Sex-Dimorphic Octadecaneuropeptide (ODN) Regulation of Ventromedial Hypothalamic Nucleus Glucoregulatory Neuron Function and Counterregulatory Hormone Secretion

• Published in: ASN neuro 2023-01, Vol.15, p.17590914231167230-17590914231167230
• Main Authors: Briski, Karen P., Napit, Prabhat R., Alhamyani, Abdulrahman, Leprince, Jérôme, Mahmood, A.S.M. Hasan
• Format: Article
• Language: English
• Subjects: AMP-activated protein kinase; AMP-Activated Protein Kinases - metabolism; Animals; Corticosterone; Down-regulation; Females; Glucagon; Glucose; Glucose - metabolism; Glutamate decarboxylase; Glycogen - metabolism; Homeostasis; Hormones - metabolism; Hormones - pharmacology; Hypoglycemia; Hypoglycemia - chemically induced; Hypoglycemia - metabolism; Hypothalamus; Hypothalamus (ventromedial); Information processing; Kinases; Male; Males; Metabolism; Neurons; Neurons - metabolism; Nitric oxide; Nitric-oxide synthase; Norepinephrine - pharmacology; Octadecaneuropeptide; Original Papers; Rats; Rats, Sprague-Dawley; Secretion; Sex; Ventromedial Hypothalamic Nucleus; Western blotting; γ-Aminobutyric acid
• ISSN: 1759-0914; 1759-0914
• DOI: 10.1177/17590914231167230

Central endozepinergic signaling is implicated in glucose homeostasis. Ventromedial hypothalamic nucleus (VMN) metabolic monitoring governs glucose counter-regulation. VMN glucose-stimulatory nitric oxide (NO) and glucose-inhibitory γ-aminobutyric acid (GABA) neurons express the energy gauge 5’-AMP-activated protein kinase (AMPK). Current research addresses the premise that the astrocyte glio-peptide octadecaneuropeptide (ODN) imposes sex-dimorphic control of metabolic sensor activity and neurotransmitter signaling in these neurons. The ODN G-protein coupled-receptor antagonist cyclo(1−8)[DLeu5]OP (LV-1075) was administered intracerebroventricularly (icv) to euglycemic rats of each sex; additional groups were pretreated icv with the ODN isoactive surrogate ODN11−18 (OP) before insulin-induced hypoglycemia. Western blotting of laser-catapult-microdissected VMN NO and GABA neurons showed that hypoglycemia caused OP-reversible augmentation of phospho-, e.g., activated AMPK and nitric oxide synthase (nNOS) expression in rostral (female) or middle (male) VMN segments or ODN-dependent suppression of nNOS in male caudal VMN. OP prevented hypoglycemic down-regulation of glutamate decarboxylase profiles in female rat rostral VMN, without affecting AMPK activity. LV-1075 treatment of male, not female rats elevated plasma glucagon and corticosterone concentrations. Moreover, OP attenuated hypoglycemia-associated augmentation of these hormones in males only. Results identify, for each sex, regional VMN metabolic transmitter signals that are subject to endozepinergic regulation. Directional shifts and gain-or-loss of ODN control during eu- versus hypoglycemia infer that VMN neuron receptivity to or post-receptor processing of this stimulus may be modulated by energy state. In male, counter-regulatory hormone secretion may be governed principally by ODN-sensitive neural pathways, whereas this endocrine outflow may be controlled by parallel, redundant ODN-dependent and -independent mechanisms in female.