UCP1-dependent and UCP1-independent metabolic changes induced by acute cold exposure in brown adipose tissue of mice

Oct 16, 2020Metabolism: clinical and experimental

Metabolic changes in mouse brown fat during cold exposure with and without UCP1 protein

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Abstract

Cold exposure increased glycolysis metabolites in wild-type mice but not in UCP1-knockout mice.

Aerobic glycolysis may be enhanced due to UCP1-mediated thermogenesis, as indicated by increased metabolites in wild-type mice.
In wild-type mice, 2865 genes were upregulated in brown adipose tissue after cold exposure, while only 838 were upregulated and 74 downregulated in UCP1-knockout mice.
Both wild-type and UCP1-knockout mice showed increased gene expression related to fatty acid β oxidation and triglyceride synthesis after cold exposure.
UCP1-knockout mice exhibited enhanced fatty acid and cholesterol biosynthesis pathways that were not dependent on UCP1-mediated thermogenesis.
Cold exposure significantly increased proline, tryptophan, and phenylalanine levels in both mouse types, with glutamine levels rising exclusively in wild-type mice.
Aspartate levels were nearly depleted in UCP1-knockout mice after cold exposure, suggesting its active utilization in both mouse types.

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BACKGROUND: Brown adipose tissue (BAT) is a site of metabolic thermogenesis mediated by mitochondrial uncoupling protein 1 (UCP1) and represents a target for a therapeutic intervention in obesity. Cold exposure activates UCP1-mediated thermogenesis in BAT and causes drastic changes in glucose, lipid, and amino acid metabolism; however, the relationship between these metabolic changes and UCP1-mediated thermogenesis is not fully understood.

METHODS: We conducted metabolomic and GeneChip array analyses of BAT after 4-h exposure to cold temperature (10 °C) in wild-type (WT) and UCP1-KO mice.

RESULTS: Cold exposure largely increased metabolites of the glycolysis pathway and lactic acid levels in WT, but not in UCP1-KO, mice, indicating that aerobic glycolysis is enhanced as a consequence of UCP1-mediated thermogenesis. GeneChip array analysis of BAT revealed that there were 2865 genes upregulated by cold exposure in WT mice, and 838 of these were upregulated and 74 were downregulated in UCP1-KO mice. Pathway analysis revealed the enrichment of genes involved in fatty acid (FA) β oxidation and triglyceride (TG) synthesis in both WT and UCP1-KO mice, suggesting that these metabolic pathways were enhanced by cold exposure independently of UCP1-mediated thermogenesis. FA and cholesterol biosynthesis pathways were enhanced only in UCP1-KO mice. Cold exposure also significantly increased the BAT content of proline, tryptophan, and phenylalanine amino acids in both WT and UCP1-KO mice. In WT mice, cold exposure significantly increased glutamine content and enhanced the expression of genes related to glutamine metabolism. Surprisingly, aspartate was almost completely depleted after cold exposure in UCP1-KO mice. Gene expression analysis suggested that aspartate was actively utilized after cold exposure both in WT and UCP1-KO mice, but it was replenished from intracellular N-acetyl-aspartate in WT mice.

CONCLUSIONS: These results revealed that cold exposure induces UCP1-mediated thermogenesis-dependent glucose utilization and UCP1-independent active lipid metabolism in BAT. In addition, cold exposure largely affects amino acid metabolism in BAT, especially UCP1-dependently enhances glutamine utilization. These results contribute a comprehensive understanding of UCP1-mediated thermogenesis-dependent and thermogenesis-independent metabolism in BAT.

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UCP1-dependent and UCP1-independent metabolic changes induced by acute cold exposure in brown adipose tissue of mice

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