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Ventromedial Hypothalamic Nucleus (VMN) Neuroestradiol: Sex Mono‐Versus Dimorphic Control of Glycogen Metabolism and Glucoregulatory Transmitter Signaling
Author(s) -
Uddin Md. Main,
Ibrahim Mostafa M.H.,
Briski Karen P.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.09549
Subject(s) - medicine , endocrinology , nitric oxide synthase , biology , glutamate decarboxylase , aromatase , chemistry , nitric oxide , enzyme , biochemistry , cancer , breast cancer
The VMN functions within the neural glucostatic network. Estradiol exerts sex‐specific control of VMN nitric oxide (NO) and γ‐aminobutyric acid (GABA) transmission, which respectively stimulates or suppresses glucose counter‐regulatory hormone secretion. In the brain, the VMN is a principal site of neuroestradiol production by aromatase. This project utilized the aromatase inhibitor letrozole (LZ) alongside combinatory high‐resolution microdissection/Western blotting to address the premise that neuroestradiol governance of VMN metabolic sensory neuron protein marker [neuronal nitric oxide synthase (nNOS); glutamate decarboxylase 65/67 (GAD)] expression is sex‐dimorphic. Glycogen metabolism impacts VMN nNOS and GAD profiles; here, LZ treatment effects on VMN glycogen synthase (GS) and phosphorylase brain‐ (GPBB; glucoprivic‐sensitive) and muscle (GPMM; norepinephrine‐sensitive) variant proteins were examined. VMN aromatase protein content was equivalent between the sexes; intracerebroventricular LZ infusion of testes‐intact male and ovariectomized, estradiol‐replaced female rats blocked insulin (INS)‐induced hypoglycemia up‐regulation of this profile. LZ elicited sex‐contingent changes in basal VMN nNOS and GAD expression, but blocked INS‐induced NO stimulation and GAD suppression in each sex. INS caused LZ‐reversible GPBB augmentation or suppression in male versus female, respectively. Male and female VMN GPMM content was correspondingly unchanged or decreased by INS; LZ reduced baseline GPMM expression in females only, but did not attenuate INS regulation in either sex. LZ correspondingly down‐ or up‐regulated baseline pyruvate recycling pathway marker protein expression in males (glutaminase) and females (malic enzyme‐1), and altered INS effects on the same proteins. Results show that neuroestradiol is required in each sex for optimal VMN metabolic transmitter signaling of hypoglycemia‐associated energy deficiency. Locally‐generated estradiol steroid involvement in sex‐specific hypoglycemic patterns of VMN glucoprivic‐sensitive GPBB expression may correlate with sex‐dimorphic glycogen mobilization during this metabolic stress. Neuroestradiol may also exert sex‐specific effects on glucogenic amino acid energy yield by actions on distinctive enzyme targets in each sex. Support or Funding Information National Institutes of Health DK‐109382