Caloric restriction mimetic 2-deoxyglucose alters metabolic and transcriptomic phenotype in association with changes in chromatin accessibility in human astrocytes [ATAC-Seq]

Caloric restriction and ketogenic diets may modify the progression of neurological disorders, including HIV-associated neurological disorders and Alzheimer’s disease, in part by influencing astrocyte function. This study examines how metabolic substrate availability affects metabolic processes and gene expression in human astrocytes. We exposed astrocytes to the glycolysis inhibitor 2-deoxyglucose (2-DG) prior to stimulation with interleukin-1β and measured extracellular flux using the Seahorse ® platform. We next analyzed gene expression and chromatin accessibility changes using RNA-sequencing and ATAC-sequencing, respectively. Finally, we tested the effects of glucose deprivation and the ketone body β-hydroxybutyrate (BHB) on inflammatory gene expression. 2-DG reduced oxygen consumption rate and extracellular acidification rate in the presence of IL-1β, while concomitantly decreasing expression of pro-inflammatory cytokines TNF, IL-6, and C3. These changes were linked to altered chromatin structure. The metabolic substrate β-hydroxybutyrate was associated with reduced cytokine expression compared to glucose. Inhibition of glycolysis attenuated IL-1β-induced inflammation and gene expression changes and altered chromatin architecture. Both glucose deprivation and BHB treatment reduced inflammatory cytokine expression, with additive effects when combined with 2-DG. These results suggest that targeting glycolysis could provide therapeutic strategies for treating neurological diseases through modulation of astrocyte-driven inflammation.