Metabolic clock generates nutrient anticipation rhythms in mTOR signaling

Khapre, Rohini V.; Patel, Sonal; Kondratova, Anna A.; Chaudhary, Amol; Velingkaar, Nikkhil; Antoch, Marina P.; Kondratov, Roman V.

doi:10.18632/aging.100686

Cited by 55 publications

(48 citation statements)

References 15 publications

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“…Moreover, some of the pathways represented among the genes oscillating only in the Arntl KO mice were linked to translation and ribosome biogenesis (Supplemental Table S2). The rhythmic activation of TORC1 in Arntl KO mouse liver may seem contradictory to previous results, which have shown liver TORC1 activation to be under circadian clock control; rhythmicity was maintained under constant darkness and under conditions of starvation (Jouffe et al 2013), and translation and ribosome biogenesis was dependent on the circadian clock in various organisms (Dong et al 2008;Piques et al 2009;Xu et al 2011;Jouffe et al 2013;Khapre et al 2014). More recent results, however, have pointed to a pivotal role of feeding rhythms in rhythmic translation of TOP mRNAs (Atger et al 2015).…”

Section: Org Downloaded Fromcontrasting

confidence: 69%

Diurnal regulation of RNA polymerase III transcription is under the control of both the feeding–fasting response and the circadian clock

et al. 2017

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RNA polymerase III (Pol III) synthesizes short noncoding RNAs, many of which are essential for translation. Accordingly, Pol III activity is tightly regulated with cell growth and proliferation by factors such as MYC, RB1, TRP53, and MAF1. MAF1 is a repressor of Pol III transcription whose activity is controlled by phosphorylation; in particular, it is inactivated through phosphorylation by the TORC1 kinase complex, a sensor of nutrient availability. Pol III regulation is thus sensitive to environmental cues, yet a diurnal profile of Pol III transcription activity is so far lacking. Here, we first use gene expression arrays to measure mRNA accumulation during the diurnal cycle in the livers of (1) wild-type mice, (2) arrhythmic Arntl knockout mice, (3) mice fed at regular intervals during both night and day, and (4) mice lacking the Maf1 gene, and so provide a comprehensive view of the changes in cyclic mRNA accumulation occurring in these different systems. We then show that Pol III occupancy of its target genes rises before the onset of the night, stays high during the night, when mice normally ingest food and when translation is known to be increased, and decreases in daytime. Whereas higher Pol III occupancy during the night reflects a MAF1-dependent response to feeding, the rise of Pol III occupancy before the onset of the night reflects a circadian clock-dependent response. Thus, Pol III transcription during the diurnal cycle is regulated both in response to nutrients and by the circadian clock, which allows anticipatory Pol III transcription.

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Section: Org Downloaded Fromcontrasting

confidence: 69%

Diurnal regulation of RNA polymerase III transcription is under the control of both the feeding–fasting response and the circadian clock

et al. 2017

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“…Indeed, it has been shown that the TORC1 pathway is rhythmically activated in mouse liver (12,49), hippocampus (50), and SCN (51), influencing in this way rhythmic ribosome biogenesis (12) or light response and circadian behavior (52,53). Moreover, the circadian clock, in coordination with feeding rhythms, seems to play a modulating role in this activation (12,54,55). Although we confirmed the rhythmic activation of the TORC1 pathway in mouse liver, it seemed that Bmal1 deletion had no effect on the rhythms of TOP genes translation; in particular, the amplitudes were indistinguishable (Fig.…”

Section: Translation Efficiency Is Regulated During the Diurnal Cyclementioning

confidence: 99%

Circadian and feeding rhythms differentially affect rhythmic mRNA transcription and translation in mouse liver

