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

Weiyi Chen,Michael A Cowley,Kristina Youngs,Victor Howard,Tara Jois,Mark W Sleeman,Lawrence Chan,Rebecca Harvey,Claudia Thalmann,Pradip Saha

doi:10.1016/j.molmet.2017.07.006

Abstract

ObjectiveCarbohydrate 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). MethodsUsing 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. ResultsLiver-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 < 0.05). This corresponded with attenuated suppression of hepatic glucose production. Although Liver-ChREBP KO mice were protected against carbohydrate-induced hepatic steatosis, they displayed worsened glucose tolerance. Liver-ChREBP KO mice did not show the expected gene expression changes in liver in response to fasted and fed states. Interestingly, hepatic ChREBP deletion also resulted in gene expression changes in white and brown adipose tissues, suggesting inter-tissue communication. This included an almost complete abolition of BAT ChREBPβ induction in the fed state (0.15-fold) (p = 0.015) along with reduced lipogenic genes. In contrast, WAT showed inappropriate increases in lipogenic genes in the fasted state along with increased PEPCK1 in both fasted (3.4-fold) and fed (5.1-fold) states (p < 0.0001). ConclusionsOverall, hepatic ChREBP is protective in regards to hepatic insulin sensitivity and whole body glucose homeostasis. Hepatic ChREBP action can influence other peripheral tissues and is likely essential in coordinating the body's response to different feeding states.

Highlights

The coordinated control to fasting and feeding to regulate energy balance is vital in providing continual fuel for cellular processes
Liver-carbohydrate response element binding protein (ChREBP) KO mice showed elevated blood glucose 30 min post receiving a glucose load orally, suggesting an impairment in the ability to clear glucose (Figure 1A) (p < 0.05). This effect was exaggerated when mice were placed on a high-fat diet for 12 weeks, where Liver-ChREBP KO mice showed greatly impaired glucose tolerance compared to control mice (Figure 1B) (p < 0.0001). This was despite no differences in body composition in high-fat diet fed mice and suggests that Liver-ChREBP KO mice are more susceptible to dietinduced glucose intolerance
To assess whether the impairments in glucose tolerance were due to problems in insulin sensitivity, hyperinsulinemic-euglycemic clamps were performed on LiverChREBP KO and control mice fed either a chow or high-fat diet

Summary

Introduction

The coordinated control to fasting and feeding to regulate energy balance is vital in providing continual fuel for cellular processes. The reliance of various tissues in the body on glucose as a fuel substrate means blood glucose concentration in particular must be maintained. This means during periods of fasting the liver releases glucose into the bloodstream. One of the key actions of insulin in the fed state is to suppress this hepatic glucose production as well as increase uptake of glucose in muscle and adipose tissues. Impairments in the action of insulin can lead to impaired fasting glucose or glucose intolerance which are key risk factors for the development of diabetes [1].

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Conclusion