title: Transcription factor AP-2beta inhibits expression and secretion of leptin, an insulin-sensitizing hormone, in 3T3-L1 adipocytes.
abstract: BACKGROUND
  We have previously reported an association between the activator protein-2beta (AP-2beta) transcription factor gene and type 2 diabetes. This gene is preferentially expressed in adipose tissue, and subjects with a disease-susceptible allele of AP-2beta showed stronger AP-2beta expression in adipose tissue than those without the susceptible allele. Furthermore, overexpression of AP-2beta led to lipid accumulation and induced insulin resistance in 3T3-L1 adipocytes.
  
  
  RESULTS
  We found that overexpression of AP-2beta 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-2beta by RNA-interference increased mRNA and protein expression of leptin. Electrophoretic mobility shift and chromatin immunoprecipitation assays revealed specific binding of AP-2beta 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-2beta. Our results clearly showed that AP-2beta directly inhibited insulin-sensitizing hormone leptin expression by binding to its promoter.
  
  
  CONCLUSIONS
  AP-2beta modulated the expression of leptin through direct interaction with its promoter region.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Fuke
authors.forename: T
authors.initials: T
authors.lastname: Yoshizaki
authors.forename: M
authors.initials: M
authors.lastname: Kondo
authors.forename: K
authors.initials: K
authors.lastname: Morino
authors.forename: T
authors.initials: T
authors.lastname: Obata
authors.forename: S
authors.initials: S
authors.lastname: Ugi
authors.forename: Y
authors.initials: Y
authors.lastname: Nishio
authors.forename: S
authors.initials: S
authors.lastname: Maeda
authors.forename: A
authors.initials: A
authors.lastname: Kashiwagi
authors.forename: H
authors.initials: H
authors.lastname: Maegawa
mesh_terms: D041721:3T3-L1 Cells / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D020738:Leptin; D012333:RNA, Messenger; D050656:Transcription Factor AP-2