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The Transcription Factor AP-2ß Causes Cell Enlargement and Insulin Resistance in 3T3-L1 Adipocytes

Division of Endocrinology and Metabolism, Department of Medicine (Y.T., H.M., S.U., K.I., Y.Na., K.E., Y.N.i., A.K.), and Department of Anatomy (T.N.), Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan; and Laboratory for Diabetic Nephropathy, SNP Research Center, Institute of Physical and Chemical Research (S.T., S.M.), Kanagawa 230-0045 Japan

Address all correspondence and requests for reprints to: Dr. Hiroshi Maegawa, Division of Endocrinology and Metabolism, Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga 520-2192, Japan. E-mail: maegawa{at}belle.shiga-med.ac.jp.

We have reported the association of variations in the activating protein-2ß (AP-2ß) 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 the disease-susceptible allele showed stronger expression in adipose tissue than those without the susceptible allele. Thus, we overexpressed the AP-2ß gene in 3T3-L1 adipocytes to clarify whether AP-2ß might play a crucial role in the pathogenesis of type 2 diabetes through dysregulation of adipocyte function. In cells overexpressing AP-2ß, cells increased in size by accumulation of triglycerides accompanied by enhanced glucose uptake. On the contrary, suppression of AP-2ß expression by small interfering RNA inhibited glucose uptake. Enhancement of glucose uptake by AP-2ß 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-2ß 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 (Gab1) and its association with PLC, indicating that Gab1 may be involved in AP-2ß-induced PLC activation. Finally, AP-2ß overexpression was found to relate to the impaired insulin signaling. We propose that AP-2ß is a candidate gene for producing adipocyte hypertrophy and may relate to the abnormal characteristics of adipocytes observed in obesity.

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