- AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
We previously reported the association between the activating enhancer-binding protein-2 beta (AP-2 beta) transcription factor gene and type 2 diabetes. This gene is preferentially expressed in adipose tissue, and subjects with the disease-susceptible allele of AP-2 beta showed stronger expression in adipose tissue than those without the susceptible allele. Furthermore, overexpression of AP-2 beta leads to lipid accumulation by enhancing glucose transport and inducing insulin resistance in 3T3-L1 adipocytes. In this study we demonstrated that overexpression of AP-2 beta in 3T3-L1 adipocytes decreased the expression and secretion of adiponectin and increased those of interleukin-6 (IL-6). Interestingly, the effects of AP-2 beta on the expressions of adiponectin and IL-6 and the mechanisms by which AP-2 beta modulated their expressions were different. We found that the promoter activity of adiponectin gene was inhibited by AP-2 beta overexpression and enhanced by knockdown of endogenous AP-2 beta, whereas IL-6 was unaffected. Electrophoretic mobility shift assays revealed the existence of putative responsive elements for AP-2 beta and NF-YA in human and mouse adiponectin promoter regions, and mutation of this AP-2 beta binding site abolished the inhibitory effect of AP-2 beta. Furthermore, chromatin immunoprecipitation assays demonstrated that AP-2 beta and NF-YA competitively bind to the same region of the adiponectin promoter. Our results clearly demonstrated that AP-2 beta directly inhibits adiponectin gene expression by displacing NF-YA and binding to its promoter. We conclude that AP-2 beta might modulate the expression of adiponectin by directly inhibiting its transcriptional activity.
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