Circadian and Feeding Rhythms Orchestrate the Diurnal Liver Acetylome

Mauvoisin, Daniel; Atger, Florian; Dayon, Loı̈c; Galindo, Antonio Núñez; Wang, Jingkui; Martín, Eva; Silva, Laetitia Da; Montoliu, Ivan; Collino, Sebastiano; Martin, François-Pierre; Ratajczak, Joanna; Cantó, Carles; Kussmann, Martin; Naef, Félix; Gachon, Frédéric

doi:10.1016/j.celrep.2017.07.065

Cited by 75 publications

(67 citation statements)

References 83 publications

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“…None of these residues belong to the binding sites for 2‐oxoglutarate/glutamate, ADP or GTP. On the other hand, acetylation of the GDH residues K187 (close to the active site, Figure a) and K503 (GTP‐binding, Figure b), which undergo the diurnal changes in brain GDH (Figure c and d), are not changed in liver GDH (Mauvoisin et al, ). The different sets of the brain and liver GDH residues undergoing acetylation in diurnal manner, imply the tissue‐specific diurnal changes in the regulatory properties of GDH.…”

Section: Discussionmentioning

confidence: 99%

Diurnal regulation of the function of the rat brain glutamate dehydrogenase by acetylation and its dependence on thiamine administration

Aleshin

Mkrtchyan

Kaehne

et al. 2020

Journal of Neurochemistry

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Glutamate dehydrogenase (GDH) is essential for the brain function and highly regulated, according to its role in metabolism of the major excitatory neurotransmitter glutamate. Here we show a diurnal pattern of the GDH acetylation in rat brain, associated with specific regulation of GDH function. Mornings the acetylation levels of K84 (near the ADP site), K187 (near the active site), and K503 (GTP‐binding) are highly correlated. Evenings the acetylation levels of K187 and K503 decrease, and the correlations disappear. These daily variations in the acetylation adjust the GDH responses to the enzyme regulators. The adjustment is changed when the acetylation of K187 and K503 shows no diurnal variations, as in the rats after a high dose of thiamine. The regulation of GDH function by acetylation is confirmed in a model system, where incubation of the rat brain GDH with acetyl‐CoA changes the enzyme responses to GTP and ADP, decreasing the activity at subsaturating concentrations of substrates. Thus, the GDH acetylation may support cerebral homeostasis, stabilizing the enzyme function during diurnal oscillations of the brain metabolome. Daytime and thiamine interact upon the (de)acetylation of GDH in vitro. Evenings the acetylation of GDH from control animals increases both IC50GTP and EC50ADP. Mornings the acetylation of GDH from thiamine‐treated animals increases the enzyme IC50GTP. Molecular mechanisms of the GDH regulation by acetylation of specific residues are proposed. For the first time, diurnal and thiamine‐dependent changes in the allosteric regulation of the brain GDH due to the enzyme acetylation are shown.

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Section: Discussionmentioning

confidence: 99%

Diurnal regulation of the function of the rat brain glutamate dehydrogenase by acetylation and its dependence on thiamine administration

Aleshin

Mkrtchyan

Kaehne

et al. 2020

Journal of Neurochemistry

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“…Given that Crat in AgRP neurons is required for metabolic flexibility and peripheral nutrient partitioning, it is tempting to speculate that the metabolic processing of incoming nutrients via Crat is a key component of the FEO. There is evidence to support this claim because feeding time influences metabolism (30)(31)(32) and circadian cycles influence mitochondrial rate-limiting enzymes and nutrient utilization (33). In a proteomic screen of AgRP neurons from WT and KO mice, we observed numerous differences in mitochondrial enzymes, NAD+-regulating enzymes, and differences in protein acetylation (17), all of which affect NAD+ bioavailability and modulate mitochondrial oxidative function across cycles of food deprivation and feeding (34).…”

