Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression

TLDR

Mammalian circadian oscillators generate ~24‑h rhythms in feeding behavior, and livers exhibit circadian transcript abundance, raising the question of whether hepatic transcript oscillations are driven by feeding rhythms, the hepatic clock, or both. The study aimed to determine whether the temporal pattern of food intake or the hepatic circadian clock governs hepatic transcript rhythms. Distinct feeding and fasting paradigms were applied to wild‑type and circadian‑clock‑deficient mice while temporal patterns of feeding and hepatic transcription were monitored. Both food availability and feeding timing shaped the repertoire, phase, and amplitude of the WT liver circadian transcriptome, whereas only a small subset of transcripts remained rhythmic without feeding; temporally restricted feeding restored rhythmic transcription in clock‑deficient mice, demonstrating that both feeding pattern and the circadian clock drive hepatic transcription.

Abstract

In mammals, the circadian oscillator generates approximately 24-h rhythms in feeding behavior, even under constant environmental conditions. Livers of mice held under constant darkness exhibit circadian rhythm in abundance in up to 15% of expressed transcripts. Therefore, oscillations in hepatic transcripts could be driven by rhythmic food intake or sustained by the hepatic circadian oscillator, or a combination of both. To address this question, we used distinct feeding and fasting paradigms on wild-type (WT) and circadian clock-deficient mice. We monitored temporal patterns of feeding and hepatic transcription. Both food availability and the temporal pattern of feeding determined the repertoire, phase, and amplitude of the circadian transcriptome in WT liver. In the absence of feeding, only a small subset of transcripts continued to express circadian patterns. Conversely, temporally restricted feeding restored rhythmic transcription of hundreds of genes in oscillator-deficient mouse liver. Our findings show that both temporal pattern of food intake and the circadian clock drive rhythmic transcription, thereby highlighting temporal regulation of hepatic transcription as an emergent property of the circadian system.