Herman, Mark AndrewPeroni, OdileVilloria, JorgeSchön, Michael R.Abumrad, Nada A.Blüher, MatthiasKlein, SamuelKahn, Barbara2013-04-152012Herman, Mark A., Odile D. Peroni, Jorge Villoria, Michael R. Schön, Nada A. Abumrad, Matthias Blüher, Samuel Klein, and Barbara B. Kahn. 2012. A novel chREBP isoform in adipose tissue regulates systemic glucose metabolism. Nature 484(7394): 333-338.0028-0836http://nrs.harvard.edu/urn-3:HUL.InstRepos:10531921The prevalence of obesity and type 2-diabetes is increasing worldwide and threatens to shorten lifespan. Impaired insulin action in peripheral tissues is a major pathogenic factor. Insulin stimulates glucose uptake in adipose tissue through the Glut4-glucose transporter and alterations in adipose-Glut4 expression or function regulate systemic insulin sensitivity. Downregulation of adipose tissue-Glut4 occurs early in diabetes development. Here we report that adipose tissue-Glut4 regulates the expression of carbohydrate responsive-element binding protein (ChREBP), a transcriptional regulator of lipogenic and glycolytic genes. Furthermore, adipose-ChREBP is a major determinant of adipose tissue fatty acid synthesis and systemic insulin sensitivity. We discovered a new mechanism for glucose-regulation of ChREBP: Glucose-mediated activation of the canonical ChREBP isoform (ChREBPα) induces expression of a novel, potent isoform (ChREBPβ) that is transcribed from an alternative promoter. ChREBPβ expression in human adipose tissue predicts insulin sensitivity indicating that it may be an effective target for treating diabetes.en-USJournal Article2013-04-1510.1038/nature10986