Receptor-Independent Metabolic Effects of Thiazolidinediones in Astrocytes

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.