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- Authors
- Herman MA
- Peroni OD
- Villoria J
- Schön MR
- Abumrad NA
- Blüher M
- Klein S
- Kahn BB
- 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
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 333-8MeSH
AdipocytesAdipose 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 ArticleResearch Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Language
eng
PubMed ID
22466288