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C/EBP Regulates Human Adiponectin Gene Transcription Through an Intronic Enhancer

¹ Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Kentucky
² Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado
³ Department of Microbiology, University of Colorado Health Sciences Center, Denver, Colorado
⁴ Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado
⁵ Nestle Research Center, Lausanne, Switzerland
⁶ Department of Food Science & Human Nutrition, Colorado State University, Fort Collins, Colorado
⁷ Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado
⁸ Department of Biochemistry & Molecular Genetics, University of Colorado Health Sciences Center, Denver, Colorado

Adiponectin is an adipose-derived hormone that enhances insulin sensitivity and plays an important role in regulating energy homeostasis. Here, we demonstrate that the DNA encoding the first intron of the human adiponectin gene contains an intronic enhancer that regulates adiponectin gene expression in an adipose tissue–specific manner. Insertion of the DNA encoding the first intron into reporter constructs containing the proximal adiponectin promoter (Pro-Int1-Luc) resulted in a 20-fold increase in activity relative to the promoter alone in 3T3-L1 adipocytes. Coexpression of CCAAT/enhancer-binding protein (C/EBP) increased luciferase activity of the Pro-Int1-Luc construct 75-fold but had no effect on the constructs containing the proximal adiponectin promoter alone. At least eight potential C/EBP response elements are located between +3000 to +10000 nucleotides within the DNA encoding the first intron, including a 34-bp core sequence for the intronic enhancer that contains three tandem C/EBP response elements. However, the intronic enhancer is not conserved between human and mouse. Overexpression or siRNA-mediated knockdown of endogenous C/EBP significantly increased or decreased, respectively, adiponectin mRNA levels in differentiated human Chub-S7 adipocytes, while neither C/EBPß nor C/EBP significantly affected adiponectin expression in mature adipocytes. Thus, C/EBP is a key transcription factor for full activation of human adiponectin gene transcription in mature adipocytes through interaction with response elements in the intronic enhancer.

Abbreviations: aP2, adipocyte-specific fatty acid–binding protein; C/EBP, CCAAT/enhancer-binding protein; EMSA, electrophoretic mobility shift assay; HEK, human embryonic kidney; PPAR, peroxisome proliferator–activated receptor; RXR, retinoid X receptor ; TK, thymidine kinase; TZD, thiazolidinedione

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