Differential regulation of oxidative stress, microbiota-derived, and energy metabolites in the mouse brain during sleep

J Cereb Blood Flow Metab. 2021 Dec;41(12):3324-3338. doi: 10.1177/0271678X211033358. Epub 2021 Jul 22.


Sleep has evolved as a universal core function to allow for restorative biological processes. Detailed knowledge of metabolic changes necessary for the sleep state in the brain is missing. Herein, we have performed an in-depth metabolic analysis of four mouse brain regions and uncovered region-specific circadian variations. Metabolites linked to oxidative stress were altered during sleep including acylcarnitines, hydroxylated fatty acids, phenolic compounds, and thiol-containing metabolites. These findings provide molecular evidence of a significant metabolic shift of the brain energy metabolism. Specific alterations were observed for brain metabolites that have previously not been associated with a circadian function including the microbiome-derived metabolite ergothioneine that suggests a regulatory function. The pseudopeptide β-citryl-glutamate has been linked to brain development and we have now discovered a previously unknown regioisomer. These metabolites altered by the circadian rhythm represent the foundation for hypothesis-driven studies of the underlying metabolic processes and their function.

Keywords: Brain metabolism; energy metabolism; gut-brain axis; metabolomics; oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism*
  • Energy Metabolism*
  • Male
  • Mice
  • Microbiota*
  • Oxidative Stress*
  • Sleep*