Down-regulation of insulin receptor substrate-1 (IRS-1) expression could modify the ability of IRS-1 to fulfill its functions. It has been proposed that the phosphorylation of IRS-1 on serine residues could promote its degradation. However, few studies have investigated the transcriptional regulation of IRS-1 in the pathogenesis of insulin resistance. Genotyping for genome-wide single nucleotide polymorphisms revealed that the transcription factor activating enhancer-binding protein-2 beta (AP-2 beta) is a novel candidate gene for conferring susceptibility to obesity and type 2 diabetes. AP-2 beta is expressed in adipose tissue and its expression is increased during the maturation of adipocytes. Overexpression of AP-2 beta leads to adipocyte hypertrophy, directly inhibits adiponectin expression, and enhanced the expression of inflammatory adipokines such as IL-6 and MCP-1. In this study, we found that overexpression of AP-2 beta in 3T3-L1 adipocytes impaired the promoter activity of IRS-1, and subsequently decreased mRNA and protein expression. Electrophoretic mobility shift assays showed that AP-2 beta bound specifically to the IRS-1 promoter region. Furthermore, site-directed mutagenesis of the AP-2 binding site located at -362 to -351, relative to the transcription start site, markedly decreased AP-2-induced suppression of IRS-1 promoter activity, whereas other putative AP-2 binding sites did not. Our results clearly showed that AP-2 beta directly decreased IRS-1 expression by binding to its promoter. Based on these findings, we speculate that the AP-2 beta transcriptional factor is a unique regulator of IRS-1 and a candidate gene for insulin resistance. (C) 2010 Elsevier Inc. All rights reserved.