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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Levine, DC; Kuo, H-Y; Hong, H-K; Cedernaes, J; Hepler, C; Wright, AG; Sommars, MA; Kobayashi, Y; Marcheva, B; Gao, P; Ilkayeva, OR; Omura, C; Ramsey, KM; Newgard, CB; Barish, GD; Peek, CB; Chandel, NS; Mrksich, M; Bass, J

Published Date

  • December 2021

Published In

Volume / Issue

  • 3 / 12

Start / End Page

  • 1621 - 1632

PubMed ID

  • 34903884

Pubmed Central ID

  • PMC8688143

Electronic International Standard Serial Number (EISSN)

  • 2522-5812

Digital Object Identifier (DOI)

  • 10.1038/s42255-021-00498-1


  • eng

Conference Location

  • Germany