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Su Myung Jung1,4, Will G. Doxsey1, Johnny Le3, John A. Haley1, Lorena Mazuecos1, Amelia K. Luciano1, Huawei Li1, Cholsoon Jang3,*, David A. Guertin1,2,5,*
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
2Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA
3Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA
4Department of Biological Sciences, Sungkyunkwan University, Suwon, South Korea
5Lead contact
*Corresponding author
Abstract
Active brown adipose tissue (BAT) consumes copious amounts of glucose, yet how glucose metabolism supports thermogenesis is unclear. By combining transcriptomics, metabolomics, and stable isotope tracing in vivo, we systematically analyze BAT glucose utilization in mice during acute and chronic cold exposure. Metabolite profiling reveals extensive temperature-dependent changes in the BAT metabolome and transcriptome upon cold adaptation, discovering unexpected metabolite markers of thermogenesis, including increased N-acetyl-amino acid production. Time-course stable isotope tracing further reveals rapid incorporation of glucose carbons into glycolysis and TCA cycle, as well as several auxiliary pathways, including NADPH, nucleotide, and phospholipid synthesis pathways. Gene expression differences inconsistently predict glucose fluxes, indicating that posttranscriptional mechanisms also govern glucose utilization. Surprisingly, BAT swiftly generates fatty acids and acyl-carnitines from glucose, suggesting that lipids are rapidly synthesized and immediately oxidized. These data reveal versatility in BAT glucose utilization, highlighting the value of an integrative-omics approach to understanding organ metabolism.
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