A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism

被引：482

作者：

Herman, Mark A. ^{[1
,2
]}

Peroni, Odile D. ^{[1
,2
]}

Villoria, Jorge ^{[1
,2
]}

Schoen, Michael R. ^{[3
]}

Abumrad, Nada A. ^{[4
]}

Blueher, Matthias ^{[5
]}

Klein, Samuel ^{[4
]}

Kahn, Barbara B. ^{[1
,2
]}

机构：

[1] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA

[2] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA

[3] Stadt Klinikum Karlsruhe, Clin Visceral Surg, D-76133 Karlsruhe, Germany

[4] Washington Univ, Sch Med, Ctr Human Nutr, St Louis, MO 63110 USA

[5] Univ Leipzig, Dept Med, D-04103 Leipzig, Germany

来源：

NATURE | 2012年 / 484卷 / 7394期

关键词：

CARBOHYDRATE-RESPONSE ELEMENT; FATTY-ACID SYNTHESIS; BINDING-PROTEIN CHREBP; UCSC GENOME BROWSER; INSULIN-RESISTANCE; DIABETES-MELLITUS; TRANSGENIC MICE; LIVER; GENE; LIPOGENESIS;

D O I：

10.1038/nature10986

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-alpha) induces expression of a novel, potent isoform (ChREBP-beta) that is transcribed from an alternative promoter. ChREBP-beta expression in human adipose tissue predicts insulin sensitivity, indicating that it may be an effective target for treating diabetes.

引用

页码：333 / U66

页数：8

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