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Modulation of CCAAT/Enhancer-Binding Protein- Gene Expression by Metabolic Signals in Rodent Adipocytes

Laboratory of Clinical Investigation (Y.W., W.L.-K., L.A., J.M.E., M.B.), Laboratory of Biological Chemistry (J.L.M.), and Laboratory of Cardiovascular Science (P.H.), National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224-6825

Address all correspondence and requests for reprints to: Michel Bernier, Ph.D., Diabetes Section, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Box 23, Baltimore, Maryland 21224-6825. E-mail: bernierm{at}vax.grc.nia.nih.gov

The transcription factor CCAAT/enhancer-binding protein- (C/EBP) is a positive modulator of transcription for several adipocyte-specific genes that play a role in energy metabolism. However, there is little information available regarding the regulation of its expression by metabolic signals. Exposure to insulin for 5–24 h attenuated C/EBP expression when 3T3-L1 adipocytes were incubated in 24 mM glucose, but not in 5.7 mM glucose. Nuclear run-on transcription assays indicated a transcriptional repression of C/EBP gene, but not that of C/EBPß. Glucosamine, a product of the hexosamine pathway, in the presence of low glucose mimicked high glucose’s ability to reduce C/EBP messenger RNA expression in insulin-treated cells. Similar results were obtained with xylitol, an activator of the pentose phosphate pathway. There was no correlation between the accumulation of hexosamine pathway metabolites (e.g. UDP-N-acetylhexosamines) and/or changes in intracellular protein glycosylation with the ability of high glucose, glucosamine, or xylitol to down-regulate C/EBP gene expression. None of these treatments caused a reduction in intracellular ATP levels. Stable transfection of 3T3-L1 cells with the 5'-flanking 468-bp sequence of the mouse C/EBP gene fused to luciferase demonstrated that promoter activity was also reduced by these nutrients. Of interest, treatment of rats with glucose or glucosamine led to a reduction in C/EBP messenger RNA levels in epididymal, but not omental, fat. Taken together, these results suggest that metabolic signals serve to down-regulate C/EBP expression both in vitro and in vivo.

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