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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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.
KeywordsGlycogen CP-316,819 Ventromedial hypothalamic nucleus Laser-catapult microdissection Glutamate decarboxylase65/67 AMPK
Arcuate hypothalamic nucleus
Dorsomedial hypothalamic nucleus
Lateral hypothalamic area
Neuronal nitric oxide synthase
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.
- Ali MH, Napit PR, Mahmood ASMH, Bheemanapally K, Alhamami HN, Uddin MM, Mandal KS, Ibrahim MMH, Briski KP (2019) Hindbrain estrogen receptor regulation of ventromedial hypothalamic glycogen metabolism and glucoregulatory transmitter expression in the hypoglycemic male rat. Neuroscience 409:253–260CrossRefGoogle Scholar
- Napit PR, Ali MH, Shakya M, Mandal SK, Bheemanapally K, Mahmood ASMH, Ibrahim MMH, Briski KP (2019) Hindbrain estrogen receptor regulation of counter-regulatory hormone secretion and ventromedial hypothalamic nucleus glycogen content and glucoregulatory transmitter signaling in hypoglycemic female rats. Neuroscience 411:211–221CrossRefGoogle Scholar
- Suh SW, Bergher JP, Anderson CM, Treadway JL, Fosgerau K, Swanson RA (2007) Astrocyte glycogen sustains neuronal activity during hypoglycemia: studies with the glycogen phosphorylase inhibitor CP-316,819 ([R-R*,S*]-5-chloro-N-[2-hydroxy-3-(methoxymethylamino)-3-oxo-1-(phenylmethyl)-propyl]-1H-indole-2-carboxamide). J Pharmacol Exp Ther 321:45–50CrossRefGoogle Scholar
- Zhu W, Czyzyk D, Paranjape SA, Zhou L, Horblitt A, Szabó G, Seashore MR, Sherwin RS, Chan O (2010) Glucose prevents the fall in ventromedial hypothalamic GABA that is required for full activation of glucose counterregulatory responses during hypoglycemia. Amer J Physiol Endocrinol Metab 298:E971–E977CrossRefGoogle Scholar