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

Publication date: 5 September 2017
Source:Cell Metabolism, Volume 26, Issue 3
Author(s): Paola Tognini, Mari Murakami, Yu Liu, Kristin L. Eckel-Mahan, John C. Newman, Eric Verdin, Pierre Baldi, Paolo Sassone-Corsi
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.

Graphical abstract

Teaser

Tognini et al. reveal how a ketogenic diet (KD) differently affects liver and intestine circadian clocks and drives tissue-specific oscillation of PPARα and its target genes. Serum and intestine βOHB shows a unique diurnal rhythmicity, associated with daily epigenetic changes exclusively in the gut.


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