PPAR  Activators Induce Growth Arrest and Process Extension in B12 Oligodendrocyte-Like Cells and Terminal Differentiation of Cultured Oligodendrocytes Alejandro D. Roth, 1 Andrea V. Leisewitz, 1 Juan E. Jung, 1 Patricia Cassina, 2 Luis Barbeito, 2 Nibaldo C. Inestrosa, 1 and Miguel Bronfman 1 * 1 Centro de Regulacio ´n Celular y Patologı ´a, Departamento de Biologı ´a Celular y Molecular, Facultad de Ciencias Biolo ´gicas y MIFAB, P. Universidad Cato ´lica de Chile, Santiago, Chile 2 Divisio ´n de Neurobiologı ´a Celular y Molecular, Instituto de Investigaciones Biolo ´ gicas Clemente Estable, Montevideo, Uruguay Peroxisome proliferator-activated receptors (PPARs) are key transcription factors in the control of lipid homeosta- sis and cell differentiation, but little is known about their function in oligodendrocytes, the major lipid-synthesizing cells in the central nervous system (CNS). Using the B12 oligodendrocyte-like cell line and rat spinal cord-derived oligodendrocytes, we evaluated the importance of PPAR in the maturation process of these cells. B12 cells express all PPAR isoforms (, /, and ), as assessed by RT-PCR, Western-blot, and transactivation assays. B12 cells respond specifically to PPAR agonists by arresting cell proliferation and extending cell processes, events that are blocked by the PPAR antagonist GW9662. In addition, alkyl-dihydroxyacetone phosphate synthase (ADAPS), a key peroxisomal enzyme involved in the syn- thesis of myelin-rich lipid plasmalogens, is increased in PPAR agonist-treated B12 cells. In contrast with B12 cells, both immature and mature isolated spinal cord oligodendrocytes presented a high and similar expres- sion level of ADAPS, as assessed by immunocytochem- istry. However, as in B12 cells, isolated spinal cord oli- godendrocytes were also found to respond specifically to PPAR agonists with a four-fold increase in the num- ber of mature cells. Our data suggest a relevant role for PPAR in oligodendrocyte lipid metabolism and differentiation. © 2003 Wiley-Liss, Inc. Key words: oligodendrocytes; B12 neural cells; differen- tiation; PPAR Peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors involved deeply in the physiologic and pharmacologic control of lipid me- tabolism and cell differentiation in a number of tissues (Fajas et al., 2001; Barbier et al., 2002). Very little is known, however, about their role in the central nervous system (CNS), where lipids make up 50% of the dry weight and where alterations in lipid metabolic pathways and myelin synthesis affect physiologic and behavioral parameters, such as in the peroxisomal assembly disorders and other demyelinating diseases (Powers and Moser, 1998). Because pharmacologic modulation of alternative metabolic pathways represents a possible therapy for these disorders (Kemp et al., 1998), understanding the role of PPARs in the CNS is of fundamental importance. Three main PPAR isoforms have been described: , , also called , and . PPAR activates genes involved in lipid catabolism, such as peroxisomal -oxidation enzymes (Michalik and Wahli, 1999), whereas PPAR is involved in various cell differentiation programs and drives the expression of enzymes involved in lipid uptake and syn- thesis, such as lipoprotein lipase, fatty acid transport pro- teins, and others (Walczak and Tontonoz, 2002). In par- ticular, PPAR is considered the master regulator gene of adipocyte differentiation (Tontonoz et al., 1994). The general function of PPAR remains unclear, although it has been suggested to regulate the expression (Bastie et al., 1999) and transcriptional activity of other PPARs (Shi et al., 2002). Although all PPARs are expressed in the CNS (Cull- ingford et al., 1998), their function in this tissue remains obscure. PPAR, the predominant subtype in the CNS (Braissant and Wahli, 1998; Cullingford et al., 1998), Contract grant sponsor: Fondo de Investigacio ´n Avanzada en Areas Priori- tarias; Contract grant number: 1398001; Contract grant sponsor: Fondo Nacional de Investigacio ´n Cientı ´fica y Tecnolo ´gica; Contract grant num- bers: 2980023 and 1990155; Contract grant sponsor: Ministerio de Plani- ficacio ´n y Cooperacio ´n (Chile). *Correspondence to: Dr. Miguel Bronfman, P. Universidad Cato ´lica de Chile, Facultad de Ciencias Biolo ´gicas, Allameda 340, Santiago, Chile. E-mail: mbronfma@genes.bio.puc.cl Received 21 November 2002; Revised 24 January 2003; Accepted 27 January 2003 Journal of Neuroscience Research 72:425– 435 (2003) © 2003 Wiley-Liss, Inc.