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

  • Mostafa M. H. Ibrahim
  • Khaggeswar Bheemanapally
  • Hussain N. Alhamami
  • Karen P. BriskiEmail author


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.


Glycogen CP-316,819 Ventromedial hypothalamic nucleus Laser-catapult microdissection Glutamate decarboxylase65/67 AMPK 





Arcuate hypothalamic nucleus


Dorsomedial hypothalamic nucleus


γ-Aminobutyric acid


Glutamate decarboxylase65/67


Glycogen phosphorylase




Insulin-induced hypoglycemia


Laser-catapult microdissection


Lateral hypothalamic area


Nitric oxide


Neuronal nitric oxide synthase


Steroidogenic factor-1


Ventromedial hypothalamic nucleus


Compliance with Ethical Standards

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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© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  1. 1.School of Basic Pharmaceutical and Toxicological Sciences, College of PharmacyUniversity of Louisiana at MonroeMonroeUSA
  2. 2.Department of Pharmacology and Toxicology, College of PharmacyKing Saud UniversityRiyadhSaudi Arabia

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