Abstract
The thiazolidinedione rosiglitazone, an agonist ligand for the nuclear receptor PPAR-gamma, improves insulin sensitivity in part by stimulating transcription of the insulin-sensitizing adipokine adiponectin. It activates PPAR-gamma-RXR-alpha heterodimers bound to PPAR-gamma response elements in the adiponectin promoter. Rosiglitazone-stimulated adiponectin protein synthesis in 3T3-L1 mouse adipocytes has been shown to be inhibited by IGFBP-3, which can be induced by hypoxia and the proinflammatory cytokine, TNF-alpha, two inhibitors of adiponectin transcription. The present study demonstrates that IGFBP-3, the hypoxia-mimetic agent cobalt chloride, and TNF-alpha inhibit rosiglitazone-induced adiponectin transcription in mouse embryo fibroblasts that stably express PPAR-gamma2. Native IGFBP-3 can bind RXR-alpha and inhibited rosiglitazone stimulated promoter activity, whereas an IGFBP-3 mutant that does not bind RXR-alpha did not. These results suggest that IGFBP-3 may mediate the inhibition of adiponectin transcription by hypoxia and TNF-alpha, and that IGFBP-3 binding to RXR-alpha may be required for the observed inhibition.