2026/07/10 by Salaheldeen Elsaid, Muhammad A. Usmani, Xiangdong Wu +3 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · Nursing · #Cancer, Hypoxia, and Metabolism #Diet, Metabolism, and Disease #Microbial Metabolites in Food Biotechnology
paper · pdf · doi:10.1080/17590914.2026.2696821
openalex publication_date 2026/07/10 · openalex created_date 2026/07/11 · openalex updated_date 2026/08/01
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.