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Functional Characterization of the Human Resistin Promoter with Adipocyte Determination- and Differentiation-Dependent Factor 1/Sterol Regulatory Element Binding Protein 1c and CCAAT Enhancer Binding Protein-

School of Biological Sciences (J.B.S., M.J.N., E.J.Y., S.Y.P., J.P., S.D.P., J.B.K.), Seoul National University, Seoul 151-742, Korea; and Department of Internal Medicine (I.K.L.), School of Medicine, Keimyung University, Dongsan-Dong, Jungu, Taegu 700-712, Korea

Address all correspondence and requests for reprints to:Jae Bum Kim, School of Biological Sciences, Building 20, Room 109, Seoul National University, NS-70, San 56-1, Sillim-Dong, Kwanak-Gu, Seoul 151-742, Korea. E-mail: jaebkim{at}snu.ac.kr.

Recent studies with murine models propose that resistin would be a possible mediator to link between obesity and insulin resistance. Although it has been reported that resistin is highly expressed and secreted by adipocytes, transcription factors that are involved in resistin gene expression have not been well characterized. To investigate the molecular mechanisms of resistin gene expression, we cloned and characterized the human resistin promoter. Sequence analysis of the resistin promoter revealed several putative binding sites for adipogenic transcription factors including adipocyte determination- and differentiation-dependent factor 1 (ADD1)/sterol regulatory element binding protein 1c (SREBP1c) and CCAAT enhancer binding protein- (C/EBP). EMSA and chromatin immunoprecipitation assays demonstrated that ADD1/SREBP1c binds to the human resistin promoter in vitro and in vivo. Expression of ADD1/SREBP1c transactivated the luciferase reporter gene activity, the promoter region of which contains a human resistin promoter in a sterol regulatory element (SRE)-dependent manner. Furthermore, ectopic expression of ADD1/SREBP1c by adenovirus significantly increased the expression of resistin mRNA in adipocytes. Human resistin promoter was also activated by C/EBP expression, although ectopic expression of both transcription factors did not show any synergistic effects on the activation of resistin promoter. Together, these data suggest that ADD1/SREBP1c and C/EBP may play discrete roles in the regulation of the resistin gene expression.

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