Editors' ChoiceMetabolism

Time to Go on a Diet

Sci. Signal.  07 Jan 2014:
Vol. 7, Issue 307, pp. ec3
DOI: 10.1126/scisignal.2005045

Organisms respond to daily light cycles by circadian rhythm, the coordination of biological processes such as sleep, feeding, and metabolism. Accordingly, disruption of circadian rhythm can affect metabolic homeostasis and contribute to obesity, diabetes, and cardiac disease. Molecular feedback loops controlled by clock genes, such as the transcription factors CLOCK and BMAL1, create oscillations in gene expression that establish circadian rhythms in cells. Eckel-Mahan et al. found that a high-fat diet (HFD) produces widespread alterations in circadian transcriptional and metabolic profiles in the liver. The livers of mice fed either a HFD or normal diet (ND) for 10 weeks were harvested every 4 hours for a day and analyzed by mass spectrometry and cDNA microarray. The HFD altered the phase and amplitude of several metabolites and transcripts and induced the oscillation of new sets of metabolites and transcripts while blocking those of others as compared with the ND. For example, the HFD prevented the oscillation in the abundance of nicotinamide adenine dinucleotide (NAD+) and enhanced the amplitude of the oscillation in the abundance of coenzyme A, both of which are metabolites involved in energy homeostasis. The HFD prevented oscillation of transcripts encoding proteins involved in proteolysis and insulin signaling and promoted oscillation of those encoding enzymes involved in protein sugar modification. The HFD did not affect the mRNA expression or protein abundance of clock genes, including CLOCK and BMAL1. However, the chromatin occupancy of CLOCK and BMAL1 and epigenetic marks associated with active transcription were lost on the promoters of genes not showing oscillating expression in mice fed the HFD. The promoters of genes showing oscillating expression in the HFD-fed mice, but not the ND-fed mice, were enriched for binding sites of the nuclear hormone receptor PPARγ, which is involved in glucose and lipid metabolism. Transcriptional and metabolic profiling of the livers of mice fed with the HFD for only 3 days or with the HFD for 10 days and then ND for 14 days revealed that these changes were both rapid (and preceded the development of obesity) and reversible. Thus, these results suggest that the affects of a HFD on the relation between metabolism and circadian rhythm could contribute to disease but can be reversed with a ND.

K. L. Eckel-Mahan, V. R. Patel, S. de Mateo, R. Orozco-Solis, N. J. Ceglia, S. Sahar, S. A. Dilag-Penilla, K. A. Dyar, P. Baldi, P. Sassone-Corsi, Reprogramming of the circadian clock by nutritional challenge. Cell 155, 1464–1478 (2013). [PubMed]