Sci. Signal., 24 April 2012
Physiology Glucose-Induced Isoform of ChREBP
Nancy R. Gough
Science Signaling, AAAS, Washington, DC 20005, USA
Diabetes and obesity are major health issues, especially in developed countries. A key response of fat to insulin is stimulation of the glucose transporter GLUT4, which increases glucose uptake and promotes glycolysis and lipogenesis. To understand the gene regulatory response to glucose uptake, Herman et al. performed global gene expression analysis of mice with adipose-specific GLUT4 overexpression (AG4OX) or knockout (AG4KO) and identified genes involved in de novo lipogenesis as those stimulated in adipose tissue of the AG4OX mice and those inhibited in the adipose tissue of the AG4KO mice. These genes are regulated by sterol regulatory element–binding protein 1c (SREBP-1c) and carbohydrate response element–binding protein (ChREBP). Only ChREBP and its specific gene targets exhibited a coordinated change in expression, suggesting that this transcription factor was predominantly responsible for the induction of the genes involved in lipogenesis. Confirming that changes in gene expression produced changes in physiology, de novo lipogenesis was increased in the white adipose tissue of the AG4OX mice compared with that in wild-type mice, and the AG4OX mice were obese, yet exhibited enhanced glucose tolerance. This increase in lipogenesis and glucose tolerance was reversed when the AG4OX mice were crossed with ChREBP genetic knockout mice, confirming the importance of ChREBP in mediating these effects of GLUT4 overexpression. In human obese, nondiabetic patients, the abundance of ChREBP transcripts correlated with insulin-stimulated glucose uptake, but there was no correlation between the abundance of GLUT4 and ChREBP transcripts. Investigation of the promoter region of the ChREBP gene revealed two carbohydrate response elements and indicated a putative alternative promoter start site and alternative first exon from the known ChREBP-α isoform, which was confirmed by 5' rapid amplification of cDNA ends. The authors named the isoform generated by this alternative promoter start site ChREBP-β. Although the expression of both isoforms in wild-type adipose tissue was reduced by fasting and stimulated by refeeding, ChREBP-β exhibited more robust changes in expression. These stronger changes in expression were also observed in the AG4OX (>4-fold increase in ChREBP-β expression compared with wild-type adipose tissue; no change in ChREBP-α) and AG4KO mice (>90% reduction in ChREBP-β expression compared with wild-type adipose tissue). Reporter gene assays with the ChREBP-β promoter in transfected cells showed that ChREBPP-α and its dimerization partner MLX were required for glucose-mediated induction of the reporter, suggesting that ChREBP-α regulates ChREBP-β expression. Analysis of human white adipose tissue showed that, whereas expression of both ChREBP-β and ChREBP-α correlated with insulin sensitivity, ChREBP-β was a statistically better predictor of insulin sensitivity. The authors suggest that selective activation of ChREBP-β may be a therapeutic target for treating diabetes and obesity-related metabolic diseases.
M. A. Herman, O. D. Peroni, J. Villoria, M. R. Schön, N. A. Abumrad, M. Blüher, S. Klein, B. B. Kahn, A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism. Nature 484, 333–338 (2012). [PubMed]
Citation: N. R. Gough, Glucose-Induced Isoform of ChREBP. Sci. Signal. 5, ec118 (2012).
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