Deletion of hepatic carbohydrate response element binding protein (ChREBP) impairs glucose homeostasis and hepatic insulin sensitivity in mice

Carbohydrate response element binding protein (ChREBP) is a transcription factor that responds to glucose and activates genes involved in the glycolytic and lipogenic pathways. Recent studies have linked adipose ChREBP to insulin sensitivity in mice. However, while ChREBP is most highly expressed in...

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Bibliographic Details
Published in:Molecular metabolism (Germany) 2017-11, Vol.6 (11), p.1381-1394
Main Authors: Jois, Tara, Chen, Weiyi, Howard, Victor, Harvey, Rebecca, Youngs, Kristina, Thalmann, Claudia, Saha, Pradip, Chan, Lawrence, Cowley, Michael A., Sleeman, Mark W.
Format: Article
Language:English
Subjects:
Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Carbohydrate Metabolism - physiology
ChREBP
Diet, High-Fat
Fatty Liver - genetics
Gene Expression Regulation - genetics
Glucose - metabolism
Glucose homeostasis
Hepatic glucose production
Homeostasis - physiology
Insulin Resistance - genetics
Insulin Resistance - physiology
Insulin sensitivity
Lipogenesis
Liver
Liver - metabolism
Mice
Mice, Knockout
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Obesity - genetics
Original
Transcription Factors - genetics
Transcription Factors - metabolism
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Summary:Carbohydrate response element binding protein (ChREBP) is a transcription factor that responds to glucose and activates genes involved in the glycolytic and lipogenic pathways. Recent studies have linked adipose ChREBP to insulin sensitivity in mice. However, while ChREBP is most highly expressed in the liver, the effect of hepatic ChREBP on insulin sensitivity remains unknown. To clarify the importance of hepatic ChREBP on glucose homeostasis, we have generated a knockout mouse model that lacks this protein specifically in the liver (Liver-ChREBP KO). Using Liver-ChREBP KO mice, we investigated whether hepatic ChREBP deletion influences insulin sensitivity, glucose homeostasis and the development of hepatic steatosis utilizing various dietary stressors. Furthermore, we determined gene expression changes in response to fasted and fed states in liver, white, and brown adipose tissues. Liver-ChREBP KO mice had impaired insulin sensitivity as indicated by reduced glucose infusion to maintain euglycemia during hyperinsulinemic-euglycemic clamps on both chow (25% lower) and high-fat diet (33% lower) (p 
ISSN:2212-8778
2212-8778
DOI:10.1016/j.molmet.2017.07.006