The peroxisome proliferator activated receptors (PPARs) are members of the nuclear receptor super-family that regulate the transcription of various enzymes involved in lipid metabolism. Fatty acid synthesis and oxidation, ketogenesis and lipoprotein metabolism are amongst the most important PPAR regulated pathways. Nonetheless, PPARs are also important regulators of cell differentiation programs. So, while the importance of lipid metabolism in cellular homeostasis is evident, its relation to cellular differentiation had been overlooked until the characterization of the PPARs and their lipid activators, the importance of which is highlighted by PPARg’s role as the master regulator gene in adipogenesis. Still, there are many tissues where the importance of the PPARs has yet to be studied. The Central Nervous System (CNS) is composed of about 50% of lipids (dry weight) and the relevance of these molecules is underscored by the cognitive impairments produced by diets with insufficient essential fatty acids. In this sense, it should be pointed out that the metabolic disorders produced by abnormal peroxisomal function have direct consequences on the formation of the myelin sheath, as is the case in X linked adrenoleukodystrophy and Zellweger syndrome. Because essential CNS processes, such as myelin deposition, require coordination between lipid metabolism and cell differentiation programs, we have hypothesized that the activation of PPAR transcription factors are important in the differentiation and lipid metabolism of glial cells. Our interest in glial cells derives from the fact that these cells carry out a more active lipid metabolism than neurons and are responsible for lipid homeostasis in the CNS. In order to test this hypothesis we have made use of the B12 cell line over primary culture because glial cultures usually represent determined cells that will differentiate regardless of culture conditions and in the case of oligodendrocytes, die shortly after terminal differentiation. Also, it should be noted that the existence of different pre-adipocytic cell lines, with diverse blockages in their differentiation program were a prime tool in the characterization of PPARg`s role in adipocyte differentiation. The results of this thesis show that the B12 cells are derived from the oligodendrocyte lineage and that they express the three PPAR subtypes. This initial characterization is of great importance because oligodendrocytes present a predominantly anabolic lipid metabolism, as exemplified by their synthesis of the myelin sheath, while astrocytes present a predominantly catabolic lipid metabolism. The large number of peroxisomes present in the B12 cells, in the absence of Acyl-CoA oxidase activity complements this characterization since Acyl-CoA oxidase is the limiting enzyme of peroxisomal b-oxidation and therefore, peroxisomes might play an anabolic role in B12 cells as they do in oligodendrocytes. We show that the B12 cells present functional PPARa and PPARg receptors. PPARa activation induces peroxisome proliferation, but PPARa specific ligand (WY14643) is incapable of inhibiting B12 cell proliferation or inducing process extension. On the other hand, PPARg agonists induce B12 cell morphological differentiation by stimulating cell process extension and inhibiting cell proliferation, suggesting that PPARg might play a relevant role in oligodendrocyte differentiation and the formation of the myelin sheath. While PPARd is present in B12 cells, bezafibrate, an activator of PPARa and PPARd is incapable of inhibiting B12 cell proliferation or inducing cell process extension. In order to evaluate the interaction of PPARs with other signal transduction pathways, B12 cell proliferation and process extension was analyzed in the presence of Retinoic Acid (AR), db-cAMP or TPA. We found that AR enhances PPAR mediated B12 cell differentiation only when using ciprofibrate and not when specific agonists are used. This effect might be related to the low levels of ciprofibrate dependent activation of the RXR-PPARg heterodimers, which makes the activation of RXR relevant to the system, while in the presence of strong PPARg ligands, the few activated RXRs present in the cell suffice to achieve B12 cell differentiation. We found that B12 cell differentiation by cAMP is not enhanced by ciprofibrate or PPAR specific agonists, suggesting that these pathways act through different effectors. The activation of PKCs by TPA results in enhanced B12 cell proliferation and a reduction of cell processes, a phenomena that is also elicited by TPA on oligodendrocyte progenitor cells. This prompted us to characterize the different PKC isoforms present in B12 cells and found that these cells present PKCd and lack PKCb when compared to immature oligodendrocytes. These findings are relevant since TPA has been found to be synergistic with ciprofibrate in HL-60 cells, possibly through a PKCb dependent mechanism, while TPA is antagonistic of ciprofibrate effects on B12 cells. PKCd expression by B12 cells might be related to the transformed characteristics of this cell line since PKCd is not expressed by immature oligodendrocytes and this PKC isozime has been linked to cell transformation. This thesis corresponds to the first report of cell differentiation by PPAR nuclear receptors in a CNS derived cell line and highlights the importance of these receptors and lipid metabolism in the differentiation of neural cells.PFCHA-BecasPFCHA-Becas