The expression of a large number of genes, including those involved in liver metabolism, is regulated by the daily pattern of circadian rhythms. When components of the circadian clock are not functioning properly, normal metabolism is disrupted, resulting in disorders such as diabetes, obesity and high blood pressure.

Now researchers have found that a diet high in fat can interrupt the components necessary for maintaining the liver's circadian rhythms, resulting in widespread changes in metabolism. Paolo Sassone-Corsi and his group at University of California-Irvine fed mice either a high-fat diet (HFD) or normal chow at the same quantities and times for a period of 10 weeks. They measured levels of metabolites every 4 h through the circadian cycle. Of the 306 metabolites they identified, 77% showed an effect of diet on their rhythmicity (Cell 155, 1464–1478; 2013).

Circadian rhythms within cells are controlled by transcriptional feedback loops that produce oscillations in gene expression. Two 'clock' compounds that regulate these feedback loops, CLOCK and BMAL1, are impeded by a HFD, preventing the normal oscillations in expression of metabolites in the liver. Of the transcripts that oscillated in expression, 49.5% were rhythmic only in the normal diet condition but not in the HFD condition.

For many of the metabolites and genes that remained oscillating in the HFD condition, the phase of their oscillations was shifted forward, disrupting the temporal coherence between their cycles and those of their related transcripts. This coherence is important for maintaining metabolic homeostasis.

The HFD also induced oscillations of transcripts and metabolites that usually do not change with the circadian clock: 38 metabolites and 654 genes were newly oscillating exclusively in HFD-fed mice. These effects were mediated both by interfering with the recruitment of CLOCK and BMAL1 to chromatin and by inducing the activity of a transcription factor called PPAR-γ.

The mice fed a HFD became obese, raising the question of whether obesity, and not greater caloric intake, was the cause for the circadian reprogramming of the metabolites. But in another group of mice, a short, 3-day exposure to HFD was enough to initiate the cycling changes even though these mice were a healthy weight.

Yet another group of mice was fed a HFD for 10 weeks followed by 2 weeks of normal chow. The rhythms in these mice normalized after returning to the normal diet, demonstrating that the HFD-induced transcriptional and epigenetic changes are reversible.