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Sex Dimorphic Glucose Transporter-2 Regulation of Hypothalamic Astrocyte Glucose and Energy Sensor Expression and Glycogen Metabolism

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Abstract

The plasma membrane glucose transporter-2 (GLUT2) monitors brain cell uptake of the critical nutrient glucose, and functions within astrocytes of as-yet-unknown location to control glucose counter-regulation. Hypothalamic astrocyte-neuron metabolic coupling provides vital cues to the neural glucostatic network. Current research utilized an established hypothalamic primary astrocyte culture model along with gene knockdown tools to investigate whether GLUT2 imposes sex-specific regulation of glucose/energy sensor function and glycogen metabolism in this cell population. Data show that GLUT2 stimulates or inhibits glucokinase (GCK) expression in glucose-supplied versus -deprived male astrocytes, but does not control this protein in female. Astrocyte 5’-AMP-activated protein kinaseα1/2 (AMPK) protein is augmented by GLUT2 in each sex, but phosphoAMPKα1/2 is coincidently up- (male) or down- (female) regulated. GLUT2 effects on glycogen synthase (GS) diverges in the two sexes, but direction of this control is reversed by glucoprivation in each sex. GLUT2 increases (male) or decreases (female) glycogen phosphorylase-brain type (GPbb) protein during glucoprivation, yet simultaneously inhibits (male) or stimulates (female) GP-muscle type (GPmm) expression. Astrocyte glycogen accumulation is restrained by GLUT2 when glucose is present (male) or absent (both sexes). Outcomes disclose sex-dependent GLUT2 control of the astrocyte glycolytic pathway sensor GCK. Data show that glucose status determines GLUT2 regulation of GS (both sexes), GPbb (female), and GPmm (male), and that GLUT2 imposes opposite control of GS, GPbb, and GPmm profiles between sexes during glucoprivation. Ongoing studies aim to investigate molecular mechanisms underlying sex-dimorphic GLUT2 regulation of hypothalamic astrocyte metabolic-sensory and glycogen metabolic proteins, and to characterize effects of sex-specific astrocyte target protein responses to GLUT2 on glucose regulation.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

AMPK:

5’-AMP-activated protein kinaseα1/2.

CNS:

central nervous system.

GCK:

glucokinase.

GKRP:

glucokinase regulatory protein.

GLUT2:

glucose transporter-2.

GPbb:

glycogen phosphorylase-brain type.

GPmm:

glycogen phosphorylase-muscle type.

GS:

glycogen synthase.

LC-ESI-MS:

uHPLC-electrospray ionization-mass spectrometry.

pAMPK:

phosphoAMPKα1/2.

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Funding

This research was supported by NIH grant DK 109382.

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Authors and Affiliations

  1. School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Rm 356 Bienville Building 1800 Bienville Drive, 71201, Monroe, LA, USA

    Madhu Babu Pasula, Prabhat R. Napit, Abdulrahman Alhamyani, Sagor C. Roy, Paul W. Sylvester, Khaggeswar Bheemanapally & Karen P. Briski

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  1. Madhu Babu Pasula
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Correspondence to Karen P. Briski.

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CRediT Statement

Madhu Babu Pasula: conceptualization, investigation, formal analysis, validation, data curation, writing – original draft, writing – review and editing, visualization; Prabhat R. Napit: conceptualization, methodology; Abdulrahman Alhamyani: conceptualization, methodology; Khaggeswar Bheemanapally: methodology, software, formal analysis, validation, data curation, visualization; Paul W. Sylvester: Resources, Writing – Review and Editing; Karen P. Briski: conceptualization, writing – original draft, writing – review and editing, supervision, project administration, funding acquisition.

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Studies performed here were approved by the University of Louisiana Monroe Institutional Animal Care and Use Committee, reference no. 19AUG-KPB-01, in accordance with the National Institutes of Health (NIH) Guide for Care and Use of Laboratory Animals, 8th Edition.

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Pasula, M.B., Napit, P.R., Alhamyani, A. et al. Sex Dimorphic Glucose Transporter-2 Regulation of Hypothalamic Astrocyte Glucose and Energy Sensor Expression and Glycogen Metabolism. Neurochem Res 48, 404–417 (2023). https://doi.org/10.1007/s11064-022-03757-z

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