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.

中文翻译：

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小鼠棕色脂肪组织中急性冷暴露引起的UCP1依赖性和UCP1非依赖性代谢变化

背景

棕色脂肪组织（BAT）是由线粒体解偶联蛋白1（UCP1）介导的代谢热生成的位点，代表肥胖症的治疗干预目标。冷暴露激活了BAT中UCP1介导的生热作用，并引起葡萄糖，脂质和氨基酸代谢的急剧变化；但是，这些代谢变化和UCP1介导的生热之间的关系尚不完全清楚。

方法

在野生型（WT）和UCP1-KO小鼠中，暴露于低温（10°C）4小时后，我们对BAT进行了代谢组学和GeneChip阵列分析。

结果

冷暴露在很大程度上增加了野生型小鼠糖酵解途径的代谢产物和乳酸水平，但在UCP1-KO小鼠中却没有，这表明由于UCP1介导的生热作用，有氧糖酵解作用得以增强。BAT的GeneChip阵列分析显示，WT小鼠中有2865个基因通过冷暴露上调，其中UCP1-KO小鼠中有838个基因上调，有74个基因下调。途径分析揭示了野生型和UCP1-KO小鼠中参与脂肪酸（FA）β氧化和甘油三酸酯（TG）合成的基因的富集，表明这些代谢途径被冷暴露增强，而不受UCP1介导的生热作用的影响。FA和胆固醇的生物合成途径仅在UCP1-KO小鼠中得到增强。冷暴露也显着增加了脯氨酸，色氨酸，在WT和UCP1-KO小鼠中都含有苯丙氨酸。在野生型小鼠中，冷暴露显着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的表达。出乎意料的是，UCP1-KO小鼠在冷暴露后天冬氨酸几乎被完全耗尽。基因表达分析表明，冷暴露后WT和UCP1-KO小鼠均可有效利用天门冬氨酸，但可从细胞内补充天门冬氨酸WT小鼠中的N-乙酰基-天冬氨酸。

结论

这些结果表明，冷暴露在BAT中诱导UCP1介导的生热依赖性葡萄糖利用和UCP1依赖性活性脂质代谢。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依赖性地提高了谷氨酰胺的利用率。这些结果有助于全面了解BAT中UCP1介导的热生成依赖性和热生成依赖性代谢。