High Extracellular Glucose Concentration Drives Palmitate-Induced Toxicity and Metabolic Dysfunction in BV2 Microglia...

Microglia exhibit targeted responses to different stimuli, including lipids, which can differ depending on the environmental conditions they encounter. These responses involve inflammatory mediators and are crucial for maintaining brain homeostasis. This study investigated whether inflammatory, metabolic, and phagocytic responses of microglia to the saturated fatty acid palmitate depend on extracellular glucose concentrations. BV2 microglial cells were cultured in low glucose (LG; 5.5 mmol/L) or high glucose (HG; 25 mmol/L) concentrations, and then exposed to palmitate (100 or 200 µmol/L) or vehicle for 24 h. Under HG, palmitate decreased cell viability, which was accompanied by an increase in inflammatory markers, which are associated with an activated state. Additionally, palmitate induced higher expression of genes related to lipid metabolism in both LG and HG, without affecting enzymes linked to glucose metabolism. HG condition led to an increase in the oxygen consumption rate (OCR) and glycolytic flux (i.e., extracellular medium acidification) compared to LG-cultured cells, with palmitate reducing OCR and glycolytic flux in both conditions. The short-chain fatty acid butyrate did not prevent palmitate-induced mitochondrial dysfunction in BV2 cells. In primary microglia, palmitate did not affect mitochondria density and cargo metabolism. Altogether, our results indicate that BV2 cells are prone to palmitate-induced stress on viability assays under HG but not LG in the medium.