A novel ChREBP isoform in adipose tissue regulates systemic glucose metabolism

By M. Herman, O. Peroni, Jorge Villoria, M. Schön, N. Abumrad, M. Blüher, S. Klein, B. Kahn. Nature, 2012

594 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Nutrition and Dietetics, Surgery

View Paper: https://www.semanticscholar.org/paper/973162b4cd5f93fc1133872d330054953ebd809f

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. Gerald I. Shulman
2. V. Samuel
3. B. Kahn
4. P. Seale
5. Haiming Cao
6. Ralph DeFronzo
7. D. Hardie
8. Max C. Petersen

In Nutrition and Dietetics

1. B. Kahn

In Surgery

1. Gerald I. Shulman
2. V. Samuel
3. B. Kahn
4. R. Medzhitov
5. M. Kotas

Citations in the corpus

• Adipose tissue plasticity in health and disease (2022, background): “In particular, carbohydrate response element-binding protein (ChREBP), liver X receptor alpha (LXR a ), and sterol response element-binding protein 1c (SREBP1c) stimulate the expression of the key DNL enzymes fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) (Herman et al., 2012).”
• What We Talk About When We Talk About Fat (2014, unknown): “Though SREBP1c is the dominant regulator of DNL in liver, that role belongs to ChREBP in WAT (Herman et al., 2012; Shimano et al., 1997).”
• Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects (2014, methodology): “ChREBP knockout in AG4OX mice completely reverses the enhanced glucose tolerance (Herman et al., 2012).”
• The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. (2016, background): “Intriguingly, adipose ChREBP expression appears directly related to insulin sensitivity in humans (85).”
• Trends in insulin resistance: insights into mechanisms and therapeutic strategy (2022, background): “ChREBP inhibition markedly decreased the expression of L-PK, ACC, and FAS, but restored liver insulin sensitivity by restoring protein kinase B (Akt), and Foxo1 phosphorylation activity with insulin.(122) This paradoxical response of SREBP-1c and ChREBP in hepatic IR is probably due to many branch e”