Time for Food: The Intimate Interplay between Nutrition, Metabolism, and the Circadian Clock

104

The molecular mechanisms underlying the events through which alterations in diurnal activities impinge on peripheral circadian clocks (PCCs), and reciprocally how the PCCs affect metabolism, thereby generating pathologies, are still poorly understood. Here, we deciphered how switching the diurnal feeding from the active to the rest phase, i.e., restricted feeding (RF), immediately creates a hypoinsulinemia during the active phase, which initiates a metabolic reprogramming by increasing FFA and glucagon levels. In turn, peroxisome proliferator-activated receptor alpha (PPARα) activation by free fatty acid (FFA), and cAMP response element-binding protein (CREB) activation by glucagon, lead to further metabolic alterations during the circadian active phase, as well as to aberrant activation of expression of the PCC components nuclear receptor subfamily 1, group D, member 1 (Nr1d1/RevErbα), Period (Per1 and Per2). Moreover, hypoinsulinemia leads to an increase in glycogen synthase kinase 3β (GSK3β) activity that, through phosphorylation, stabilizes and increases the level of the RevErbα protein during the active phase. This increase then leads to an untimely repression of expression of the genes containing a RORE DNA binding sequence (DBS), including the Bmal1 gene, thereby initiating in RF mice a 12-h PCC shift to which the CREB-mediated activation of Per1, Per2 by glucagon modestly contributes. We also show that the reported corticosterone extraproduction during the RF active phase reflects an adrenal aberrant activation of CREB signaling, which selectively delays the activation of the PPARα-RevErbα axis in muscle and heart and accounts for the retarded shift of their PCCs.shifted eating | shifted peripheral circadian clocks | metabolic alterations | RevErbα | PPARα P ioneering studies (1, 2) have established that switching the feeding time in mice from the "active" phase [dark period of the light-dark (L/D) cycle] to the "rest" phase (light period), i.e., restricted feeding (RF), overrides the suprachiasmatic nucleus (SCN) circadian clock (CC)-derived signals and acts as a "zeitgeber" for peripheral CCs (PCCs), leading to a 12-h shift in the time at which components of PCCs are expressed. Numerous studies have shown that under homeostatic conditions, the functions of PCCs and metabolism are tightly linked and that perturbations in their interactions leads to pathologies, e.g., obesity and metabolic syndrome (3-5).The identity of some of the molecular pathways that couple PCCs to metabolism are known (3-5), but it is largely unknown how environmental cues, e.g., altered feeding schedules, may directly perturb the expression of individual CC components (5-7), thereby leading to obesity and a metabolic syndrome-like pathology (5). Assuming that specific metabolic perturbations generated by switching the feeding time could selectively affect the time of expression of some of the CC core components, we looked for both metabolic and PCC alterations at early RF times. We report here a comprehensive temporal analysis, an...

Section: An Increased Glucagon Secretion Results In An Activation Of mentioning

confidence: 74%

mentioning

confidence: 99%

Shifting the feeding of mice to the rest phase creates metabolic alterations, which, on their own, shift the peripheral circadian clocks by 12 hours

Mukherji

Kobiita

Chambon

2015

104

“…In addition to SIRT1, other redox-sensing nuclear proteins are likely to be affected by intranuclear organization of NADH metabolism. Among these proteins, BMAL1 and NPAS2/CLOCK are β-HLH-PAS domain-containing transcription factors, which heterodimerize and drive the expression of circadian genes (54). This notion is relevant, because SIRT1 modulates circadian gene expression (6,9,19).…”

Section: Discussionmentioning

confidence: 99%

Spatial dynamics of SIRT1 and the subnuclear distribution of NADH species

Aguilar-Arnal

Ranjit

Stringari

et al. 2016

Self Cite

Sirtuin 1 (SIRT1) is an NAD + -dependent deacetylase that functions as metabolic sensor of cellular energy and modulates biochemical pathways in the adaptation to changes in the environment. SIRT1 substrates include histones and proteins related to enhancement of mitochondrial function as well as antioxidant protection. Fluctuations in intracellular NAD + levels regulate SIRT1 activity, but how SIRT1 enzymatic activity impacts on NAD + levels and its intracellular distribution remains unclear. Here, we show that SIRT1 determines the nuclear organization of protein-bound NADH. Using multiphoton microscopy in live cells, we show that free and bound NADH are compartmentalized inside of the nucleus, and its subnuclear distribution depends on SIRT1. Importantly, SIRT6, a chromatin-bound deacetylase of the same class, does not influence NADH nuclear localization. In addition, using fluorescence fluctuation spectroscopy in single living cells, we reveal that NAD + metabolism in the nucleus is linked to subnuclear dynamics of active SIRT1. These results reveal a connection between NAD + metabolism, NADH distribution, and SIRT1 activity in the nucleus of live cells and pave the way to decipher links between nuclear organization and metabolism.S irtuins (SIRTs) are a conserved family of deacetylases that target a variety of proteins located in virtually all cellular compartments (1). Deacetylation by SIRTs may control many functional aspects of target proteins (2). Because SIRT deacetylase activity depends on the energy carrier NAD + , these enzymes are thought to operate as cellular metabolic sensors. In addition, because histones are targeted by nuclear SIRT, these enzymes could link variations in cellular metabolism to chromatin function.There are seven mammalian SIRTs (SIRT1 to SIRT7) with distinct subcellular locations. SIRT2 is mainly cytoplasmic; SIRT3, SIRT4, and SIRT5 are found in the mitochondrial compartment; and SIRT1, SIRT6, and SIRT7 are located in the cell nucleus (1). In mammals, SIRT1 contributes to development and protects from metabolic and cardiovascular disease, neurodegeneration, and cancer (3). SIRT1 has been reported to promote healthy aging and regulate lifespan (4, 5). At the cellular level, SIRT1 regulates lipid and glucose homeostasis, apoptosis, DNA repair, and mitochondrial function. Variations in NAD + levels control SIRT1 activity (6-9), a relevant finding in the regulation of circadian rhythms (10). Circadian rhythms in NAD + levels have been observed (11,12), which lead to fluctuating SIRT1 deacetylase activity (9) that, in turn, results into cyclic acetylation of specific SIRT1 targets (6, 9, 13). SIRT1 and SIRT6 segregate circadian metabolism by driving transcription of a differential subset of circadian genes (14). SIRT6 is a chromatinbound protein that was first characterized as a regulator of genome stability (15). The other nuclear SIRT, SIRT7, appears to be highly localized in the nucleolus and possibly involved in Pol-I-dependent transcription (16), and it has been shown to regula...

“…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 clockwork with the metabolic state of the cell (6). During the last decades, efforts have been made to produce a comprehensive knowledge of the transcriptional regulation orchestrated by the circadian clock (7)(8)(9) and feeding rhythms (10,11).…”

mentioning

confidence: 99%

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

Atger

Gobet

Marquis

et al. 2015

217

287

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...