Consumption of Fructose by Cultured Primary Rat Astrocytes

Fructose has recently gained substantial interest in the context of diseases that are connected with sucrose-rich diets. Several studies have shown that astrocytes are able to metabolize fructose to some extent but less efficiently than glucose. To study whether and how fructose can fuel astrocytic energy metabolism, we used cultured primary astrocytes as model. These cells consumed fructose in a time- and concentration-dependent manner that followed apparent Michaelis-Menten type kinetics with a K_M value of 2.8 ± 0.9 mM and a V_Max value of 325 ± 32 nmol/(mg × h). Although the specific consumption of glucose and the production of lactate from glucose were around 4 times higher than the respective values for fructose, the loss of astrocytic cellular ATP during starvation was prevented by both fructose and glucose with similar concentration dependencies. However, severe differences were observed for fructose- and glucose-fed astrocytes, if the mitochondrial oxidative phosphorylation was impaired. For fructose-treated astrocytes the application of inhibitors of mitochondrial ATP regeneration almost doubled the low basal glycolytic lactate production, but this was insufficient to prevent a rapid and severe loss in cellular ATP content and subsequent cell toxicity. In contrast, for glucose-treated cells a strong upregulation of glycolysis was connected with a slow ATP loss and a delayed onset of toxicity. Although hexokinase in astrocytic cell lysates was found to have a high K_M value for fructose (4.4 ± 1.1 mM), hardly any free fructose was found in astrocytic lysates even after exposure to 10 mM fructose, suggesting that not the phosphorylation but rather the uptake of fructose limits astrocytic fructose consumption. The data presented demonstrate that millimolar concentrations of fructose are required to make this hexose a suitable extracellular substrate for astrocytic metabolism and that fructose metabolism provides energy mainly by mitochondrial respiration.