Adiponectin gene activation by thiazolidinediones requires PPAR gamma 2, but not C/EBP alpha-evidence for differential regulation of the aP2 and adiponectin genes

• Published in: Biochemical and biophysical research communications 2003-09, Vol.308 (4), p.933-939
• Main Authors: Gustafson, Birgit, Jack, Maia M, Cushman, Samuel W, Smith, Ulf
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Adipocytes - metabolism; Adiponectin; Animals; Anticonvulsants - pharmacology; CCAAT-Enhancer-Binding Protein-alpha - metabolism; Cell Differentiation; Cell Line; Culture Media - pharmacology; Cytokines - metabolism; Fibroblasts - metabolism; Fructose - analogs & derivatives; Fructose - pharmacology; Gene Expression Regulation; Genes, Reporter; Intercellular Signaling Peptides and Proteins; Interleukin-6 - metabolism; Ligands; Luciferases - metabolism; Mice; Phenotype; Promoter Regions, Genetic; Proteins - genetics; Proteins - metabolism; Receptors, Cytoplasmic and Nuclear - metabolism; RNA, Messenger - metabolism; Thiazoles - pharmacology; Thiazolidinediones; Time Factors; Topiramate; Transcription Factors - metabolism; Transcription, Genetic; Transcriptional Activation; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0006-291X
• DOI: 10.1016/S0006-291X(03)01518-3

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.