Laboratory of Biochemistry, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
Department of Nutrition and Metabolism, Institute of Health Biosciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
Metabolism. 2020 Dec;113:154396. doi: 10.1016/j.metabol.2020.154396. Epub 2020 Oct 14.
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.
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.
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.
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.
棕色脂肪组织 (BAT) 是由线粒体解偶联蛋白 1 (UCP1) 介导的代谢产热的部位，是肥胖治疗干预的靶点。冷暴露激活 BAT 中的 UCP1 介导的产热，并导致葡萄糖、脂质和氨基酸代谢的剧烈变化；然而，这些代谢变化与 UCP1 介导的产热之间的关系尚未完全阐明。
我们对野生型 (WT) 和 UCP1-KO 小鼠在冷暴露 (10°C) 4 小时后进行了 BAT 的代谢组学和 GeneChip 阵列分析。
冷暴露大大增加了 WT 小鼠糖酵解途径和乳酸水平的代谢物，但 UCP1-KO 小鼠则没有，表明有氧糖酵解是 UCP1 介导的产热的结果而增强。WT 小鼠冷暴露后，BAT 的 GeneChip 阵列分析显示有 2865 个基因上调，其中 838 个在 UCP1-KO 小鼠中上调，74 个下调。通路分析显示，WT 和 UCP1-KO 小鼠中涉及脂肪酸 (FA) β氧化和甘油三酯 (TG) 合成的基因富集，表明这些代谢途径在不依赖 UCP1 介导的产热的情况下，由冷暴露增强。FA 和胆固醇生物合成途径仅在 UCP1-KO 小鼠中增强。冷暴露还显著增加了 WT 和 UCP1-KO 小鼠 BAT 脯氨酸、色氨酸和苯丙氨酸氨基酸的含量。在 WT 小鼠中，冷暴露显著增加了谷氨酰胺含量并增强了与谷氨酰胺代谢相关的基因表达。令人惊讶的是，UCP1-KO 小鼠在冷暴露后几乎完全耗尽了天冬氨酸。基因表达分析表明，WT 和 UCP1-KO 小鼠在冷暴露后都积极利用天冬氨酸，但 WT 小鼠中从细胞内 N-乙酰天冬氨酸中补充天冬氨酸。
这些结果表明，冷暴露诱导 UCP1 介导的产热依赖性葡萄糖利用和 UCP1 不依赖的活性脂质代谢在 BAT 中发生。此外，冷暴露在很大程度上影响了 BAT 中的氨基酸代谢，尤其是 UCP1 依赖性增强了谷氨酰胺的利用。这些结果为 UCP1 介导的产热依赖性和产热非依赖性代谢在 BAT 中的作用提供了全面的理解。
