Background:

We have previously reported an association between the activator protein-2β (AP-2β) transcription factor gene and type 2 diabetes. This gene is preferentially expressed in adipose tissue, and subjects with a disease-susceptible allele of AP-2β showed stronger AP-2β expression in adipose tissue than those without the susceptible allele. Furthermore, overexpression of AP-2β led to lipid accumulation and induced insulin resistance in 3T3-L1 adipocytes.

Result:

We found that overexpression of AP-2β in 3T3-L1 adipocytes decreased the promoter activity of leptin, and subsequently decreased both messenger RNA (mRNA) and protein expression and secretion. Furthermore, knockdown of endogenous AP-2β by RNA-interference increased mRNA and protein expression of leptin. Electrophoretic mobility shift and chromatin immunoprecipitation assays revealed specific binding of AP-2β to leptin promoter regions in vitro and in vivo. In addition, site-directed mutagenesis of the AP-2-binding site located between position+ 34 and+ 42 relative to the transcription start site abolished the inhibitory effect of AP-2β. Our results clearly showed that AP-2β directly inhibited insulin-sensitizing hormone leptin expression by binding to its promoter.

Conclusion:

AP-2β modulated the expression of leptin through direct interaction with its promoter region.

Introduction

We recently identified the human activator protein-2β (AP-2β) transcription factor gene (TFAP2B) located on chromosome 6p12 as a susceptibility gene for type 2 diabetes in a genome-wide association study. 1 Several variations in the TFAP2B gene were significantly associated with obese type 2 diabetes in Japanese and British individuals. 1 Furthermore, a polymorphism in the first intron of TFAP2B directly affects transcriptional activity of the gene, and subjects with the disease-susceptible allele have greater expression of AP-2β in their adipose tissue than those without the susceptible allele. 2 We have also reported that mouse AP-2β (Tcfap2b) was preferentially expressed in adipose tissue and that its expression increased during adipocyte differentiation in 3T3-L1 adipocytes. 1 In addition, we observed that overexpression of AP-2β led to lipid accumulation by enhancing glucose transport, thereby inducing insulin resistance in 3T3-L1 adipocytes. 3 Moreover, we reported that AP-2β could inhibit transcriptional activity of the adiponectin gene by binding to the adiponectin promoter and could increase the expression of interleukin-6 gene and monocyte chemoattractant protein-1 (MCP-1) gene in 3T3-L1 adipocytes. 4, 5 These phenomena are considered to have crucial roles in the pathogenesis of obesity-related diseases, such as metabolic syndrome and type 2 diabetes.