by this discrete VMN neuron population on neural circuitries that govern glucose homeostasis.