A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism

The 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 (also known as SLC2A4) glucose transporter, and alterations in adipose tissue GLUT4 expression or function regulate systemic insulin sensitivity. Downregulation of human and mouse 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; also known as MLXIPL), 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 find a new mechanism for glucose regulation of ChREBP: glucose-mediated activation of the canonical ChREBP isoform (ChREBP-α) induces expression of a novel, potent isoform (ChREBP-β) that is transcribed from an alternative promoter. ChREBP-β expression in human adipose tissue predicts insulin sensitivity, indicating that it may be an effective target for treating diabetes. Downregulation of the glucose transporter GLUT4 in adipose tissue occurs early in the development of type 2 diabetes; here GLUT4-mediated glucose uptake is shown to induce a novel form of the transcription factor ChREBP, which regulates de novo lipogenesis and systemic glucose metabolism. ChREBP variant a possible antidiabetes target In obesity and type 2 diabetes, GLUT4, the major insulin-responsive glucose transporter, is downregulated selectively in adipose tissue. Here, it is shown that GLUT4-mediated glucose uptake induces the transcription factor ChREBP, which regulates the expression of lipogenic and glycolytic genes. ChREBP is a major determinant of adipose-tissue fatty-acid synthesis and systemic insulin sensitivity. Glucose-mediated activation of ChREBP-α induces expression of a newly identified isoform, ChREBP-β, which predicts insulin sensitivity in human adipose tissue. Thus, ChREBP-β may be an effective target for treating diabetes.