NADH inhibition of SIRT1 links energy state to transcription during time-restricted feeding

Daniel C. Levine, Hsin Yu Kuo, Hee Kyung Hong, Jonathan Cedernaes, Chelsea Hepler, Alexandra G. Wright, Meredith A. Sommars, Yumiko Kobayashi, Biliana Marcheva, Peng Gao, Olga R. Ilkayeva, Chiaki Omura, Kathryn M. Ramsey, Christopher B. Newgard, Grant D. Barish, Clara Bien Peek, Navdeep S. Chandel, Milan Mrksich, Joseph Bass*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

In mammals, circadian rhythms are entrained to the light cycle and drive daily oscillations in levels of NAD+, a cosubstrate of the class III histone deacetylase sirtuin 1 (SIRT1) that associates with clock transcription factors. Although NAD+ also participates in redox reactions, the extent to which NAD(H) couples nutrient state with circadian transcriptional cycles remains unknown. Here we show that nocturnal animals subjected to time-restricted feeding of a calorie-restricted diet (TRF-CR) only during night-time display reduced body temperature and elevated hepatic NADH during daytime. Genetic uncoupling of nutrient state from NADH redox state through transduction of the water-forming NADH oxidase from Lactobacillus brevis (LbNOX) increases daytime body temperature and blood and liver acyl-carnitines. LbNOX expression in TRF-CR mice induces oxidative gene networks controlled by brain and muscle Arnt-like protein 1 (BMAL1) and peroxisome proliferator-activated receptor alpha (PPARα) and suppresses amino acid catabolic pathways. Enzymatic analyses reveal that NADH inhibits SIRT1 in vitro, corresponding with reduced deacetylation of SIRT1 substrates during TRF-CR in vivo. Remarkably, Sirt1 liver nullizygous animals subjected to TRF-CR display persistent hypothermia even when NADH is oxidized by LbNOX. Our findings reveal that the hepatic NADH cycle links nutrient state to whole-body energetics through the rhythmic regulation of SIRT1.

Original languageEnglish (US)
Pages (from-to)1621-1632
Number of pages12
JournalNature Metabolism
Volume3
Issue number12
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Cell Biology
  • Physiology (medical)

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