Circadian clock feedback cycle through NAMPT-Mediated NAD+ biosynthesis

Department of Medicine, Northwestern University Feinberg School of Medicine, 2200 Campus Drive, Evanston, IL 60208-3500, USA.
Science (Impact Factor: 33.61). 04/2009; 324(5927):651-4. DOI: 10.1126/science.1171641
Source: PubMed


The circadian clock is encoded by a transcription-translation feedback loop that synchronizes behavior and metabolism with the light-dark cycle. Here we report that both the rate-limiting enzyme in mammalian nicotinamide adenine dinucleotide (NAD+) biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT), and levels of NAD+ display circadian oscillations that are regulated by the core clock machinery in mice. Inhibition of NAMPT promotes oscillation of the clock gene Per2 by releasing CLOCK:BMAL1 from suppression by SIRT1. In turn, the circadian transcription factor CLOCK binds to and up-regulates Nampt, thus completing a feedback loop involving NAMPT/NAD+ and SIRT1/CLOCK:BMAL1.

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Available from: Jun Yoshino, Sep 30, 2015
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    • "However, NAD + levels can change up to $2-fold in response to diverse physiological stimuli. For example, NAD + levels increase in response to energy stresses, such as glucose deprivation (Fulco et al., 2008), fasting (Cantó et al., 2010; Rodgers et al., 2005), CR (Chen et al., 2008), and exercise (Cantó et al., 2010; Costford et al., 2010), and fluctuate in a circadian fashion (Nakahata et al., 2009; Ramsey et al., 2009). So, where and how do these changes take place in the cell? "
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    ABSTRACT: NAD(+) has emerged as a vital cofactor that can rewire metabolism, activate sirtuins, and maintain mitochondrial fitness through mechanisms such as the mitochondrial unfolded protein response. This improved understanding of NAD(+) metabolism revived interest in NAD(+)-boosting strategies to manage a wide spectrum of diseases, ranging from diabetes to cancer. In this review, we summarize how NAD(+) metabolism links energy status with adaptive cellular and organismal responses and how this knowledge can be therapeutically exploited. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell metabolism 06/2015; DOI:10.1016/j.cmet.2015.05.023 · 17.57 Impact Factor
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    • "Increased SIRT1 activity enhances mitochondrial biogenesis, suppresses inflammation, prevents apoptosis following DNA damage, and generally promotes cell survival in degenerative conditions (Banks et al., 2008; Chen et al., 2005; Jiang et al., 2012; Kang et al., 2009; Kim et al., 2007a; Pfluger et al., 2008; Yuan et al., 2011). The deacetylase activity of SIRT1 is limited by cellular levels of NAD + , which fluctuate in response to changing rates of NAD + biosynthesis and consumption (Houtkooper et al., 2010; Nakahata et al., 2009; Ramsey et al., 2009; Revollo et al., 2004). Several protein regulators of SIRT1 also have been identified, including the positive regulators AROS (active regulator of SIRT1) and Necdin (Hasegawa and Yoshikawa, 2008; Kim et al., 2008) and an inhibitory protein DBC1 (deleted in breast cancer 1) (Kim et al., 2008; Zhao et al., 2008). "
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    ABSTRACT: The NAD(+)-dependent protein deacetylase SIRT1 regulates energy metabolism, responses to stress, and aging by deacetylating many different proteins, including histones and transcription factors. The mechanisms controlling SIRT1 enzymatic activity are complex and incompletely characterized, yet essential for understanding how to develop therapeutics that target SIRT1. Here, we demonstrate that the N-terminal domain of SIRT1 (NTERM) can trans-activate deacetylation activity by physically interacting with endogenous SIRT1 and promoting its association with the deacetylation substrate NF-κB p65. Two motifs within the NTERM domain contribute to activation of SIRT1-dependent activities, and expression of one of these motifs in mice is sufficient to lower fasting glucose levels and improve glucose tolerance in a manner similar to overexpression of SIRT1. Our results provide insights into the regulation of SIRT1 activity and a rationale for pharmacological control of SIRT1-dependent activities. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 03/2015; 10(10). DOI:10.1016/j.celrep.2015.02.036 · 8.36 Impact Factor
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    • "To be finely tuned, the molecular clock constantly receives feedback from the metabolic signaling in the cell. For example, the CLOCK/BMAL1 complex is known to be regulated by the redox status of the cell reflected by the NAD(P) + /NAD(P)H ratio, which is rhythmic [14]. Indeed , NAD + and NADH, respectively, inhibits and stimulates CLOCK/BMAL1 binding capacity to E-Boxes [15]. "
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    ABSTRACT: Proteomic technologies using mass spectrometry (MS) offer new perspectives in circadian biology, in particular the possibility to study post-translational modifications (PTMs). To date, only very few studies have been carried out to decipher the rhythmicity of protein expression in mammals with large-scale proteomics. Although signaling has been shown to be of high relevance, comprehensive characterization studies of PTMs are even more rare. This review aims at describing the actual landscape of circadian proteomics and the opportunities and challenges appearing on the horizon. Emphasis was given to signaling processes for their role in metabolic heath as regulated by circadian clocks and environmental factors. Those signaling processes are expected to be better and more deeply characterized in the coming years with proteomics.This article is protected by copyright. All rights reserved
    Proteomics 01/2015; 15(2-3). DOI:10.1002/pmic.201400187 · 3.81 Impact Factor
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