IGFBP-3, hypoxia and TNF-α inhibit adiponectin transcription

Abstract

The thiazolidinedione rosiglitazone, an agonist ligand for the nuclear receptor PPAR-γ, improves insulin sensitivity in part by stimulating transcription of the insulin-sensitizing adipokine adiponectin. It activates PPAR-γ–RXR-α heterodimers bound to PPAR-γ 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-α, two inhibitors of adiponectin transcription. The present study demonstrates that IGFBP-3, the hypoxia-mimetic agent cobalt chloride, and TNF-α inhibit rosiglitazone-induced adiponectin transcription in mouse embryo fibroblasts that stably express PPAR-γ2. Native IGFBP-3 can bind RXR-α and inhibited rosiglitazone stimulated promoter activity, whereas an IGFBP-3 mutant that does not bind RXR-α did not. These results suggest that IGFBP-3 may mediate the inhibition of adiponectin transcription by hypoxia and TNF-α, and that IGFBP-3 binding to RXR-α may be required for the observed inhibition.