Transcription factor AP-2beta inhibits expression and secretion of leptin, an insulin-sensitizing hormone, in 3T3-L1 adipocytes

Int J Obes (Lond). 2010 Apr;34(4):670-8. doi: 10.1038/ijo.2009.295. Epub 2010 Jan 12.

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.

Result: 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.

Conclusion: AP-2beta modulated the expression of leptin through direct interaction with its promoter region.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells / metabolism
  • Adipocytes / metabolism*
  • Adipose Tissue / metabolism*
  • Animals
  • Biological Transport
  • Gene Expression Regulation / genetics
  • Humans
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology*
  • Leptin / genetics
  • Leptin / metabolism*
  • Mice
  • Mutagenesis, Site-Directed
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism
  • Transcription Factor AP-2 / genetics
  • Transcription Factor AP-2 / metabolism*

Substances

  • Leptin
  • RNA, Messenger
  • Transcription Factor AP-2