Comprehensive quantification of metabolic flux during acute cold stress in mice

Marc R. Bornstein, Michael D. Neinast, Xianfeng Zeng, Qingwei Chu, Jessie Axsom, Chelsea Thorsheim, Kristina Li, Megan C. Blair, Joshua D. Rabinowitz, Zoltan Arany

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Cold-induced thermogenesis (CIT) is widely studied as a potential avenue to treat obesity, but a thorough understanding of the metabolic changes driving CIT is lacking. Here, we present a comprehensive and quantitative analysis of the metabolic response to acute cold exposure, leveraging metabolomic profiling and minimally perturbative isotope tracing studies in unanesthetized mice. During cold exposure, brown adipose tissue (BAT) primarily fueled the tricarboxylic acid (TCA) cycle with fat in fasted mice and glucose in fed mice, underscoring BAT's metabolic flexibility. BAT minimally used branched-chain amino acids or ketones, which were instead avidly consumed by muscle during cold exposure. Surprisingly, isotopic labeling analyses revealed that BAT uses glucose largely for TCA anaplerosis via pyruvate carboxylation. Finally, we find that cold-induced hepatic gluconeogenesis is critical for CIT during fasting, demonstrating a key functional role for glucose metabolism. Together, these findings provide a detailed map of the metabolic rewiring driving acute CIT.

Original languageEnglish (US)
Pages (from-to)2077-2092.e6
JournalCell Metabolism
Volume35
Issue number11
DOIs
StatePublished - Nov 7 2023

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Physiology
  • Cell Biology

Keywords

  • FBP1
  • brown adipose tissue
  • cold exposure
  • flux
  • gluconeogenesis
  • glucose
  • metabolomics
  • pyruvate carboxylase
  • thermogenesis

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