Impaired Expression of the Inducible cAMP Early Repressor Accounts for Sustained Adipose CREB Activity in Obesity

OBJECTIVE-Increase in adipose cAMP-responsive element-binding protein (CREB) activity promotes adipocyte dysfunction and systemic insulin resistance in obese mice. This is achieved by increasing the expression of activating transcription factor 3 (ATF3). In this study, we investigated whether impaired expression of the inducible cAMP early repressor (ICER), a transcriptional antagonist of CREB, is responsible for the increased CREB activity in adipocytes of obese mice and humans. RESEARCH DESIGN AND METHODS-Total RNA and nuclear proteins were prepared from visceral adipose tissue (VAT) of human nonobese or obese subjects and white adipose tissue (WAT) of C57B16-Rj mice that were fed with normal or high-fat diet for 16 weeks. The expression of genes was monitored by real-time PCR, Western blotting, and eleclromobility shift assays. RNA interference was used to silence the expression of Icer. RESULTS-The expression of Icer/ICER was reduced in VAT and WAT of obese humans and mice, respectively. Diminution of Icer/ICER was restricted to adipocytes and was accompanied by a rise of Atf3/ATF3 and diminution of Adipoq/ADIPOQ and Glut4/GLUT4. Silencing the expression of Icer in 3T3-L1 adipocytes mimicked the results observed in human and mice cells and hampered glucose uptake, thus confirming the requirement of Icer for appropriate adipocyte function. CONCLUSIONS-Impaired expression of ICER contributes to elevation in CREB target genes and, therefore, to the development of insulin resistance in obesity. Diabetes 60:3169-3174, 2011