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

Abstract

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 thermogenesisindependent metabolism in BAT.

Metabolomic Analysis Reveals Changes in Plasma Metabolites in Response to Acute Cold Stress and Their Relationships to Metabolic Health in Cold-Acclimatized Humans

“…Clearly, the pathways affected by acute cold mostly involved amino acid metabolism and the citric acid cycle. Interestingly, several of these metabolic pathways were also affected in brown adipose tissue (BAT) after 2–6 h of cold exposure in mice: alanine and aspartate metabolism [ 16 ]; alanine, aspartate and glutamate metabolism; glycine, serine and threonine metabolism; and pyruvate metabolism and the citric acid cycle (TCA) [ 8 ]. It is important to note that several amino acids in rodent BAT seemed to be regulated in the opposite direction when compared with the changes in human plasma related to cold exposure.…”

“…For example, methionine, isoleucine and valine were all increased in BAT after 4–6 h of cold exposure [ 8 ] and serine and threonine increased in BAT after 4–6 [ 8 ] and 12 h [ 17 ] of acute cold exposure in non-acclimatized mice, but they all decreased or had a trend to decrease (isoleucine) in plasma of cold-acclimatized humans after ice-water swimming. Similarly, levels of 15 out of 19 amino acids measured after 4 h cold exposure (4 °C) were increased in BAT of wild-type mice [ 16 ]. This could indicate that the decrease in plasma amino acids may reflect their uptake and utilization by BAT in humans.…”

Increased expression level of ANGPTL8 in white adipose tissue under acute and chronic cold treatment

“…Furthermore, the reduction in the expression level of this gene over the course of time in cold conditions suggests the possibility of a switch in the mechanism associated with metabolic changes in BAT. A recent study showed that cold conditions induce UCP1 dependent/independent thermogenesis in BAT [ 28 ]. The reduction in the expression of ATGL under acute cold conditions further supports that under acute cold conditions the process of lipolysis in BAT is not dependent on ATGL[ 29 ].…”

Non-shivering Thermogenesis Signalling Regulation and Potential Therapeutic Applications of Brown Adipose Tissue

“…The classical method is cold exposure. Acute cold exposure (10°C, 4 h) induces UCP1-mediated thermogenesis-dependent glucose utilization by affecting amino acid metabolism in BAT 109 . Chronic cold exposure (6°C, 10 days) has also been shown to activate glucose oxidation in BAT and WAT browning 110 .…”