KLF10 integrates circadian timing and sugar signaling to coordinate hepatic metabolism.

Anthony A Ruberto,Michèle Teboul,Mohamed Mehiri,Johana S Revel,Malayannan Subramaniam,Luc Martin,Aline Gréchez-Cassiau,Sophie Guérin,Franck Delaunay

doi:10.7554/elife.65574

Abstract

The mammalian circadian timing system and metabolism are highly interconnected, and disruption of this coupling is associated with negative health outcomes. Krüppel-like factors (KLFs) are transcription factors that govern metabolic homeostasis in various organs. Many KLFs show a circadian expression in the liver. Here, we show that the loss of the clock-controlled KLF10 in hepatocytes results in extensive reprogramming of the mouse liver circadian transcriptome, which in turn alters the temporal coordination of pathways associated with energy metabolism. We also show that glucose and fructose induce Klf10, which helps mitigate glucose intolerance and hepatic steatosis in mice challenged with a sugar beverage. Functional genomics further reveal that KLF10 target genes are primarily involved in central carbon metabolism. Together, these findings show that in the liver KLF10 integrates circadian timing and sugar metabolism-related signaling, and serves as a transcriptional brake that protects against the deleterious effects of increased sugar consumption.

Highlights

The mammalian circadian timing system aligns most biological processes with the Earth’s light/dark (LD) cycle to ensure optimal coordination of physiology and behavior over the course of the day (Bass and Lazar, 2016)
In this study, using a hepatocytespecific Klf10 knockout mouse model, we show that KLF10 is required for the temporal coordination of various biological pathways associated with energy metabolism, and that it has a protective role in shielding mice from adverse effects associated with sugar overload
Upon assessing genes involved in the glucose and fructose metabolism pathway, we found that Klf10Δhep mice on the chow + SSW diet displayed higher expression of the gene encoding for the rate-limiting glycolytic enzyme encoding Pklr compared to Klf10flox/flox mice on the same diet (Figure 4A)

Summary

Introduction

The mammalian circadian timing system aligns most biological processes with the Earth’s light/dark (LD) cycle to ensure optimal coordination of physiology and behavior over the course of the day (Bass and Lazar, 2016). Krüppel-like factors (KLFs) form another family of transcription regulators, a majority of which has been involved the physiology of metabolic organs including the liver (Hsieh et al, 2019). Many of these KLFs are clock-controlled genes in mouse liver (Ceglia et al, 2018; Yoshitane et al., 2014). This suggests KLFs as additional factors for the circadian regulation of hepatic metabolism. In this study, using a hepatocytespecific Klf knockout mouse model, we show that KLF10 is required for the temporal coordination of various biological pathways associated with energy metabolism, and that it has a protective role in shielding mice from adverse effects associated with sugar overload

Results

Discussion

Materials and methods