Hijacking Sodium-Glucose Cotransporters: Fructose Drives Neuronal and Microglial Dysfunction.

Overview

Authors: Salaheldeen Elsaid¹, Muhammad Asad Usmani¹, Xiangdong Wu¹, Junkai Hu¹, Nigus Ambaye¹, Sui Seng Tee¹

ORCID iDs: Salaheldeen Elsaid, Muhammad Asad Usmani, Xiangdong Wu, Junkai Hu, Nigus Ambaye, Sui Seng Tee

Department of Radiology, School of Medicine, University of Maryland, Baltimore, Maryland, USA

Journal: ASN neuro, volume 18, issue 1, article 2696821

Dates: received 19 April 2026; accepted 25 June 2026; published online 10 July 2026; in print 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1080/17590914.2026.2696821 · PMID 42429375 · PMCID PMC13360499 · OpenAlex W7167902829

Open access: gold, a free copy (OpenAlex)

Status: data only

Categories: mouse (organism), cellular / molecular (subfield)

Methods: Statistics

Keywords: Fructose uptake, hippocampal neurons, microglia, neuroinflammation, SGLTs

MeSH: Fructose*, Hippocampus*, Microglia*, Neurons*, Sodium-Glucose Transport Proteins*, Sodium-Glucose Transporter 1*, Animals, Fructokinases, Mice, Sodium (* major topic)

Topic: Diet, Metabolism, and Disease (Endocrinology, Diabetes and Metabolism, Medicine), according to OpenAlex

Funding: NIA NIH HHS (R21 AG084142); NCI NIH HHS (R21 CA245492)

Citations: not cited yet (Europe PMC); 48 references in the paper

Research resources: anti-IL-6 RRID:AB_223576, anti-CD9 RRID:AB_2798139

Abstract

Excess fructose consumption has been implicated in metabolic disease, yet its impact on brain physiology and cellular metabolism remains poorly understood. The hippocampus expresses fructose transporters and fructolytic enzymes, suggesting potential vulnerability to fructose-induced metabolic stress. Here, we investigated fructose uptake mechanisms and downstream functional responses in BV2 microglia and HT22 hippocampal neurons using sodium manipulation, pharmacological inhibition, transporter expression profiling, and live-cell fluorescent sugar uptake assays. Hippocampal neurons exhibited strong sodium-sensitive, phlorizin-responsive fructose uptake, accompanied by reduced expression of facilitated hexose transporters and selective induction of Sglt1. In contrast, microglia demonstrated both sodium-sensitive and sodium-independent components of fructose uptake, associated with coordinated remodeling of GLUT and SGLT family members. Functionally, fructose exposure was associated with membrane hyperpolarization and reduced extracellular vesicle (EV) release in neurons, whereas microglia displayed membrane depolarization, enhanced EV secretion, and induction of pro-inflammatory genes. Knockdown of ketohexokinase (KHK) attenuated inflammatory gene expression and EV release in microglia, while pharmacological inhibition of sodium-dependent transport selectively reduced EV secretion. Complementary secondary analysis of hippocampal RNA-seq data from mice exposed to high-fat/high-fructose feeding revealed coordinated regulation of sodium-coupled transporters, ion channels, and synaptic gene programs, with partial normalization following SGLT inhibition. Together, these findings identify cell-type-specific fructose handling strategies in hippocampal neurons and microglia and suggest that sodium-dependent transport and fructolytic metabolism differentially influence membrane polarization, vesicle signaling, and inflammatory activation under metabolic stress.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

geo:GSE261887 — at NCBI GEO; found in the text, “RNA-Seq Analysis of Hippocampal Tissue”

Versions

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 6 authors, 5 keywords, 10 MeSH terms, 2 funders, 48 references, 2 RRIDs.

Cite

This paper

Elsaid, S., Usmani, M. A., Wu, X., Hu, J., Ambaye, N., & Tee, S. S. (2026). Hijacking Sodium-Glucose Cotransporters: Fructose Drives Neuronal and Microglial Dysfunction. ASN neuro, 18(1), 2696821. https://doi.org/10.1080/17590914.2026.2696821

BibTeX

@article{elsaid2026hijacking, author = {Elsaid, Salaheldeen and Usmani, Muhammad Asad and Wu, Xiangdong and Hu, Junkai and Ambaye, Nigus and Tee, Sui Seng}, title = {{Hijacking Sodium-Glucose Cotransporters: Fructose Drives Neuronal and Microglial Dysfunction}}, journal = {ASN neuro}, year = {2026}, month = jul, volume = {18}, number = {1}, pages = {2696821}, publisher = {Taylor \& Francis}, issn = {1759-0914}, doi = {10.1080/17590914.2026.2696821}, url = {https://doi.org/10.1080/17590914.2026.2696821}, pmid = {42429375}, pmcid = {PMC13360499} }

RIS

TY - JOUR AU - Elsaid, Salaheldeen AU - Usmani, Muhammad Asad AU - Wu, Xiangdong AU - Hu, Junkai AU - Ambaye, Nigus AU - Tee, Sui Seng TI - Hijacking Sodium-Glucose Cotransporters: Fructose Drives Neuronal and Microglial Dysfunction T2 - ASN neuro J2 - ASN Neuro PY - 2026 DA - 2026/07/10 VL - 18 IS - 1 SP - 2696821 SN - 1759-0914 PB - Taylor & Francis DO - 10.1080/17590914.2026.2696821 UR - https://doi.org/10.1080/17590914.2026.2696821 LA - en ER -

CSL-JSON

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