PPAR gamma activators induce differentiation of B12 oligodendrocyte‐like cells and rat spinal cord oligodendrocytes

Abstract

The regulation of CNS lipid metabolism by nuclear receptors and their relation to cell differentiation remains undetermined. Since myelinating oligodendrocytes are the major lipid‐synthesizing cells in the CNS, we characterized the effect of PPAR activation in a CNS derived cell line that expresses oligodendrocyte markers and compared these effects with oligodendrocyte primary cultures (90–95% pure). The rat glioma derived B12 cell line express the three major PPAR isoforms (PPAR α, β and γ) and present a large number of peroxisomes, indicating an important lipid metabolism. Treatment with ciprofibrate, a general PPAR activator and clinical hypolipidemic, induces proliferation arrest, process extension and a moderate rise in the expression of acyl‐CoA oxidase, a specific marker of peroxisomal proliferation. Cell growth arrest by ciprofibrate is enhanced 100‐fold by low concentrations of retinoic acid (0.01 μm), suggesting the involvement of the PPAR‐retinoid acid receptor heterodimers. Since ciprofibrate possibly acts by modifying the concentration of endogenous PPAR ligands, we traced its effects to PPARγ by using isoform specific ligands: Troglitazone and 15‐deoxy‐prostaglandin J2, both of which induce growth arrest and process extension in B12 cells. These effects were corroborated on rat spinal cord derived oligodendrocytes primary cultures, where a significant rise in the number of mature oligodendrocytes is observed in response to PPARγ activators. These results show that PPARγ, a master gene in the differentiation of adipose tissue could be involved in the lipid metabolism of maturing oligodendrocytes.