Unbound MEDLINE

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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  • Authors

    Herman MA, Peroni OD, Villoria J, Schön MR, Abumrad NA, Blüher M, Klein S, Kahn BB

    Institution

    Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.

    Source

    Nature 484:7394 2012 Apr 19 pg 333-8

    MeSH

    Adipocytes
    Adipose Tissue
    Adiposity
    Animals
    Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
    Blood Glucose
    Body Mass Index
    Body Weight
    Cells, Cultured
    Cohort Studies
    Cross-Sectional Studies
    Diabetes Mellitus
    Female
    Gene Expression Regulation
    Genotype
    Glucose
    Glucose Intolerance
    Glucose Transporter Type 4
    Homeostasis
    Humans
    Insulin
    Insulin Resistance
    Lipogenesis
    Male
    Mice
    Mice, Knockout
    Molecular Sequence Data
    Nuclear Proteins
    Obesity
    Promoter Regions, Genetic
    Protein Isoforms
    RNA, Messenger
    Transcription Factors

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22466288