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Circulating blood eNAMPT drives the circadian rhythms in locomotor activity and energy expenditure

Author

Listed:
  • Jae Woo Park

    (University of Ulsan College of Medicine)

  • Eun Roh

    (Hallym University Sacred Heart Hospital)

  • Gil Myoung Kang

    (Asan Institute for Life Science)

  • So Young Gil

    (Asan Institute for Life Science)

  • Hyun Kyong Kim

    (Asan Institute for Life Science)

  • Chan Hee Lee

    (Hallym University)

  • Won Hee Jang

    (University of Ulsan College of Medicine)

  • Se Eun Park

    (University of Ulsan College of Medicine)

  • Sang Yun Moon

    (University of Ulsan College of Medicine)

  • Seong Jun Kim

    (University of Ulsan College of Medicine)

  • So Yeon Jeong

    (University of Ulsan College of Medicine)

  • Chae Beom Park

    (University of Ulsan College of Medicine)

  • Hyo Sun Lim

    (University of Ulsan College of Medicine)

  • Yu Rim Oh

    (University of Ulsan College of Medicine)

  • Han Na Jung

    (Asan Institute for Life Science
    University of Ulsan College of Medicine)

  • Obin Kwon

    (Seoul National University College of Medicine)

  • Byung Soo Youn

    (OsteoNeuroGen)

  • Gi Hoon Son

    (Korea University College of Medicine)

  • Se Hee Min

    (Asan Institute for Life Science
    University of Ulsan College of Medicine)

  • Min-Seon Kim

    (Asan Institute for Life Science
    University of Ulsan College of Medicine)

Abstract

Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor of critical enzymes including protein deacetylase sirtuins/SIRTs and its levels in mammalian cells rely on the nicotinamide phosphoribosyltransferase (NAMPT)-mediated salvage pathway. Intracellular NAMPT (iNAMPT) is secreted and found in the blood as extracellular NAMPT (eNAMPT). In the liver, the iNAMPT−NAD+ axis oscillates in a circadian manner and regulates the cellular clockwork. Here we show that the hypothalamic NAD+ levels show a distinct circadian fluctuation with a nocturnal rise in lean mice. This rhythm is in phase with that of plasma eNAMPT levels but not with that of hypothalamic iNAMPT levels. Chemical and genetic blockade of eNAMPT profoundly inhibit the nighttime elevations in hypothalamic NAD+ levels as well as those in locomotor activity (LMA) and energy expenditure (EE). Conversely, elevation of plasma eNAMPT by NAMPT administration increases hypothalamic NAD+ levels and stimulates LMA and EE via the hypothalamic NAD+−SIRT−FOXO1−melanocortin pathway. Notably, obese animals display a markedly blunted circadian oscillation in blood eNAMPT−hypothalamic NAD+−FOXO1 axis as well as LMA and EE. Our findings indicate that the eNAMPT regulation of hypothalamic NAD+ biosynthesis underlies circadian physiology and that this system can be significantly disrupted by obesity.

Suggested Citation

  • Jae Woo Park & Eun Roh & Gil Myoung Kang & So Young Gil & Hyun Kyong Kim & Chan Hee Lee & Won Hee Jang & Se Eun Park & Sang Yun Moon & Seong Jun Kim & So Yeon Jeong & Chae Beom Park & Hyo Sun Lim & Yu, 2023. "Circulating blood eNAMPT drives the circadian rhythms in locomotor activity and energy expenditure," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37517-6
    DOI: 10.1038/s41467-023-37517-6
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    References listed on IDEAS

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    1. Frédéric Picard & Martin Kurtev & Namjin Chung & Acharawan Topark-Ngarm & Thanaset Senawong & Rita Machado de Oliveira & Mark Leid & Michael W. McBurney & Leonard Guarente, 2004. "Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ," Nature, Nature, vol. 429(6993), pages 771-776, June.
    2. Frédéric Picard & Martin Kurtev & Namjin Chung & Acharawan Topark-Ngarm & Thanaset Senawong & Rita Machado de Oliveira & Mark Leid & Michael W. McBurney & Leonard Guarente, 2004. "Correction: Corrigendum: Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ," Nature, Nature, vol. 430(7002), pages 921-921, August.
    3. Joseph T. Rodgers & Carlos Lerin & Wilhelm Haas & Steven P. Gygi & Bruce M. Spiegelman & Pere Puigserver, 2005. "Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1," Nature, Nature, vol. 434(7029), pages 113-118, March.
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