Abstract
Thiazodinedione (TZD) agonists of the peroxisome proliferator activated receptor gamma (PPAR) exert metabolic effects in glial cells. In primary astrocytes, TZDs are cytoprotective and have anti-inflammatory actions; in contrast, in glioma cells TZDs are cytotoxic. Although PPAR is considered their primary target, TZDs including pioglitazone and troglitazone also bind to a mitochondrial protein MitoNEET; whether their metabolic effects are mediated by activation of PPAR or MitoNEET are not known. We generated PPAR null astrocytes by crossing a PPAR floxxed mouse with a transgenic line expressing CRE recombinase under control of the GFAP promoter. PPAR deficient astrocytes showed reduced lactate production under basal conditions and in response to pioglitazone; however at later times similar levels of lactate were produced. In the presence of troglitazone lactate production was similar in PPAR null cells as wildtype astrocytes. In astrocytes in which MitoNEET expression was reduced using siRNA, basal lactate production was lower than control cells, however the cells increased lactate production in response to TZDs. When MitoNEET was decreased in the PPAR null astrocytes, responses to TZDs were reduced compared to non-infected cells. These results indicate that metabolic effects of TZDs are not exclusively mediated via PPAR, but involve binding to MitoNEET. Real time PCR revealed significantly greater MitoNEET mRNA in glioma cells than astrocytes. Differences in MitoNEET expression or activity could therefore contribute to differential effects of TZDs on astrocyte versus glioma cells.
Highlights
Thiazolidinediones (TZDs) are synthetic compounds used as oral anti-diabetic drugs
In order to determine whether the metabolic effects of pioglitazone on astrocyte metabolism are mediated through peroxisome proliferator activated receptor gamma (PPAR) we made use of PPAR conditional astrocyte knockout mice [11]
In this report we have shown that the ability of two TZDs, pioglitazone and troglitazone to increase lactate production in astrocytes is not fully dependent on PPAR
Summary
Thiazolidinediones (TZDs) are synthetic compounds used as oral anti-diabetic drugs. TZDs, which include Troglitazone, Pioglitazone, and Rosiglitazone, are agonists of peroxisome proliferator activated receptor gamma (PPAR) of the PPAR family. In addition to effects on energy and fuel metabolism, several studies report TZD involvement in suppression of cell proliferation, induction of cytotoxicity; and perturbation of mitochondrial function. In these studies the rapid occurrence of agonist induced effects, the lack of correlation between the effects and the affinity for PPAR, and the incability of antagonists to block the effects suggest PPAR independent action by TZDs. In primary cultures of astrocytes, we reported that TZDs caused a rapid increase in glucose consumption and lactate production, associated with an rapid decrease in mitochondrial membrane potential followed by a subsequent hyperpolarization [5]. Our data show that knockdown of MitoNEET in astrocytes accomplished by siRNA leads to an increase in lactate production; In contrast, the effects of pioglitazone on lactate production are comparable in PPAR expressing versus null cells
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