KLF10 integrates circadian timing and sugar signaling to coordinate hepatic metabolism
- Université Côte d'Azur, France
- Université Côte d'Azur, CNRS, Inserm, France
- Mayo Clinic, United States
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.
Data availability
Sequencing data have been deposited in European Nucleotide Archive under accession codes PRJEB39035, 696 PRJEB39036, PRJEB40195.All data generated or annalysed during this study are included in the manuscript and supplemental files. Source data files have been provided for figures 1-7.
Article and author information
Author details
Funding
Agence Nationale de la Recherche (ANR-15-CE14-0016-01)
- Franck Delaunay
- Michèle Teboul
Agence Nationale de la Recherche (ANR-18-CE14-0019-02)
- Franck Delaunay
- Michèle Teboul
Agence Nationale de la Recherche (ANR-11-LABX-0028-01)
- Anthony A Ruberto
- Franck Delaunay
- Michèle Teboul
Agence Nationale de la Recherche (ANR-15-IDEX-01)
- Franck Delaunay
- Michèle Teboul
Canceropole Provence Cote d'Azur (MetaboCell)
- Mohamed Mehiri
Universite Cote d'Azur (ATER)
- Johana S Revel
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal studies were approved by the local committee for animal ethics Comité Institutionnel d'Éthique Pour l'Animal de Laboratoire (CIEPAL-Azur; Authorized protocols: PEA 244 and 557) and conducted in accordance with the CNRS and INSERM institutional guidelines.
Copyright
© 2021, Ruberto et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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KLF10 integrates circadian timing and sugar signaling to coordinate hepatic metabolism
eLife 10:e65574.
https://doi.org/10.7554/eLife.65574
Further reading
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- Cell Biology
- Chromosomes and Gene Expression
We investigated the role of the nucleolar protein Treacle in organizing and regulating the nucleolus in human cells. Our results support Treacle’s ability to form liquid-like phase condensates through electrostatic interactions among molecules. The formation of these biomolecular condensates is crucial for segregating nucleolar fibrillar centers from the dense fibrillar component and ensuring high levels of ribosomal RNA (rRNA) gene transcription and accurate rRNA processing. Both the central and C-terminal domains of Treacle are required to form liquid-like condensates. The initiation of phase separation is attributed to the C-terminal domain. The central domain is characterized by repeated stretches of alternatively charged amino acid residues and is vital for condensate stability. Overexpression of mutant forms of Treacle that cannot form liquid-like phase condensates compromises the assembly of fibrillar centers, suppressing rRNA gene transcription and disrupting rRNA processing. These mutant forms also fail to recruit DNA topoisomerase II binding protein 1 (TOPBP1), suppressing the DNA damage response in the nucleolus.
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- Cell Biology
The primary cilium is a microtubule-based organelle that cycles through assembly and disassembly. In many cell types, formation of the cilium is initiated by recruitment of preciliary vesicles to the distal appendage of the mother centriole. However, the distal appendage mechanism that directly captures preciliary vesicles is yet to be identified. In an accompanying paper, we show that the distal appendage protein, CEP89, is important for the preciliary vesicle recruitment, but not for other steps of cilium formation (Kanie et al., 2025). The lack of a membrane-binding motif in CEP89 suggests that it may indirectly recruit preciliary vesicles via another binding partner. Here, we identify Neuronal Calcium Sensor-1 (NCS1) as a stoichiometric interactor of CEP89. NCS1 localizes to the position between CEP89 and the centriole-associated vesicle marker, RAB34, at the distal appendage. This localization was completely abolished in CEP89 knockouts, suggesting that CEP89 recruits NCS1 to the distal appendage. Similar to CEP89 knockouts, preciliary vesicle recruitment as well as subsequent cilium formation was perturbed in NCS1 knockout cells. The ability of NCS1 to recruit the preciliary vesicle is dependent on its myristoylation motif and NCS1 knockout cells expressing a myristoylation defective mutant failed to rescue the vesicle recruitment defect despite localizing properly to the centriole. In sum, our analysis reveals the first known mechanism for how the distal appendage recruits the preciliary vesicles.
