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Effects of Intracerebroventricular Glycogen Phosphorylase Inhibitor CP-316,819 Infusion on Hypothalamic Glycogen Content and Metabolic Neuron AMPK Activity and Neurotransmitter Expression in Male Rat

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Abstract

Brain glycogen is a vital energy source during metabolic imbalance. Metabolic sensory neurons in the ventromedial hypothalamic nucleus (VMN) shape glucose counter-regulation. Insulin-induced hypoglycemic (IIH) male rats were infused icv with the glycogen breakdown inhibitor CP-316,819 (CP) to investigate whether glycogen-derived fuel controls basal and/or hypoglycemic patterns of VMN gluco-regulatory neuron energy stability and transmitter signaling. CP caused dose-dependent amplification of basal VMN glycogen content and either mobilization (low dose) or augmentation (high dose) of this depot during IIH. Drug treatment also prevented hypoglycemic diminution of tissue glucose in multiple structures. Low CP dose caused IIH-reversible augmentation of AMPK activity and glutamate decarboxylase (GAD) protein levels in laser-microdissected VMN GABA neurons, while the higher dose abolished hypoglycemic adjustments in these profiles. VMN steroidogenic factor-1 (SF-1) neurons exhibited suppressed (low CP dose) or unchanged (high CP dose) basal SF-1 expression and AMPK refractoriness of hypoglycemia at each dose. CP caused dose-proportionate augmentation of neuronal nitric oxide synthase protein and enhancement (low dose) or diminution (high dose) of this profile during IIH; AMPK activity in these cells was decreased in high dose-pretreated IIH rats. CP exerted dose-dependent effects on basal and hypoglycemic patterns of glucagon, but not corticosterone secretion. Results verify that VMN GABA, SF-1, and nitrergic neurons are metabolic sensory in function and infer that these populations may screen unique aspects of neurometabolic instability. Correlation of VMN glycogen augmentation with attenuated hypoglycemic VMN gluco-regulatory neuron AMPK activity implies that expansion of this fuel reservoir preserves cellular energy stability during this metabolic threat.

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Abbreviations

CP-316,819:

[R-R*,S*]-5-chloro-N-[2-hydroxy-3-(methoxymethylamino)-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide

ARH:

Arcuate hypothalamic nucleus

DMN:

Dorsomedial hypothalamic nucleus

GABA:

γ-Aminobutyric acid

GAD65/67 :

Glutamate decarboxylase65/67

GP:

Glycogen phosphorylase

icv :

Intracerebroventricular

IIH:

Insulin-induced hypoglycemia

LCM:

Laser-catapult microdissection

LHA:

Lateral hypothalamic area

NO:

Nitric oxide

nNOS:

Neuronal nitric oxide synthase

SF-1:

Steroidogenic factor-1

VMN:

Ventromedial hypothalamic nucleus

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Correspondence to Karen P. Briski.

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Experimental procedures were carried out in accordance with the Guide for the Care and Use of Laboratory Animals, 8th Edition, and approved by the University of Louisiana at Monroe Institutional Animal Care and Use Committee.

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Mostafa M.H. Ibrahim, Khaggeswar Bheemanapally, and Hussain N. Alhamami shared first authorship

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Ibrahim, M.M.H., Bheemanapally, K., Alhamami, H.N. et al. Effects of Intracerebroventricular Glycogen Phosphorylase Inhibitor CP-316,819 Infusion on Hypothalamic Glycogen Content and Metabolic Neuron AMPK Activity and Neurotransmitter Expression in Male Rat. J Mol Neurosci 70, 647–658 (2020). https://doi.org/10.1007/s12031-019-01471-0

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