The liver-clock coordinates rhythmicity of peripheral tissues in response to feeding

Abstract

The mammalian circadian system consists of a central clock in the brain that synchronizes clocks in peripheral tissues. While the hierarchy between the central and peripheral clocks is established, little is known regarding the specificity and functional organization of peripheral clocks. Here, we employ altered feeding paradigms in conjunction with liver-clock mutant mice to map disparities and interactions between peripheral rhythms. We find that peripheral clocks largely differ in their responses to feeding-time. Disruption of the liver-clock, despite its prominent role in nutrient processing, does not affect rhythmicity of clocks in other peripheral tissues. Yet, unexpectedly, liver-clock disruption strongly modulates peripheral tissues’ transcriptional rhythmicity, primarily upon daytime feeding. Concomitantly, liver-clock mutant mice exhibit impaired glucose and lipid homeostasis, which are aggravated by daytime feeding. Overall, our findings suggest that, upon nutrient challenge, the liver-clock buffers the effect of feeding-related signals on rhythmicity of peripheral tissues, irrespective of their clocks.

Protocol for setup and circadian analysis of inverted feeding in mice

“…examined clocks in liver, adipose tissue, lung, quadriceps, kidney, and heart and profiled transcriptomes in liver, adipose tissue, and lung in male mice. The findings are consistent with ours, that is, peripheral tissues exhibit distinct patterns of phase entrainment of diurnal transcriptomes to inverted feeding ( Xin et al., 2021 ; Manella et al., 2021 ). Thus, a comparison of AL vs DRF provides strength to our study.…”

“…Very recently, Manella et al. have used Alb-Cre+ male mice as the wildtype control, and recapitulated our observations in males under a 30-day inverted feeding, or daytime feeding as they called it ( Manella et al., 2021 ). Sexual dimorphism is emerging as a key factor in studying circadian rhythm ( Anderson and FitzGerald, 2020 ; Weger et al., 2019 ).…”

“…Very recently, Manella et al. have reported similar findings that Arntl and Nr1d1 transcripts show decreased amplitude or rhythmicity in quadriceps, kidney, and heart in their control mice (male C57BL/6 Alb-Cre+) after a 30-day DRF, though light intensity is not shown ( Manella et al., 2021 ). We recommend reporting light intensity for inverted feeding studies.…”

“…A complete experimental design would ideally be three groups, i.e., DRF, AL, and NRF. Several studies compared DRF and AL in mouse liver and other peripheral tissues ( Vollmers et al., 2009 ; Manella et al., 2021 ). Regarding liver, all three studies including ours demonstrate that liver clock and hepatic diurnal transcriptome entrains to inverted feeding.…”

Circadian Clock-Controlled Checkpoints in the Pathogenesis of Complex Disease

“…Feeding rhythm is crucial in clock synchronization in the body ( Reinke and Asher, 2019 ), yet different peripheral clocks seem to respond with a broad spectrum of kinetics ( Xin et al, 2021 ). Inverted feeding readily reverses circadian rhythms in liver and adipose tissue ( Manella et al, 2021 ; Xin et al, 2021 ). Recently, a multi-omics study indicated that diurnal rhythms of transcriptomes, metabolomes, and clocks in the heart and kidney are resistant to circadian entrainment by feeding rhythm ( Xin et al, 2021 ).…”