Distinct Circadian Signatures in Liver and Gut Clocks Revealed by Ketogenic Diet

Cell Metab. 2017 Sep 5;26(3):523-538.e5. doi: 10.1016/j.cmet.2017.08.015.


The circadian clock orchestrates rhythms in physiology and behavior, allowing organismal adaptation to daily environmental changes. While food intake profoundly influences diurnal rhythms in the liver, how nutritional challenges are differentially interpreted by distinct tissue-specific clocks remains poorly explored. Ketogenic diet (KD) is considered to have metabolic and therapeutic value, though its impact on circadian homeostasis is virtually unknown. We show that KD has profound and differential effects on liver and intestine clocks. Specifically, the amplitude of clock-controlled genes and BMAL1 chromatin recruitment are drastically altered by KD in the liver, but not in the intestine. KD induces nuclear accumulation of PPARα in both tissues but with different circadian phase. Also, gut and liver clocks respond differently to carbohydrate supplementation to KD. Importantly, KD induces serum and intestinal β-hydroxyl-butyrate levels to robustly oscillate in a circadian manner, an event coupled to tissue-specific cyclic histone deacetylase (HDAC) activity and histone acetylation.

Keywords: PPARα; circadian clock; histone acetylation; intestine; ketogenic diet; liver; β-hydroxyl-butyrate.

MeSH terms

  • 3-Hydroxybutyric Acid / blood
  • 3-Hydroxybutyric Acid / metabolism
  • ARNTL Transcription Factors / metabolism
  • Acetylation / drug effects
  • Animals
  • Chromatin / metabolism
  • Circadian Clocks* / drug effects
  • Circadian Clocks* / genetics
  • Circadian Rhythm* / drug effects
  • Circadian Rhythm* / genetics
  • Diet, Ketogenic*
  • Epigenesis, Genetic / drug effects
  • Fructose / pharmacology
  • Gastrointestinal Tract / physiology*
  • Gene Knockdown Techniques
  • Histones / metabolism
  • Liver / drug effects
  • Liver / physiology*
  • Metabolome / genetics
  • Mice
  • Models, Biological
  • Organ Specificity / drug effects
  • Organ Specificity / genetics
  • PPAR alpha / metabolism
  • Promoter Regions, Genetic / genetics
  • Respiration / drug effects
  • Sucrose / pharmacology
  • Transcription, Genetic / drug effects
  • Transcriptome / genetics


  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Chromatin
  • Histones
  • PPAR alpha
  • Fructose
  • Sucrose
  • 3-Hydroxybutyric Acid