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 53 publications

(63 citation statements)

References 119 publications

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“…Peripheral clocks respond differentially to entraining signals, such as feeding and light, implying tissue-specific mechanisms that recognize or even suppress such signals ( 10 , 36 ). Interestingly, recent evidence suggests that the liver and muscle clocks are able to buffer the response of specific peripheral clocks to feeding-related signals ( 9, 10 ), highlighting a potential role for inter-peripheral clock communication in regulating how a tissue responds to brain clock signals. Here, we expand this concept, implicating the local clock as both a transducer and repressor of systemic signals.…”

Section: Discussionmentioning

confidence: 99%

Epidermal clock integration and gating of brain signals guarantees skin homeostasis

Mortimer

Zinna

Laudanna

et al. 2022

Preprint

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In mammals, an integrated network of molecular oscillators drives daily rhythms of tissue-specific homeostatic processes. This network is required for maintaining health and can be compromised by physiological aging, disease, and lifestyle choices. However, critical elements and properties of this network, such as key signaling nodes, the mechanisms of communication, and how physiological coherence is maintained, remain undefined. To dissect this system, we constructed a minimal clock network comprising only two nodes: the peripheral epidermal clock and the central brain clock. We observe that communication between the brain and epidermal clock is sufficient for wild-type core clock activity and specific homeostatic processes in the epidermis, yet full daily physiology requires input from other clock nodes. Moreover, our results show that the epidermal clock selectively suppresses or interprets systemic signals to ensure coherence of specific homeostatic processes, such as the cell cycle, identifying a previously-unrecognized gatekeeper role for this peripheral clock. This novel approach for dissecting a tissue's daily physiology reveals the specific rhythmic processes controlled by secondary tissues and niche components, opening the possibility of identifying the sources of age-related circadian disruption and potentially developing therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Epidermal clock integration and gating of brain signals guarantees skin homeostasis

Mortimer

Zinna

Laudanna

et al. 2022

Preprint

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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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“…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%

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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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 53 publications

References 119 publications

Epidermal clock integration and gating of brain signals guarantees skin homeostasis

Epidermal clock integration and gating of brain signals guarantees skin homeostasis

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

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

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