The transcription factor Cabut coordinates energy metabolism and the circadian clock in response to sugar sensing.
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.
Biological Chemistry Department, Silberman Institute of Life Sciences The Hebrew University of Jerusalem, Jerusalem, Israel.
Osnat
O
Bartok
Department of Biosciences, University of Helsinki, Helsinki, Finland Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
Mari
M
Teesalu
Biological Chemistry Department, Silberman Institute of Life Sciences The Hebrew University of Jerusalem, Jerusalem, Israel.
Reut
R
Ashwall-Fluss
Biological Chemistry Department, Silberman Institute of Life Sciences The Hebrew University of Jerusalem, Jerusalem, Israel.
Varun
V
Pandey
Biological Chemistry Department, Silberman Institute of Life Sciences The Hebrew University of Jerusalem, Jerusalem, Israel.
Mor
M
Hanan
Department of Biosciences, University of Helsinki, Helsinki, Finland Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
Bohdana M
BM
Rovenko
Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
Minna
M
Poukkula
Department of Biosciences, University of Helsinki, Helsinki, Finland Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
Essi
E
Havula
Department of Cell Biology, Silberman Institute of Life Sciences The Hebrew University of Jerusalem, Jerusalem, Israel Center for Bioengineering, The Hebrew University of Jerusalem, Jerusalem, Israel.
Arieh
A
Moussaieff
Howard Hughes Medical Institute, Brandeis University, Waltham, MA, USA.
Sadanand
S
Vodala
Department of Cell Biology, Silberman Institute of Life Sciences The Hebrew University of Jerusalem, Jerusalem, Israel Center for Bioengineering, The Hebrew University of Jerusalem, Jerusalem, Israel.
Yaakov
Y
Nahmias
Biological Chemistry Department, Silberman Institute of Life Sciences The Hebrew University of Jerusalem, Jerusalem, Israel ville.hietakangas@helsinki.fi skadener@mail.huji.ac.il.
Sebastian
S
Kadener
Department of Biosciences, University of Helsinki, Helsinki, Finland Institute of Biotechnology, University of Helsinki, Helsinki, Finland ville.hietakangas@helsinki.fi skadener@mail.huji.ac.il.
Ville
V
Hietakangas
D000818:Animals; D057906:Circadian Clocks / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D004734:Energy Metabolism / Q000502:physiology*; D005247:Feeding Behavior / Q000502:physiology*; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D005990:Glycerol / Q000378:metabolism; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome / Q000502:physiology*
C506602:Cbt protein, Drosophila; D029721:Drosophila Proteins; D014157:Transcription Factors; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D005947:Glucose; D005990:Glycerol
cabut; circadian; metabolism; nutrient sensing; transcription