Circadian Clock Feedback Cycle Through NAMPT-Mediated NAD+ Biosynthesis

By K. Ramsey, Jun Yoshino, Cynthia S. Brace, Dana Abrassart, Yumiko Kobayashi, Biliana Marcheva, Heekyung Hong, Jason L. Chong, Ethan D. Buhr, Choogon Lee and 3 more. Science, 2009

1,093 citations recorded by the source corpus.

Circadian Oscillations The 24-hour day-night cycle plays an important role in mammalian physiology and behavior and, as most travelers are well aware, there is an intimate link between our in-built circadian clocks and metabolic rhythms. This link is in part forged by the protein deacetylase SIRT1, which regulates the clock's molecular circuitry. SIRT1 uses as a cofactor the cellular metabolite NAD+, which is synthesized through a salvage pathway that includes the enzyme nicotinamide phosphoribosyltransferase (NAMPT) (see the Perspective by Wijnen). Ramsey et al. (p. 651; published online 19 March) and Nakahata et al. (p. 654, published online 12 March) now show that NAMPT and NAD+ levels oscillate during the daily 24-hour cycle and that this oscillation is regulated by the circadian clock. Furthermore, the oscillations in NAD+ modulate the activity of SIRT1 feeding back into the circadian clock. A transcriptional-enzymatic feedback loop controls interactions between metabolism and circadian rhythms in mouse cells. 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.

Subfields: Cellular and Molecular Neuroscience, Endocrine and Autonomic Systems, Plant Science

View Paper: https://www.semanticscholar.org/paper/59b6c19acdacc427081986e9a3eb17f5e68ae956

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Citations in the corpus

MYC on the Path to Cancer (2012, background): “The metabolic gene NAMPT, which is involved in NAD synthesis, is a circadian gene responsive to Clock/Bmal in the liver (Ramsey et al., 2009).”
Fasting, circadian rhythms, and time restricted feeding in healthy lifespan (2016, background): “1054 Cell Metabolism 23, June 14, 2016 also affect the circadian clock (Asher et al., 2008; Masri and Sassone-Corsi, 2013; Nakahata et al., 2008, 2009; Ramsey et al., 2009).”
Time restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high fat diet (2012, positive): “Several genes encoding enzymes of purine and pyrimidine biosynthesis and nucleotide salvage pathways are the direct targets of the circadian activator BMAL1 (Uridine monophosphate synthase [Umps] and Thymidine kinase 1 [Tk1]) and/or exhibit rhythmic expression patterns (phosphoribosylpyrophosphate s”
Reprogramming of the Circadian Clock by Nutritional Challenge (2013, positive): “Accumulating evidence supports the notion that oscillating metabolites are also important for the maintenance of cellular rhythmicity (Dallmann et al., 2012; Eckel-Mahan et al., 2012; Nakahata et al., 2009; O’Neill et al., 2011; Ramsey et al., 2009) but the extent to which the circadian metabolome i”
NAD+ intermediates: The biology and therapeutic potential of NMN and NR (2017, positive): “…a critical metabolic regulator in many different organs and tissues in response to changes in NAD+ availability, whereas NAMPT functions as a pacemaker that produces circadian oscillatory NAD+ production (Nakahata et al., 2009; Ramsey et al., 2009) and fine-tunes SIRT1 activity at a systemic level.”
Influence of Metabolism on Epigenetics and Disease (2013, positive): “When NAD+ levels were measured in liver tissue of wild-type mice, two ultradian sets of peaks and troughs of NAD+ abundance were observed per 24 hr cycle (Ramsey et al., 2009).”
SIRT1 and other sirtuins in Metabolism (2013, background): “AMPK activates SIRT1 by up-regulating the gene encoding the NAD+ synthetic enzyme, NAMPT [78,79].”