GHRH Neurons from the Ventromedial Hypothalamic Nucleus Provide Dynamic and Sex-Specific Input to the Brain Glucose-Regulatory Network

• Published in: Neuroscience 2023-10, Vol.529, p.73-87
• Main Authors: Sapkota, Subash, Haider Ali, Md, Alshamrani, Ayed A., Napit, Prabhat R., Roy, Sagor C., Pasula, Madhu Babu, Briski, Karen P.
• Format: Article
• Language: English
• Subjects: Animals; Female; GAD65; Ghrh; Glucose - metabolism; glutaminase; Glycogen - metabolism; Growth Hormone-Releasing Hormone - metabolism; Hypoglycemia - metabolism; Hypoglycemic Agents; insulin-induced hypoglycemia; Lactates - metabolism; Male; Neurons - metabolism; Rats; Rats, Sprague-Dawley; RNA, Messenger - metabolism; RNA, Small Interfering - metabolism; sex differences; SF-1; Ventromedial Hypothalamic Nucleus - metabolism
• ISSN: 0306-4522; 1873-7544; 1873-7544
• DOI: 10.1016/j.neuroscience.2023.08.006

•The ventromedial hypothalamic nucleus (VMN) controls growth hormone (GH) secretion.•Growth hormone-releasing hormone (Ghrh) siRNA was delivered to VMN of each sex.•Gene silencing blunted hypoglycemic corticosterone (both sexes) and GH (male only) output.•Ghrh neuron glucostatic transmitter expression is revealed by single-cell multiplex qPCR.•Data infer that Ghrh/SF-1 neurons may be an effector of SF-1 control of counter-regulation. The ventromedial hypothalamic nucleus (VMN) controls glucose counter-regulation, including pituitary growth hormone (GH) secretion. VMN neurons that express the transcription factor steroidogenic factor-1/NR5A1 (SF-1) participate in glucose homeostasis. Research utilized in vivo gene knockdown tools to determine if VMN growth hormone-releasing hormone (Ghrh) regulates hypoglycemic patterns of glucagon, corticosterone, and GH outflow according to sex. Intra-VMN Ghrh siRNA administration blunted hypoglycemic hypercorticosteronemia in each sex, but abolished elevated GH release in males only. Single-cell multiplex qPCR showed that dorsomedial VMN (VMNdm) Ghrh neurons express mRNAs encoding Ghrh, SF-1, and protein markers for glucose-inhibitory (γ-aminobutyric acid) or -stimulatory (nitric oxide; glutamate) neurotransmitters. Hypoglycemia decreased glutamate decarboxylase67 (GAD67) transcripts in male, not female VMNdm Ghrh/SF-1 neurons, a response that was refractory to Ghrh siRNA. Ghrh gene knockdown prevented, in each sex, hypoglycemic down-regulation of Ghrh/SF-1 nerve cell GAD65 transcription. Ghrh siRNA amplified hypoglycemia-associated up-regulation of Ghrh/SF-1 neuron nitric oxide synthase mRNA in male and female, without affecting glutaminase gene expression. Ghrh gene knockdown altered Ghrh/SF-1 neuron estrogen receptor-alpha (ERα) and ER-beta transcripts in hypoglycemic male, not female rats, but up-regulated GPR81 lactate receptor mRNA in both sexes. Outcomes infer that VMNdm Ghrh/SF-1 neurons may be an effector of SF-1 control of counter-regulation, and document Ghrh modulation of hypoglycemic patterns of glucose-regulatory neurotransmitter along with estradiol and lactate receptor gene transcription in these cells. Co-transmission of glucose-inhibitory and -stimulatory neurochemicals of diverse chemical structure, spatial, and temporal profiles may enable VMNdm Ghrh neurons to provide complex dynamic, sex-specific input to the brain glucose-regulatory network.