topiramate and 2-4-thiazolidinedione

We examined the role of PPAR gamma 2 and C/EBP alpha for adiponectin and aP2 gene activation in C/EBP alpha(-/-) fibroblasts by stably expressing PPAR gamma 2 or C/EBP alpha. PPAR gamma 2, but not PPAR gamma 1, mRNA markedly increased during the differentiation to adipocytes in cells expressing C/EBP alpha. Both infected cell lines differentiated to an adipocyte phenotype and the mRNA for both aP2 and adiponectin increased in parallel. However, adiponectin mRNA was considerably higher when C/EBP alpha was present, suggesting that this transcription factor is important for full gene activation. Thiazolidinediones markedly activated the gene in PPAR gamma 2-expressing cells in the absence of C/EBP alpha, suggesting that the adiponectin promoter may have functional PPAR gamma-response elements. Several observations showed that the adiponectin and aP2 genes can be differentially regulated in adipocytes: (1) Topiramate, an anti-epileptic agent with weight-reducing properties, increased adiponectin mRNA levels and secretion, but did not, like the thiazolidinediones, increase aP2 expression; (2) IL-6 reduced adiponectin, but significantly increased, aP2 expression; and (3) TNFalpha inhibited adiponectin, but paradoxically increased, aP2 expression in PPAR gamma 2-infected C/EBP alpha null cells. These data show that activation of the adiponectin gene can be separated from effects on adipogenic genes.

Topics: 3T3 Cells; Adipocytes; Adiponectin; Animals; Anticonvulsants; CCAAT-Enhancer-Binding Protein-alpha; Cell Differentiation; Cell Line; Culture Media; Cytokines; Fibroblasts; Fructose; Gene Expression Regulation; Genes, Reporter; Intercellular Signaling Peptides and Proteins; Interleukin-6; Ligands; Luciferases; Mice; Phenotype; Promoter Regions, Genetic; Proteins; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Thiazoles; Thiazolidinediones; Time Factors; Topiramate; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Tumor Necrosis Factor-alpha