We have reported the association of variations in the AP-2 transcription factor gene with type 2 diabetes. This gene was preferentially expressed in 3T3-L1 adipocytes in a differentiation-stage-dependent manner and preliminary experiments showed that subjects with disease susceptible allele showed stronger expression in adipose tissue than did those without susceptible allele. Thus, we overexpressed AP-2 gene in 3T3-L1 adipocytes to clarify whether AP-2 might play crucial roles in the pathogenesis of type 2 diabetes through dysregulation of adipocyte function. In cells overexpressing AP-2, cells increased in size by accumulation of triglycerides accompanied with enhanced glucose uptake. On the contrary, suppression of AP-2 expression by siRNA inhibited glucose uptake. Enhancement of glucose uptake by AP-2 overexpression was attenuated by inhibitors of phospholipase C (PLC) and atypical protein kinase C (PKC) /, but not by a phosphatidylinositol 3-kinase (PI3-K) inhibitor. Consistently, we found activation of PLC and atypical PKC, but not PI3-K by AP-2 expression. Furthermore, overexpression of PLC enhanced glucose uptake and this activation was inhibited by an atypical PKC inhibitor, suggesting that the enhanced glucose uptake may be mediated through PLC and atypical PKC/, but not PI3-K. Moreover, we observed the increased tyrosine phosphorylation of Grb2-associated binder-1 (Gab-1) and its association with PLC, indicating that Gab-1 may be involved in AP-2-induced PLC activation. Finally, AP-2 overexpression was found to relate to the impaired insulin signaling. We propose that AP-2 is a candidate gene for leading to adipocyte hypertrophy and may relate to the abnormal characteristics of adipocytes observed in obesity.