The transcription factor Cabut coordinates energy metabolism and the circadian clock in response to sugar sensing

Osnat Bartok, Mari Teesalu, Reut Ashwall-Fluss, Varun Pandey, Mor Hanan, Bohdana M. Rovenko, Minna Poukkula, Essi Havula, Arieh Moussaieff, Sadanand Vodala, Yaakov Nahmias, Sebastian Kadener*, Ville Hietakangas

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Nutrient sensing pathways adjust metabolism and physiological functions in response to food intake. For example, sugar feeding promotes lipogenesis by activating glycolytic and lipogenic genes through the Mondo/ChREBP-Mlx transcription factor complex. Concomitantly, other metabolic routes are inhibited, but the mechanisms of transcriptional repression upon sugar sensing have remained elusive. Here, we characterize cabut (cbt), a transcription factor responsible for the repressive branch of the sugar sensing transcriptional network in Drosophila. We demonstrate that cbt is rapidly induced upon sugar feeding through direct regulation by Mondo-Mlx. We found that CBT represses several metabolic targets in response to sugar feeding, including both isoforms of phosphoenolpyruvate carboxykinase (pepck). Deregulation of pepck1 (CG17725) in mlx mutants underlies imbalance of glycerol and glucose metabolism as well as developmental lethality. Furthermore, we demonstrate that cbt provides a regulatory link between nutrient sensing and the circadian clock. Specifically, we show that a subset of genes regulated by the circadian clock are also targets of CBT. Moreover, perturbation of CBT levels leads to deregulation of the circadian transcriptome and circadian behavioral patterns. Synopsis Sugar feeding in flies induces specific gene expression but also triggers a repressive branch via transcription factor Cabut. Induction of Cabut alters accumulation of the metabolic enzyme PEPCK and provides a regulatory link between nutrient sensing and the circadian clock. Transcriptional regulator Cabut is directly activated by Mondo-Mlx upon sugar feeding. Cabut represses metabolic genes upon sugar feeding. Cabut represses the expression of both isoforms of the phosphoenolpyruvate carboxykinase PEPCK. Deregulation of PEPCK1 contributes to the metabolic imbalance and lethality of mlx mutant animals. Cabut represses the cycling of metabolic target genes of the circadian clock. Sugar feeding in flies induces specific gene expression but also triggers a repressive branch via transcription factor Cabut. Induction of Cabut alters accumulation of the metabolic enzyme PEPCK and provides a regulatory link between nutrient sensing and the circadian clock.

Original languageAmerican English
Pages (from-to)1538-1553
Number of pages16
JournalEMBO Journal
Volume34
Issue number11
DOIs
StatePublished - 3 Jun 2015

Bibliographical note

Publisher Copyright:
© 2015 The Authors.

Keywords

  • cabut
  • circadian
  • metabolism
  • nutrient sensing
  • transcription

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