Sex-dimorphic estrogen receptor regulation of ventromedial hypothalamic nucleus glucoregulatory neuron adrenergic receptor expression in hypoglycemic male and female rats

• Published in: Brain research 2019-10, Vol.1720, p.146311-146311, Article 146311
• Main Authors: Uddin, M. Main, Mahmood, A.S.M. Hasan, Ibrahim, Mostafa M.H., Briski, Karen P.
• Format: Article
• Language: English
• Subjects: Glutamate decarboxylase65/67; Glutaminase; Laser-catapult microdissection; MPP; Neuronal nitric oxide synthase; PHTPP
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2019.146311

•Norepinephrine acts on the ventromedial hypothalamic nucleus (VMN) to control counter-regulation.•Estrogen receptor-alpha (ERα)- and -beta (ERβ) control VMN gluco-inhibitory signaling.•ERα- or -β antagonist was delivered to rats of each sex before insulin-induced hypoglycemia (IIH).•VMN γ-aminobutyric acid (GABA) and nitric oxide (NO) neurons were analyzed by Western blot.•GABA and NO neurons exhibit ER-dependent sex-specific reactivity to NE and estradiol during IIH. The ventromedial hypothalamic nucleus (VMN) is a vital component of the neural circuitry that regulates glucostasis. Norepinephrine (NE) controls VMN gluco-inhibitory γ-aminobutyric acid (GABA) and gluco-stimulatory nitric oxide (NO) transmission. Sex-specific insulin-induced hypoglycemic (IIH) patterns of VMN GABA signaling are estrogen receptor-alpha (ERα)- and -beta (ERβ)-dependent. Current research utilized combinatory immunocytochemistry, laser-microdissection, and Western blot techniques in a pharmacological approach to address the hypothesis that ERα and/or -β mediate sex-dimorphic VMN GABAergic and/or nitrergic nerve cell receptivity to NE and estradiol during IIH. The impact of these ER on expression of the pyruvate recycling pathway marker proteins glutaminase (GLS) and malic enzyme-1 (ME-1) was also examined. Both VMN neuron populations express ERα, ERβ, and G protein-coupled estrogen receptor-1 (GPER), along with alpha1, alpha2, and beta1 adrenergic receptor (AR) proteins. NO neurons exhibited ERα/β-dependent (beta1 AR, GPER) and -independent (alpha1 AR) sex differences in receptor protein responses to hypoglycemia. Similarly, sex-dimorphic effects of IIH on alpha1 AR, alpha2 AR, and ERα profiles in GABA neurons involve ERα/β. These ERs also underlie divergent adjustments in gluco-regulatory nerve cell GLS and ME-1 protein expression in hypoglycemic males and females. Sex-specific nitrergic and GABAergic nerve cell sensitivity to NE and E, respectively, during IIH may contribute to sex-contingent patterns of neurotransmitter signaling.