Section: Discussionmentioning

confidence: 99%

Carnitine acetyltransferase (Crat) in hunger‐sensing AgRP neurons permits adaptation to calorie restriction

et al. 2018

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Hunger-sensing agouti-related peptide (AgRP) neurons ensure survival by adapting metabolism and behavior to low caloric environments. This adaption is accomplished by consolidating food intake, suppressing energy expenditure, and maximizing fat storage (nutrient partitioning) for energy preservation. The intracellular mechanisms responsible are unknown. Here we report that AgRP carnitine acetyltransferase (Crat) knockout (KO) mice exhibited increased fatty acid utilization and greater fat loss after 9 d of calorie restriction (CR). No differences were seen in mice with ad libitum food intake. Eleven days ad libitum feeding after CR resulted in greater food intake, rebound weight gain, and adiposity in AgRP Crat KO mice compared with wild-type controls, as KO mice act to restore pre-CR fat mass. Collectively, this study highlights the importance of Crat in AgRP neurons to regulate nutrient partitioning and fat mass during chronically reduced caloric intake. The increased food intake, body weight gain, and adiposity in KO mice after CR also highlights the detrimental and persistent metabolic consequence of impaired substrate utilization associated with CR. This finding may have significant implications for postdieting weight management in patients with metabolic diseases.-Reichenbach, A., Stark, R., Mequinion, M., Lockie, S. H., Lemus, M. B., Mynatt, R. L., Luquet, S., Andrews, Z. B. Carnitine acetyltransferase (Crat) in hunger-sensing AgRP neurons permits adaptation to calorie restriction.

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“…The rhythmicity that is observable at the proteomic level is expected to reflect significant contributions from protein synthesis, protein degradation and protein secretion, all of which could in principle have a time of day-dependent component. Diurnal patterns of post-translational protein 115 modifications, such as phosphorylations [25,26] and acetylations [27], play roles in the complex interplay between the clock and the proteome as well.…”

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confidence: 99%

Emerging Roles of Translational Control in Circadian Timekeeping

Castelo-Szekely

Gatfield

2020

Journal of Molecular Biology

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A large part of mammalian physiology and behaviour shows regular daily variations. This temporal organisation is driven by the activity of an endogenous circadian clock, whose molecular basis consists of diurnal waves in gene expression. Circadian transcription is the major driver of these rhythms, yet post-transcriptional mechanisms, some of which occur in response to systemic cues and in a tissue-specific fashion, have central roles in ultimately establishing the oscillatory gene expression programme as well. Regulatory control that occurs at the level of translation is emerging as an important player in the generation and modulation of protein accumulation rhythms. As a mechanism, translation lies at a privileged position to integrate genetically encoded rhythmic signals with other, external and internal stimuli, including nutrient-derived cues. In this review, we summarise our current knowledge of how diurnal control of translation affects both bulk protein levels and gene-specific protein biosynthesis. We discuss mechanisms of regulation, in particular with regard to the complex interplay between circadian cycles and feeding/fasting cycles, as well as emerging roles for upstream open reading frames (uORFs) in clock control. cyanobacterial clocks can operate in the absence of any transcription at all and that self-sustained rhythmic phosphorylation of the essential clock component KaiC even occurs in vitro using recom-2 binant clock proteins and ATP [4]. Transcription-independent molecular rhythms have also been observed in human erythrocytes. In these naturally nucleus-free cells, antioxidant proteins known as peroxiredoxins undergo changes in their redox status, which show self-sustained, entrainable, and 35 temperature-compensated 24-hour periodicity in the absence of transcription and translation [5]. In the wake of such surprising discoveries (and as a consequence of the technical advances made in the fields of high-throughput nucleic acid sequencing and proteomics), the longstanding concept which places daily changes in transcriptional activity at the heart of rhythmic gene expression was revisited as well. A more nuanced picture has arisen that accords a significant role to post-transcriptional 40 mechanisms in the generation of rhythmic clock outputs in mammals. Furthermore, it has become clear that a significant proportion of RNA and protein oscillations is not necessarily a direct output of the local, cellular clock, but rather driven by systemic cues, in particular by signals related to feeding.This review aims at presenting and discussing our current knowledge of how one of the implicated 45 post-transcriptional mechanism, i.e. translation, can generate, modulate, and sustain circadian rhythms. Our main focus will lie on the mammalian circadian system. Before we delve into the details, however, we shall take this opportunity for a brief digression into findings from two of the more exotic organisms that have been used in circadian clock research, namely green algae and marine dinoflagellates. It i...

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Circadian and Feeding Rhythms Orchestrate the Diurnal Liver Acetylome

Cited by 75 publications

References 83 publications

Diurnal regulation of the function of the rat brain glutamate dehydrogenase by acetylation and its dependence on thiamine administration

Diurnal regulation of the function of the rat brain glutamate dehydrogenase by acetylation and its dependence on thiamine administration

Carnitine acetyltransferase (Crat) in hunger‐sensing AgRP neurons permits adaptation to calorie restriction

Emerging Roles of Translational Control in Circadian Timekeeping

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