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A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism

Author

Listed:
  • Mark A. Herman

    (Diabetes and Metabolism, Harvard Medical School)

  • Odile D. Peroni

    (Diabetes and Metabolism, Harvard Medical School)

  • Jorge Villoria

    (Diabetes and Metabolism, Harvard Medical School)

  • Michael R. Schön

    (Städtisches Klinikum Karlsruhe, Clinic of Visceral Surgery, Karlsruhe 76133, Germany)

  • Nada A. Abumrad

    (Center for Human Nutrition, Washington University School of Medicine)

  • Matthias Blüher

    (University of Leipzig)

  • Samuel Klein

    (Center for Human Nutrition, Washington University School of Medicine)

  • Barbara B. Kahn

    (Diabetes and Metabolism, Harvard Medical School)

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.

Suggested Citation

  • Mark A. Herman & Odile D. Peroni & Jorge Villoria & Michael R. Schön & Nada A. Abumrad & Matthias Blüher & Samuel Klein & Barbara B. Kahn, 2012. "A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism," Nature, Nature, vol. 484(7394), pages 333-338, April.
    • Handle: RePEc:nat:nature:v:484:y:2012:i:7394:d:10.1038_nature10986
    DOI: 10.1038/nature10986
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    Cited by:

    1. Liora S. Katz & Gabriel Brill & Pili Zhang & Anil Kumar & Sharon Baumel-Alterzon & Lee B. Honig & Nicolás Gómez-Banoy & Esra Karakose & Marius Tanase & Ludivine Doridot & Alexandra Alvarsson & Bennett, 2022. "Maladaptive positive feedback production of ChREBPβ underlies glucotoxic β-cell failure," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Alexander J. Hu & Wei Li & Calvin Dinh & Yongzhao Zhang & Jamie K. Hu & Stefano G. Daniele & Xiaoli Hou & Zixuan Yang & John M. Asara & Guo-fu Hu & Stephen R. Farmer & Miaofen G. Hu, 2024. "CDK6 inhibits de novo lipogenesis in white adipose tissues but not in the liver," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Shuai Yan & Anna Santoro & Micah J. Niphakis & Antonio M. Pinto & Christopher L. Jacobs & Rasheed Ahmad & Radu M. Suciu & Bryan R. Fonslow & Rachel A. Herbst-Graham & Nhi Ngo & Cassandra L. Henry & Dy, 2024. "Inflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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