Adiponectin gene activation by thiazolidinediones requires PPARγ2, but not C/EBPα—evidence for differential regulation of the aP2 and adiponectin genes☆

Abstract We examined the role of PPARγ2 and C/EBPα for adiponectin and aP2 gene activation in C/EBPα −/− fibroblasts by stably expressing PPARγ2 or C/EBPα. PPARγ2, but not PPARγ1, mRNA markedly increased during the differentiation to adipocytes in cells expressing C/EBPα. 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/EBPα was present, suggesting that this transcription factor is important for full gene activation. Thiazolidinediones markedly activated the gene in PPARγ2-expressing cells in the absence of C/EBPα, suggesting that the adiponectin promoter may have functional PPARγ-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) TNFα inhibited adiponectin, but paradoxically increased, aP2 expression in PPARγ2-infected C/EBPα null cells. These data show that activation of the adiponectin gene can be separated from effects on adipogenic genes.