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

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 Rim Oh, Han Na Jung, Obin Kwon, Byung Soo Youn, Gi Hoon Son, Se Hee Min and Min-Seon Kim ()
Additional contact information
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
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
Min-Seon Kim: Asan Institute for Life Science

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37517-6

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