Integration of feeding behavior by the liver circadian clock reveals network dependency of metabolic rhythms

Greco, Carolina; Koronowski, Kevin B.; Smith, Jacob G.; Shi, Jiejun; Kunderfranco, Paolo; Carriero, Roberta; Chen, Siwei; Samad, Muntaha; Welz, Patrick-Simon; Zinna, Valentina M.; Mortimer, Thomas; Chun, Sung Kook; Shimaji, Kohei; Petrus, Paul; Kumar, Arun; Vaca-Dempere, Mireia; Deryagian, Oleg; Van, Cassandra; Kuhn, José Manuel Monroy; Lutter, Dominik; Seldin, Marcus M.; Masri, Selma; Li, Wei; Baldi, Pierre; Dyar, Kenneth A.; Muñoz‐Cánoves, Pura; Benitah, Salvador Aznar

doi:10.1126/sciadv.abi7828

Cited by 75 publications

(93 citation statements)

References 119 publications

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“…Thus, the central clock is sufficient for driving ∼27% of the hepatic transcriptome, which is higher than the ∼13% driven by the local autonomous liver clock ( 9 ). Interestingly, the liver-RE mice displayed a higher recovery (∼41%) of the circadian liver transcriptome once feeding rhythms were introduced ( 22 ), suggesting that regulation by both the local clock and by feeding rhythms were additive rather than redundant (27%+13%=41%). The transcription phases were distributed throughout the day in WT livers, while most hepatic mRNA peak at ZT6 and ZT18 in brain-RE mice (Fig.…”

Section: Mainmentioning

confidence: 99%

“…We hypothesized that metabolic oscillations are driven by rhythmic feeding behavior; a process restored in the BRE mice (Extended Fig 2C). First, ad hoc analyses were performed on data from our published study ( 22 ) which assessed hepatic metabolite and transcript rhythms in KO mice that were night fed (NF), i.e. food was available only in the mouse’s active phase.…”

Section: Mainmentioning

confidence: 99%

“…However, interestingly, our data suggest that peripheral clocks are not only synchronized by food intake, but buffer and integrate the metabolic rhythms. Recently, we demonstrated an integrative role for the autonomous liver clock in the presence of feeding/fasting cycles ( 22 ), revealing cooperation between feeding/fasting cycles and the local clockwork in defining local rhythmic transcription. Supporting our findings, the hepatic clock has also been shown to shield untimely food intake and protect feeding-driven transcriptional rhythms in other peripheral tissues, such as the lung ( 32 ).…”

Section: Mainmentioning

confidence: 99%

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The central clock suffices to drive the majority of circulatory metabolic rhythms

Petrus

Smith

Koronowski

et al. 2022

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Life on Earth anticipates recurring 24-h environmental cycles via genetically-encoded molecular clocks active in all mammalian organs. Communication between these clocks is believed to control circadian homeostasis. Metabolism can be considered a form of inter-tissue communication language that results in temporal coordination of systemic metabolism between tissues. Here we characterize the extent to which clocks in different organs employ this means of communication, an area which remains largely unexplored. For this, we analysed the metabolome of serum from mice with tissue-specific expression of the clock gene Bmal1. Notably, having functional hepatic and muscle clocks can only drive a minority (13%) of the oscillating metabolites in circulation. Conversely, limiting Bmal1 expression to Syt10-expressing neurons (which are enriched in the suprachiasmatic nucleus [SCN], the master pacemaker that regulates circadian rhythms) restores rhythms to 57% of circulatory metabolites and 28% of liver transcripts, and rescues glucose intolerance. Importantly, these parameters were also restored in clock-less mice upon rhythmic feeding, indicating that the central clock mainly regulates metabolic rhythms via behavior. These findings explicate the circadian communication between tissues and highlight the importance of the central clock in governing those signals.

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Section: Mainmentioning

confidence: 99%

Section: Mainmentioning

confidence: 99%

Section: Mainmentioning

confidence: 99%

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The central clock suffices to drive the majority of circulatory metabolic rhythms

Petrus

Smith

Koronowski

et al. 2022

Preprint

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“…d-e , RNA sequencing of livers and gastrocnemius muscles harvested around the clock under 12 hr light: 12 hr dark conditions (n=3). Liver sequencing data for WT-Alfp Cre, KO and Liver-RE from ( 8 ). No full-length Bmal1 mRNA or protein of any size is detected in KO mice-see Extended Data Figure 1a–d.…”

Section: Independence Of Liver and Muscle Autonomous Clocks In Vivomentioning

confidence: 99%

“…Using Liver-RE mice, we previously demonstrated the liver core clock is partially autonomous, oscillating with reduced amplitude and a ~2-4 hour phase advance versus WT ( 4 , 8 ). To assess muscle clock autonomy, and probe potential muscle-liver connections, we performed RNA-Sequencing on gastrocnemius muscles (predominantly fast-twitch fibers ( 10 )) and livers harvested every 4-hours over the diurnal cycle.…”

Section: Independence Of Liver and Muscle Autonomous Clocks In Vivomentioning

confidence: 99%

Interrogating Metabolic Interactions Between Skeletal Muscle and Liver Circadian Clocks In Vivo

Smith

Koronowski

Greco

et al. 2022

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Expressed throughout the body, the circadian clock system achieves daily metabolic homeostasis at every level of physiology, with clock disruption associated with metabolic disease (1, 2). Molecular clocks present in the brain, liver, adipose, pancreas and skeletal muscle each contribute to glucose homeostasis (3). However, it is unclear; 1) which organ clocks provide the most essential contributions, and 2) if these contributions depend on inter-organ communication. We recently showed that the liver clock alone is insufficient for most aspects of daily liver glucose handling and requires connections with other clocks (4). Considering the pathways that link glucose metabolism between liver and skeletal muscle, we sought to test whether a clock connection along this axis is important. Using our previous published methodology for tissue-specific rescue of Bmal1 in vivo (4, 5), we now show that in the absence of feeding-fasting cycles, liver and muscle clocks are not sufficient for systemic glucose metabolism, nor do they form a functional connection influencing local glucose handling or daily transcriptional rhythms in each tissue. However, the introduction of a daily feeding-fasting rhythm enables a synergistic state between liver and muscle clocks that leads to restoration of systemic glucose tolerance. These findings reveal limited autonomous capabilities of liver and muscle clocks and highlight the need for inter-organ clock communication for glucose homeostasis which involves at least two peripheral metabolic organs.

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Circadian transcriptome processing and analysis: a workflow for muscle stem cells

et al. 2023

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Circadian rhythms coordinate biological processes with Earth's 24‐h daily light/dark cycle. In the last years, efforts in the field of chronobiology have sought to understand the ways in which the circadian clock controls transcription across tissues and cells. This has been supported by the development of different bioinformatic approaches that allow the identification of 24‐h oscillating transcripts. This workflow aims to describe how to isolate muscle stem cells for RNA sequencing analysis from a typical circadian experiment and introduces bioinformatic tools suitable for the analysis of circadian transcriptomes.

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Integration of feeding behavior by the liver circadian clock reveals network dependency of metabolic rhythms

Abstract: The inner workings of the clock system rely on communicating signals between distal tissues to maintain daily metabolism.

Cited by 75 publications

References 119 publications

The central clock suffices to drive the majority of circulatory metabolic rhythms

The central clock suffices to drive the majority of circulatory metabolic rhythms

Interrogating Metabolic Interactions Between Skeletal Muscle and Liver Circadian Clocks In Vivo

Circadian transcriptome processing and analysis: a workflow for muscle stem cells

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