Pioglitazone enhances pyruvate and lactate oxidation in cultured neurons but not in cultured astroglia

Abstract

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists play important roles in the regulation of energy metabolism and are widely used for patients with type 2 diabetes. PPARgamma agonists reportedly reduce plasma glucose levels by recruiting glucose transporters to the cellular membrane, resulting in the enhanced uptake of glucose. However, only a limited number of studies have examined the effect of PPARgamma on cerebral glucose metabolism. In the present study, we examined the effects of a PPARgamma agonist, pioglitazone, on glucose metabolism in cultured rat neurons and astroglia. Cultures of neurons or astroglia were prepared from Sprague-Dawley rats. The cells were treated with pioglitazone (0-50 muM) for 48 hours prior to assay. Lactate released into the culture medium (an index of glycolytic glucose metabolism) and [U-(14)C]lactate or [1-(14)C]pyruvate oxidation (an index of oxidative glucose metabolism) were measured. In addition, the production of cellular reactive oxygen species (ROS) was determined utilizing an H(2)DCFDA assay. Forty-eight hours of exposure to pioglitazone (0.5 and 5 muM) resulted in dose-dependent increases in lactate release into the astroglial culture medium but not into the neuronal culture medium. [U-(14)C]lactate oxidation and [1-(14)C]pyruvate oxidation were enhanced in the neurons, but not in the astroglia. These actions of pioglitazone were not inhibited by 2-chloro-5-nitrobenzanilide (GW9662), a potent antagonist of PPARgamma, and were not mimicked by N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino)ethyl]-l-tyrosine (GW1929), a non-thiazolidinedione PPARgamma agonist. Pioglitazone enhanced aerobic glycolysis and lactate release in astroglia, while the oxidative metabolism of glucose, but not glycolysis, was augmented in neurons without increasing ROS production. These results indicate that pioglitazone may enhance the efficiency of glucose metabolism in the brain.