Atger

Gobet

Marquis

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

217

287

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Diurnal oscillations of gene expression are a hallmark of rhythmic physiology across most living organisms. Such oscillations are controlled by the interplay between the circadian clock and feeding rhythms. Although rhythmic mRNA accumulation has been extensively studied, comparatively less is known about their transcription and translation. Here, we quantified simultaneously temporal transcription, accumulation, and translation of mouse liver mRNAs under physiological light-dark conditions and ad libitum or night-restricted feeding in WT and brain and muscle Arnt-like 1 (Bmal1)-deficient animals. We found that rhythmic transcription predominantly drives rhythmic mRNA accumulation and translation for a majority of genes. Comparison of wild-type and Bmal1 KO mice shows that circadian clock and feeding rhythms have broad impact on rhythmic gene expression, Bmal1 deletion affecting surprisingly both transcriptional and posttranscriptional levels. Translation efficiency is differentially regulated during the diurnal cycle for genes with 5′-Terminal Oligo Pyrimidine tract (5′-TOP) sequences and for genes involved in mitochondrial activity, many harboring a Translation Initiator of Short 5′-UTR (TISU) motif. The increased translation efficiency of 5′-TOP and TISU genes is mainly driven by feeding rhythms but Bmal1 deletion also affects amplitude and phase of translation, including TISU genes. Together this study emphasizes the complex interconnections between circadian and feeding rhythms at several steps ultimately determining rhythmic gene expression and translation.circadian rhythms | ribosome profiling | mRNA translation | 5′-TOP sequences | TISU motifs L iving organisms on Earth are subjected to light-dark cycles caused by rotation of the Earth around the sun. To anticipate these changes, virtually all organisms have acquired a circadian timing system during evolution that allows a better adaptation to their environment. As a consequence, most aspects of their physiology are orchestrated in a rhythmic way by the circadian clock (from the Latin circa diem, meaning "about a day"), an endogenous and autonomous oscillator with a period of around 24 h (1, 2). Not surprisingly, perturbations of this clock in mammals lead to pathologies including psychiatric, metabolic, and vascular disorders (1,3,4). At the organismal scale, the oscillatory clockwork is organized in a hierarchal manner. Within the suprachiasmatic nuclei (SCN) of the hypothalamus, the "master clock" receives light input via the retina and communicates timing signals to "enslave" oscillators in peripheral organs (1, 2). The molecular oscillator consists of interconnected transcriptional and translational feedback loops, in which multiple layers of control, including temporal posttranscriptional and posttranslational regulation, play important roles (5). These additional layers of regulation are largely coordinated by systemic cues originating from circadian clock and/or feeding-coordinated rhythmic metabolism, allowing the adjustment of the molecular clo...

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“…Activity of the mTOR pathway in the suprachiasmatic nucleus (SCN) is stimulated by light and mutations in the mTOR kinase itself or in the mTOR effector protein eukaryotic initiation factor 4E binding protein (4E-BP) regulate circadian timing(Cao et al, 2011; Cao et al, 2015; Cao et al, 2008; Cao et al, 2010; Cao et al, 2013). Interestingly, mTOR pathway activity demonstrates circadian oscillations(Cao et al, 2013; Cornu et al, 2014; Jouffe et al, 2013; Khapre et al, 2014; Lipton et al, 2015). Heterozygous mutations of either mTOR in mice or Tsc1/2 orthologs in Drosophila clock neurons can result in circadian arrhythmia, together suggesting that a delicate balance of mTOR signaling is required for optimizing circadian synchrony(Cao et al, 2013; Zheng and Sehgal, 2010).…”

Section: Introductionmentioning

confidence: 99%

Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy

Lipton¹,

Boyle²,

Yuan³

et al. 2017

Cell Reports

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SUMMARY Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder characterized by mutations in either the TSC1 or TSC2 genes whose products form a critical inhibitor of the mechanistic target of rapamycin (mTOR). Loss of TSC1/2 gene function renders an mTOR-overactivated state. Clinically, TSC manifests with epilepsy, intellectual disability, autism, and sleep dysfunction. Here we report that mouse models of TSC have abnormal circadian rhythms. We show that mTOR regulates the proteostasis of the core clock protein BMAL1, affecting its translation, degradation, and subcellular localization. This results in elevated levels of BMAL1 and a dysfunctional clock that displays abnormal timekeeping in constant conditions and exaggerated responses to phase resetting. Genetically lowering the dose of BMAL1 rescues circadian behavioral phenotypes in TSC mouse models. These findings indicate that BMAL1 deregulation is a feature of the mTOR-activated state and suggest a molecular mechanism for mitigating circadian phenotypes in a neurodevelopmental disorder.

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Metabolic clock generates nutrient anticipation rhythms in mTOR signaling

Cited by 55 publications

References 15 publications

Diurnal regulation of RNA polymerase III transcription is under the control of both the feeding–fasting response and the circadian clock

Diurnal regulation of RNA polymerase III transcription is under the control of both the feeding–fasting response and the circadian clock

Circadian and feeding rhythms differentially affect rhythmic mRNA transcription and translation in mouse liver

Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy

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