Neural substrates for estrogen regulation of glucose homeostasis remain unclear. Female rat dorsal vagal complex (DVC) A2 noradrenergic neurons are estrogen-and metabolic-sensitive. The ventromedial hypothalamic nucleus (VMN) is a key component of the brain network that governs counter-regulatory responses to insulin-induced hypoglycemia (IIH). Here, the selective estrogen receptor-alpha (ERα) or -beta (ERβ) antagonists MPP and PHTPP were administered separately to the caudal fourth ventricle to address the premise that these hindbrain ER variants exert distinctive control of VMN reactivity to IIH in the female sex. Data show that ERα governs hypoglycemic patterns of VMN astrocyte glycogen metabolic enzyme, e.g. glycogen synthase and phosphorylase protein expression, whereas ERβ mediates local glycogen breakdown. DVC ER also regulate VMN neurotransmitter signaling of energy sufficiency [γ-aminobutyric acid] or deficiency [nitric oxide, steroidogenic factor-1] during IIH. Neither hindbrain ER mediates IIH-associated diminution of VMN norepinephrine (NE) content. Both ER oppose hypoglycemic hyperglucagonemia, while ERβ contributes to reduced corticosterone output. Outcomes reveal that input from the female hindbrain to the VMN is critical for energy reserve mobilization, metabolic transmitter signaling, and counter-regulatory hormone secretion during hypoglycemia, and that ER control those cues. Evidence that VMN NE content is not controlled by hindbrain ERα or -β implies that these receptors may regulate VMN function via NE-independent mechanisms, or alternatively, that other neurotransmitter signals to the VMN may control local substrate receptivity to NE.

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Estrogen receptor-alpha (ERα) and -beta (ERβ) occur in key elements of the brain glucohomeostatic network in both sexes, including the hindbrain dorsal vagal complex (DVC), but the influence of distinct receptor populations on this critical function is unclear. The ventromedial hypothalamic nucleus (VMN) maintains glucose balance by integrating nutrient, endocrine, and neurochemical cues, including metabolic sensory information supplied by DVC A2 noradrenergic neurons. Current research utilized the selective ERα and ERβ antagonists MPP and PHTPP to characterize effects of DVC ERs on VMN norepinephrine (NE) activity and metabolic neurotransmitter signaling in insulin-induced hypoglycemic (IIH) male rats. Data show that ERβ inhibits VMN glycogen synthase and stimulates phosphorylase protein expression, while attenuating hypoglycemic augmentation of glycogen content. Furthermore, both ERs attenuate VMN glucose concentrations during IIH. Hypoglycemic up-regulation of nitric oxide (NO) and brain-derived neurotrophic factor (BDNF) signaling was correspondingly driven by ERα or -β, whereas GABA and steroidogenic factor-1 were respectively suppressed independently of ER input or by ERβ. IIH intensified VMN NE accumulation by ERβ-dependent mechanisms, but did not alter NE levels in other gluco-regulatory loci. ERβ amplified the magnitude of insulin-induced decline in blood glucose. Both ER regulate corticosterone, but not glucagon secretion during IIH and oppose hypoglycemic diminution of circulating free fatty acids. These findings identify distinguishing versus common VMN functions targeted by DVC ERα and -β. Sex differences in hypoglycemic VMN NE accumulation, glycogen metabolism, and transmitter signaling may involve, in part, discrepant regulatory involvement or differential magnitude of impact of these hindbrain ERs.

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The astrocyte gliotransmitter octadecaneuropeptide (ODN) is a cleavage product of diazepam‐binding inhibitor (DBI) and an endogenous central benzodiazepine receptor ligand. ODN regulation of feeding responses to excess or diminished glucose availability in the brain infers ability to modulate neural metabolic‐sensory function [Lanfray et al., 2013]. The ventromedial hypothalamic nucleus (VMN), a principal component of the neural glucostatic network, integrates nutrient and other cues to shape glucose counter‐regulation. Our studies show that VMN gluco‐stimulatory nitric oxide (NO) and gluco‐inhibitory g‐aminobutyric acid (GABA) neurons express the ultra‐sensitive energy sensor 5′‐AMP‐activated protein kinase (AMPK). This research examined the premise that ODN exerts sex‐specific effects on hypoglycemic patterns of VMN nitrergic and/or GABAergic nerve cell sensor activation and neurotransmitter signaling. Testes‐intact male and ovariectomized, estradiol‐replaced female rats were pretreated by intracerebroventricular administration of the ODN octapeptide (OP) fragment or vehicle prior to insulin injection. VMN NO and GABA cells were identified by immunocytochemistry prior to combinatory laser‐catapult dissection/high‐sensitivity Western blotting. Results identified nitrergic cells exhibiting OP‐reversible effects of hypoglycemia on expression profiles of the NO marker protein neuronal nitric oxide synthase (nNOS), AMPK, and phospho (activated)‐AMPK in distinctive regions of the male and female VMN. In each sex, OP effects on GABA neuron AMPK protein content and activation were also observed at specific levels of the VMN. Outcomes provide novel evidence that ODN may critically impact VMN substrate fuel screening. Further studies are needed to characterize neuroanatomical connectivity of OP‐sensitive nitrergic and GABAergic neurons within central metabolic pathways, and to examine whether metabolic cues that regulate VMN astrocyte ODN release, astrocyte reactivity to ODN‐controlling signals, and metabolic‐sensory nerve cell receptivity to ODN are sex‐dimorphic. Support or Funding Information NIH DK 109382