CORTICOSTERONE REPROGRAMS ASTROCYTE METABOLISM TOWARD A PENTOSE PHOSPHATE PATHWAY-DRIVEN ANTIOXIDANT STATE

Astrocytes are central regulators of brain energy metabolism and redox homeostasis. Prolonged exposure to corticosterone (CORT) disrupts cerebral glucose utilization and contributes to the etiology of psychiatric disorders, such as depression. However, the metabolic adaptations of astrocytes under sustained CORT exposure remain poorly understood.
We show that prolonged CORT treatment induced a morphological shift in astrocytes from a protoplasmic to a fibrous-like phenotype. Integrated transcriptomic and metabolomic analyses revealed coordinated metabolic reprogramming, characterized by increased glucose uptake, reduced glycolytic flux, and redirection of glucose metabolism toward the pentose phosphate pathway (PPP). CORT treatment upregulated the rate-limiting enzyme G6PD, elevated NADPH levels, increased glutathione intermediate l-pyroglutamic acid levels, and lowered the GSH/GSSG ratio, consistent with response to oxidative stress and activation of antioxidant defenses.
Functional analyses revealed enhanced glucose uptake despite a marked reduction in ATP production from glycolysis and mitochondrial respiration. Glycogen stores were depleted, and lactate release into the extracellular medium increased, reflecting impaired mitochondrial pyruvate oxidation. This metabolic shift was accompanied by increased expression of PDK2 and PDK4, inhibiting pyruvate dehydrogenase and favoring pyruvate diversion to lactate. Interestingly, CORT downregulated GLUT1 while upregulating GLUT3 and GLUT4 expression, suggesting a compensatory remodeling of glucose transporter usage to maintain glucose influx under prolonged stress.
Together, these findings highlight a glucocorticoid-induced metabolic switch that favors antioxidant capacity over energy production. While this adaptation may enhance astrocyte resilience under stress, it may also reduce their capacity to sustain neuronal metabolism, thereby unveiling novel targets for therapeutic intervention in stress-related disorders.