Diet-Induced Up-Regulation of Gene Expression in Adipocytes Without Changes in DNA Methylation

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The expansion of white adipose tissue (WAT) mass during the development ofobesity is mediated in part through an increase in adipocyte size. Although geneexpression profiles associated with adipogenesis in vitro and the development of obesityin vivo have been characterized by DNA microarray analysis, the role of chromatin andchromatin-modifying proteins in the regulation of gene expression related to adipocytehypertrophy has remained unclear. We have now shown that maintenance of C57BL/6Jmice on a high-fat diet for 16 weeks resulted in marked up-regulation of the expressionof leptin, Mest (mesoderm specific transcript; also known as paternally expressed gene1, or Peg1), and sFRP5 (secreted frizzled-related protein 5) genes in WAT.Furthermore, the demethylating agent 5-aza-2′-deoxycytidine increased the amount ofMest/Peg1 mRNA, but not that of leptin or sFRP5 mRNAs, in mouse 3T3-L1adipocytes. However, analysis by matrix-assisted laser desorption ionizationtime-of-flight (MALDI-TOF) mass spectrometry revealed that maintenance of mice ona high-fat diet for various times did not affect the level of methylation at specific CpGsites in the promoter regions of leptin, Mest/Peg1, and sFRP5 genes in WAT. Ourresults indicate that the diet-induced up-regulation of leptin, Mest/Peg1, and sFRP5gene expression in WAT during the development of obesity in mice is not mediateddirectly by changes in DNA methylation.