Effects of ventromedial hypothalamic nucleus GAD gene knockdown on growth hormone-releasing hormone neuron transcriptomic profile in female rats.

BACKGROUND

Recent studies in male rats identify ventromedial hypothalamic nucleus (VMN)-dorsomedial division (VMNdm) growth hormone-releasing (Ghrh) neurons as a potential target for VMN γ-aminobutyric acid (GABA) control of counterregulatory hormone secretion.

METHODS AND

RESULTS

Current research used a female rat model to examine whether GABA regulation of eu- and/or hypoglycemic Ghrh neuron metabolic sensor, counterregulatory transmitter, and estrogen receptor (ER) gene profiles and contra-regulatory endocrine function is sex-dimorphic. Intra-VMN glutamate decarboxylase-2 (GAD2/GAD65) siRNA administration amplified transcripts encoding counterregulatory-enhancing neuropeptide (Ghrh) or enzyme marker proteins (glutaminase, neuronal nitric oxide synthase) in laser-catapult-microdissected Ghrh neurons from vehicle (V)- or insulin (INS)-injected females. Conversely, GAD2 siRNA down-regulated eu- and hypoglycemic GAD1 mRNA profiles. Steroidogenic factor-1 transcripts were correspondingly unaffected or inhibited in GAD2 siRNA pretreated V- versus INS-injected rats. VMN GAD2 gene knockdown up-regulated Ghrh neuron 5'-AMP-activated protein kinase alpha1 and - 2 gene expression in eu- and hypoglycemic animals. GAD2 siRNA caused glucose-dependent changes in lactate and estrogen receptor mRNA expression as gene knockdown inhibited transcription in euglycemic females while amplifying these gene profiles during hypoglycemia. GAD2 siRNA administration attenuated hypoglycemic hypercorticosteronemia and -glucagonemia and reversed down-regulated growth hormone (GH) secretion.

CONCLUSIONS

Present findings importantly document female-specific GABA regulation of VMNdm Ghrh neuron metabolic signal reception, energy monitoring, and counterregulatory neurotransmitter release, as well as sex-dimorphic VMN GABAergic control of baseline (corticosterone, glucagon, GH) and hypoglycemic (GH) hormone outflow. Ongoing studies aim to discover how GABA-dependent input from these distinctive neurons to the female glucostatic neural network may affect counterregulation in that sex.