Regulation of adipocyte 11beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) by CCAAT/enhancer-binding protein (C/EBP) beta isoforms, LIP and LAP


  • C.L. Esteves
  • V. Kelly
  • V. Bégay
  • T.Y. Man
  • N.M. Morton
  • A. Leutz
  • J.R. Seckl
  • K.E. Chapman


  • PLoS ONE


  • PLoS ONE 7 (5): e37953


  • 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) catalyses intracellular regeneration of active glucocorticoids, notably in liver and adipose tissue. 11 beta-HSD1 is increased selectively in adipose tissue in human obesity, a change implicated in the pathogenesis of metabolic syndrome. With high fat (HF)-feeding, adipose tissue 11 beta-HSD1 is down-regulated in mice, plausibly to counteract metabolic disease. Transcription of 11 beta-HSD1 is directly regulated by members of the CCAAT/enhancer binding protein (C/EBP) family. Here we show that while total C/EBP beta in adipose tissue is unaltered by HF diet, the ratio of the C/EBP beta isoforms liver-enriched inhibitor protein (LIP) and liver-enriched activator protein (LAP) (C/EBP beta-LIP:LAP) is increased in subcutaneous adipose. This may cause changes in 11 beta-HSD1 expression since genetically modified C/EBP beta((+/L)) mice, with increased C/EBP beta-LIP:LAP ratio, have decreased subcutaneous adipose 11 beta-HSD1 mRNA levels, whereas C/EBP beta(Delta uORF) mice, with decreased C/EBP beta-LIP:LAP ratio, show increased subcutaneous adipose 11 beta-HSD1. C/EBP beta-LIP:LAP ratio is regulated by endoplasmic reticulum (ER) stress and mTOR signalling, both of which are altered in obesity. In 3T3-L1 adipocytes, 11 beta-HSD1 mRNA levels were down-regulated following induction of ER stress by tunicamycin but were up-regulated following inhibition of mTOR by rapamycin. These data point to a central role for C/EBP beta and its processing to LIP and LAP in transcriptional regulation of 11 beta-HSD1 in adipose tissue. Down-regulation of 11 beta-HSD1 by increased C/EBP beta-LIP:LAP in adipocytes may be part of a nutrient-sensing mechanism counteracting nutritional stress generated by HF diet.