Phosphorylation of CCAAT/enhancer-binding protein alpha regulates GLUT4 expression and glucose transport in adipocytes.
The transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha) is required during adipogenesis for development of insulin-stimulated glucose uptake. Modes for regulating this function of C/EBPalpha have yet to be determined. Phosphorylation of C/EBPalpha on Ser-21 has been implicated in the regulation of granulopoiesis and hepatic gene expression. To explore the role of Ser-21 phosphorylation on C/EBPalpha function during adipogenesis, we developed constructs in which Ser-21 was mutated to alanine (S21A) to model dephosphorylation. In two cell culture models deficient in endogenous C/EBPalpha, enforced expression of S21A-C/EBPalpha resulted in normal lipid accumulation and expression of many adipogenic markers. However, S21A-C/EBPalpha had impaired ability to activate the Glut4 promoter specifically, and S21A-C/EBPalpha expression resulted in diminished GLUT4 and adiponectin expression, as well as reduced insulin-stimulated glucose uptake. No defects in insulin signaling or GLUT4 vesicle trafficking were identified with S21A-C/EBPalpha expression, and when exogenous GLUT4 expression was enforced to normalize expression in S21A-C/EBPalpha cells, insulin-responsive glucose transport was reconstituted, suggesting that the primary defect was a deficit in GLUT4 levels. Mice in which endogenous C/EBPalpha was replaced with S21A-C/EBPalpha displayed reduced GLUT4 and adiponectin protein expression in epididymal adipose tissue and increased blood glucose compared with wild-type littermates. These results suggest that phosphorylation of C/EBPalpha on Ser-21 may regulate adipocyte gene expression and whole body glucose homeostasis.[1]References
- Phosphorylation of CCAAT/enhancer-binding protein alpha regulates GLUT4 expression and glucose transport in adipocytes. Cha, H.C., Oak, N.R., Kang, S., Tran, T.A., Kobayashi, S., Chiang, S.H., Tenen, D.G., MacDougald, O.A. J. Biol. Chem. (2008) [Pubmed]
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