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. 2019 Jul 15:411:211-221.
doi: 10.1016/j.neuroscience.2019.05.007. Epub 2019 May 12.

Hindbrain Estrogen Receptor Regulation of Ventromedial Hypothalamic Glycogen Metabolism and Glucoregulatory Transmitter Expression in the Hypoglycemic Female Rat

Prabhat R Napit  1 , Md Haider Ali  1 , Manita Shakya  1 , Santosh K Mandal  1 , Khaggeswar Bheemanapally  1 , A S M Hasan Mahmood  1 , Mostafa M H Ibrahim  1 , K P Briski  2
Affiliations

Hindbrain Estrogen Receptor Regulation of Ventromedial Hypothalamic Glycogen Metabolism and Glucoregulatory Transmitter Expression in the Hypoglycemic Female Rat

Prabhat R Napit et al. Neuroscience. .

Abstract

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 ERs 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 ERs 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 ERs 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.

Keywords: estrogen receptor-beta; glutamate decarboxylase; glycogen; glycogen phosphorylase; nitric oxide synthase; ventromedial hypothalamic nucleus.

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Figures

Figure 1.
Figure 1.. Effects of Caudal Fourth Ventricular (CV4) Administration of the ERα Antagonist 1,3-Bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP) or ERβ Antagonist 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP) on Ventromedial Hypothalamic Nucleus (VMN) Metabolic Neurotransmitter Marker Protein Responses to Insulin-Induced Hypoglycemia (IIH) in the Female Rat.
Micropunch-dissected VMN tissue obtained from estradiol-implanted ovariectomized female rats pretreated by CV4 delivery of MPP, PHTPP, or vehicle prior to sc insulin (INS) injection was pooled within treatment groups for Western blot analysis of glutamate decarboxylase65/67 (GAD65/67; Panel A), neuronal nitric oxide synthase (nNOS; Panel B), steroidogenic factor-1 (SF-1; Panel C), or brain-derived neurotrophic factor (BDNF; Panel D). Data depict mean normalized protein optical density (O.D.) values ± S.E.M. for vehicle-pretreated animals injected sc with vehicle- (V/V; solid white bars; n=5) or INS (V/INS; solid gray bars; n=5) or INS- injected rats pretreated with MPP (MPP/INS; diagonal-striped gray bars; n=5) or PHTPP (PHTPP/INS; cross-hatched gray bars; n=5. *p<0.05; **p<0.01; ***p<0.001.
Figure 2.
Figure 2.. Impact of DVC ERα or ERβ Antagonism on Hypoglycemic Patterns of VMN Glycogen Synthase (GS) and Glycogen Phosphorylase (GP) Protein Expression and Tissue Glycogen and Glucose Concentrations.
Panels A and B depict mean normalized GS and GP O.D. values ± S.E.M., respectively, from triplicate Western blot analyses of pooled VMN tissue from V/V (solid white bars), V/INS (solid gray bars), MPP/INS (diagonal-striped gray bars), and PHTPP/INS (cross-hatched gray bars) treatment groups. Panels C and D illustrate effects of INS in the presence or absence of pharmacological blockade of DVC ER on mean HPLC measures of VMN tissue glycogen and glucose content ± S.E.M., respectively, for n=5 animals per treatment group. *p<0.05; **p<0.01; ***p<0.001.
Figure 3.
Figure 3.. Effects of DVC ERα or ERβ Antagonism on Hypoglycemic Site-Specific Norepinephrine (NE) Accumulation in Hypoglycemic Female Rats.
Micropunches of the VMN (Panel A), arcuate hypothalamic nucleus (Panel B), dorsomedial hypothalamic nucleus (DMN), and lateral hypothalamic area (LHA) were analyzed by ELISA methods for assessment of tissue NE content. Data depict mean NE levels + S.E.M. for V/V (solid white bars; n=5), V/INS (solid gray bars; n=5), MPP/INS (diagonal-striped gray bars; n=5), and PHTPP/INS (cross-hatched gray bars; n=5) treatment groups. *p<0.05; **p<0.01; ***p<0.001.
Figure 4.
Figure 4.. CV4 MPP versus PHTPP Pretreatment on Glucose, Glucagon, Corticosterone, and Free Fatty Acid (FFA) Responses to Insulin Injection of Female Rats.
Data show circulating glucose (Panel A), glucagon (Panel B), corticosterone (Panel C), and FFA (Panel D) levels + S.E.M. levels in V/V (solid white bars; n=5), V/INS (solid gray bars; n=5), MPP/INS (diagonal-striped gray bars; n=5), and PHTPP/INS (cross-hatched gray bars; n=5) treatment groups. *p<0.05; **p<0.01; ***p<0.001.
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References

    1. Alhamami HN, Uddin MM, Mahmood ASMH, Briski KP. Lateral but not medial hypothalamic AMPK activation occurs at the hypoglycemic nadir in insulin-injected male rats: Impact of caudal dorsomedial hindbrain catecholamine signaling. Neuroscience 2018; 379:103–114. - PubMed
    1. Alhamami HN, Alshamrani A, Briski. Effects of the glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol on ventromedial hypothalamic nucleus 5’-adenosine monophosphate-activated protein kinase activity and metabolic neurotransmitter biosynthetic enzyme protein expression in eu- versus hypoglycemic male rats. Physiological Reports 2018; 103: 236–249
    1. Alenazi FSH, Ibrahim BA, Briski KP. Estradiol regulates effects of hindbrain activator 5- aminoimidazole- 4-carboxamide-riboside administration on hypothalamic adenosine 5’-monophosphate-activated protein kinase activity and metabolic neurotransmitter mRNA and protein expression. J. Neurosci. Res 2014; 93: 651–659. - PubMed
    1. Bai W, Fang X, Zhao W, Huang S, Zhang H, Qian M. Determination of oligosaccharides and monosaccharides in Hakka rice wine by precolumn high-performance liquid chromatography. J. Food Drug Anal. 2015; 23: 645–651. - PMC - PubMed
    1. Briski KP, Koshy Cherian A, Genabai NK, Vavaiya KV. In situ coexpression of glucose and monocarboxylate transporter mRNAs in metabolic-sensitive dorsal vagal complex catecholaminergic neurons: transcriptional reactivity to insulin-induced hypoglycemia (IIH) and caudal hindbrain glucose or lactate repletion during IIH. Neuroscience 2009; 164: 1152–1160. - PubMed

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