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A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism

Abstract

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.

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Figure 1: Genetically altering adipose tissue glucose flux regulates the expression of ChREBP and its lipogenic targets.
Figure 2: ChREBP is essential for the effects of adipose tissue GLUT4 on adiposity, DNL, and glucose homeostasis.
Figure 3: ChREBP is regulated in mouse and human adipose tissue in pathological conditions.
Figure 4: Expression of the novel ChREBP-β isoform is regulated in a glucose- and ChREBP-dependent manner.
Figure 5: Adipose tissue ChREBP-β expression predicts insulin sensitivity.

Accession codes

Primary accessions

GenBank/EMBL/DDBJ

Gene Expression Omnibus

Data deposits

The ChREBP-β sequence data has been deposited in NCBI Genbank under accession number JQ437838. The microarray data has been deposited in NCBI Gene Expression Omnibus under accession number GSE35378.

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Acknowledgements

We thank H. Towle for providing reagents and discussion. We thank P. Pissios, I. Astapova, E. Rosen and the Rosen laboratory for discussions, K. Uyeda for providing ChREBP KO mice, and E. Shu for technical assistance. This work was supported by NIH R37 DK43051 (B.B.K.), K08 DK076726 (M.A.H.), BADERC DK057521 (B.B.K., M.A.H.), BNORC DK046200 (M.A.H.), the Picower and JPB Foundations (B.B.K.), a Fellowship from the Radcliffe Institute for Advanced Study (B.B.K.), DK056341 (Nutrition and Obesity Research Unit) (S.K.), DK037948 (S.K.), and the Deutsche Forschungsgemeinschft DFG, KFO152, BL833/1 (M.B.).

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Authors

Contributions

M.A.H. and B.B.K. planned the experiments, interpreted the data, and wrote the paper. M.A.H. designed and performed the molecular biology experiments to discover ChREBP-β and executed all other experiments in the paper except the human studies. O.D.P. and J.V. assisted with experimental design and provided technical support. N.A.A., M.R.S., M.B. and S.K. performed the human studies.

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Correspondence to Barbara B. Kahn.

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The authors declare no competing financial interests.

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Herman, M., Peroni, O., Villoria, J. et al. A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism. Nature 484, 333–338 (2012). https://doi.org/10.1038/nature10986

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