Nutrition and circadian rhythms: how a ketogenic diet specifically affects the endogenous clock in liver and intestine

In the last decades, evidence has shown that the circadian clock plays a major role in maintaining whole body metabolic homeostasis. Changes in the dietary regimen deeply affect the liver endogenous clock, however little is known about the effect of a food challenge on other peripheral clocks. Ketogenic diets are low carbohydrate diets that have become very popular to lose weight. This study demonstrates how a ketogenic diet strongly and specifically influences the endogenous clock and the circadian physiology of two different peripheral tissues: liver and intestine.

HFSP Long-Term Fellow Paola Tognini and colleagues
authored on Wed, 04 October 2017

Sleep-wake cycle, changes in body temperature, and hormone blood levels are just few daily patterns governed by the endogenous clock. Circadian (from the Latin “circa” = around, and “die” = day) rhythms are involved in sustaining important biological processes and their alteration, such as during shift-work or frequent transoceanic flights, can drastically perturb our physiology and health. Virtually, all the tissues of our body contain an internal clock, which synchronizes the specific tissue physiology to stimuli coming from the external world.

Metabolic homeostasis and circadian clock functions are profoundly linked. Time of food and its composition, such as a western high fat diet, has been shown to affect the liver endogenous clock, impinging on its circadian rhythmicity both transcriptionally and metabolically. However, little is known about how the intestinal clock is affected by food and how different peripheral clocks specifically interpret a nutritional stress.


Figure legend: Schematic representation of the changes in circadian gene expression affecting the clock in liver and intestine upon ketogenic diet feeding.


To answer this question, Paola Tognini and colleagues, at University of California Irvine, fed C57BL/6J mice to a ketogenic diet. A ketogenic diet is a high fat, very low carbohydrate, adequate protein diet that has been broadly used to treat refractory epilepsy in kids. More recently, ketogenic diets have been used for obesity, type 2 diabetes, to lose weight and several other indications. The liver and intestine of animals fed to ketogenic diet displayed a specific reprogramming of daily oscillation in gene expression that was dictated by distinct molecular pathways. In particular, in the liver, the core-clock transcription factor BMAL1 showed an increase in chromatin recruitment at specific times of the day accompanied by an enhancement in the amplitude of oscillation of its target genes. On the other hand, the transcriptome analysis revealed that the transcription factor PPAR-alpha pathway was enriched and diurnal in the intestine, following a distinct phase of oscillation. Genome-wide analysis showed that PPAR-alpha target genes displayed a specific daily rhythmicity in the intestine upon ketogenic diet. Intriguingly, beta-hydroxyl-butyrate, an important metabolite produced by the activation of the ketogenic biochemical pathway, started to oscillate in the serum and the intestine with the same profile of PPAR-alpha target genes. Indeed, to dissect the molecular mechanisms underlining the effect of ketogenic diet on gene expression, the authors analyzed histone acetylation on the promoter of PPAR-alpha targets, being beta-hydroxyl-butyrate an endogenous histone-deacetylase enzyme inhibitor. Strikingly, in the intestine histone acetylation and histone deacetylase inhibition perfectly followed the 24-hour oscillation of beta-hydroxyl-butyrate. In contrast, this effect was not present in the liver.

This finding unravels the tissue-specific molecular mechanisms involved in the daily reprogramming of peripheral clock physiology upon a nutritional stress, and highlights the important link between epigenetics and nutrition.


Distinct Circadian Signatures in Liver and Gut Clocks Revealed by Ketogenic Diet. Tognini P., Murakami M., Liu Y., Eckel-Mahan K.L., Newman J.C., Verdin E., Baldi P., Sassone-Corsi P. Cell Metabolism. 2017 Sep 5;26(3):523-538.e5. doi: 10.1016/j.cmet.2017.08.015

Article featured in “Research highlight”: Ketogenic diet rewires Circadian clock. Claire Greenhill. Nature Reviews Endocrinology (2017) doi:10.1038/nrendo.2017.129

Link to the article: