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mTORC1 is Required for Brown Adipose Tissue Recruitment and Metabolic Adaptation to Cold

View Article: PubMed Central - PubMed

ABSTRACT

In response to cold, brown adipose tissue (BAT) increases its metabolic rate and expands its mass to produce heat required for survival, a process known as BAT recruitment. The mechanistic target of rapamycin complex 1 (mTORC1) controls metabolism, cell growth and proliferation, but its role in regulating BAT recruitment in response to chronic cold stimulation is unknown. Here, we show that cold activates mTORC1 in BAT, an effect that depends on the sympathetic nervous system. Adipocyte-specific mTORC1 loss in mice completely blocks cold-induced BAT expansion and severely impairs mitochondrial biogenesis. Accordingly, mTORC1 loss reduces oxygen consumption and causes a severe defect in BAT oxidative metabolism upon cold exposure. Using in vivo metabolic imaging, metabolomics and transcriptomics, we show that mTORC1 deletion impairs glucose and lipid oxidation, an effect linked to a defect in tricarboxylic acid (TCA) cycle activity. These analyses also reveal a severe defect in nucleotide synthesis in the absence of mTORC1. Overall, these findings demonstrate an essential role for mTORC1 in the regulation of BAT recruitment and metabolism in response to cold.

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mTORC1 loss severely impairs lipid metabolism in BAT following chronic cold exposure.Control and Ad-RaptorKO mice were cold exposed for 14 days and fasted during 6 hours before BAT collection. (A) Metabolites entering in the synthesis of glycerolipids from glucose measured by metabolomics. Metabolites in bold are statistically different between control and Ad-RaptorKO mice (n = 3; mean +/− SEM; t-test; *P < 0.05). (B) Diacylglycerol (DG) species measured by metabolomics. Metabolites in bold are statistically different between control and Ad-RaptorKO mice (n = 3; mean +/− SEM; t-test; *P < 0.05). (C) Expression of genes entering in the synthesis or the breakdown of glycerolipids extracted from the microarray dataset. Genes in bold are statistically different between control and Ad-RaptorKO mice (n = 4; mean +/− SEM; SAM t-test; *FDR < 0.05). (D) Lipogenic metabolites produced from the TCA cycle measured by metabolomics (n = 3; mean +/− SEM; t-test). (E) Lipogenic gene expression extracted from the microarray dataset. Genes in bold are statistically different between control and Ad-RaptorKO mice (n = 4; mean +/− SEM; SAM t-test; *FDR < 0.05). (F) Schematic summary of transcriptomics and metabolomics data.
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f5: mTORC1 loss severely impairs lipid metabolism in BAT following chronic cold exposure.Control and Ad-RaptorKO mice were cold exposed for 14 days and fasted during 6 hours before BAT collection. (A) Metabolites entering in the synthesis of glycerolipids from glucose measured by metabolomics. Metabolites in bold are statistically different between control and Ad-RaptorKO mice (n = 3; mean +/− SEM; t-test; *P < 0.05). (B) Diacylglycerol (DG) species measured by metabolomics. Metabolites in bold are statistically different between control and Ad-RaptorKO mice (n = 3; mean +/− SEM; t-test; *P < 0.05). (C) Expression of genes entering in the synthesis or the breakdown of glycerolipids extracted from the microarray dataset. Genes in bold are statistically different between control and Ad-RaptorKO mice (n = 4; mean +/− SEM; SAM t-test; *FDR < 0.05). (D) Lipogenic metabolites produced from the TCA cycle measured by metabolomics (n = 3; mean +/− SEM; t-test). (E) Lipogenic gene expression extracted from the microarray dataset. Genes in bold are statistically different between control and Ad-RaptorKO mice (n = 4; mean +/− SEM; SAM t-test; *FDR < 0.05). (F) Schematic summary of transcriptomics and metabolomics data.

Mentions: The metabolomics data presented above showed that Ad-RaptorKO mice accumulated high levels of DHAP, a key glycolytic intermediate used for the synthesis of glycerolipids. Downstream of DHAP, we observed an elevation in glycerol 3-phosphate and lysophosphatidic acid (LPA) accumulation in BAT of Ad-RaptorKO mice (Fig. 5A, see also the metabolic map in Fig. 5G). This effect was linked to a dramatic increase in the content of various diacylglycerols (DG) (Fig. 5B). Although several TG species were also higher in BAT of Ad-RaptorKO mice than in control animals, this trend was not as striking as what was observed for DG (Figure S4). Nevertheless, these results indicate that an important fraction of glycolytic intermediates are shuttled onto the glycerol moiety of glycerolipids in Ad-RaptorKO mice. As reported above for glycolysis and PPP, these effects were not caused by an elevation in the expression of genes coding for proteins regulating this process. Indeed, we observed that several genes promoting glycerolipid synthesis were decreased rather than increased in BAT of Ad-RaptorKO mice (Fig. 5C). Triacylglycerol synthesis involves the sequential esterification of acyl-CoA on glycerol 3-phosphate, phosphatidic acid, and DG respectively. The acyl-CoA molecules are provided either by circulating lipids or can be synthesized de novo from the conversion of citrate to malonyl-CoA (see the metabolic map in Fig. 5F). Here, we observed a reduction in citrate and acetyl-CoA levels in BAT of Ad-RaptorKO (Fig. 5D). We also measured a profound defect in the expression of genes coding for proteins required for de novo fatty acid synthesis (Fig. 5E). These results suggest that the fatty acids contributing to the elevation in glycerolipid synthesis in BAT of Ad-RaptorKO mice are most likely derived from circulating lipids rather than de novo lipogenesis.


mTORC1 is Required for Brown Adipose Tissue Recruitment and Metabolic Adaptation to Cold
mTORC1 loss severely impairs lipid metabolism in BAT following chronic cold exposure.Control and Ad-RaptorKO mice were cold exposed for 14 days and fasted during 6 hours before BAT collection. (A) Metabolites entering in the synthesis of glycerolipids from glucose measured by metabolomics. Metabolites in bold are statistically different between control and Ad-RaptorKO mice (n = 3; mean +/− SEM; t-test; *P < 0.05). (B) Diacylglycerol (DG) species measured by metabolomics. Metabolites in bold are statistically different between control and Ad-RaptorKO mice (n = 3; mean +/− SEM; t-test; *P < 0.05). (C) Expression of genes entering in the synthesis or the breakdown of glycerolipids extracted from the microarray dataset. Genes in bold are statistically different between control and Ad-RaptorKO mice (n = 4; mean +/− SEM; SAM t-test; *FDR < 0.05). (D) Lipogenic metabolites produced from the TCA cycle measured by metabolomics (n = 3; mean +/− SEM; t-test). (E) Lipogenic gene expression extracted from the microarray dataset. Genes in bold are statistically different between control and Ad-RaptorKO mice (n = 4; mean +/− SEM; SAM t-test; *FDR < 0.05). (F) Schematic summary of transcriptomics and metabolomics data.
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f5: mTORC1 loss severely impairs lipid metabolism in BAT following chronic cold exposure.Control and Ad-RaptorKO mice were cold exposed for 14 days and fasted during 6 hours before BAT collection. (A) Metabolites entering in the synthesis of glycerolipids from glucose measured by metabolomics. Metabolites in bold are statistically different between control and Ad-RaptorKO mice (n = 3; mean +/− SEM; t-test; *P < 0.05). (B) Diacylglycerol (DG) species measured by metabolomics. Metabolites in bold are statistically different between control and Ad-RaptorKO mice (n = 3; mean +/− SEM; t-test; *P < 0.05). (C) Expression of genes entering in the synthesis or the breakdown of glycerolipids extracted from the microarray dataset. Genes in bold are statistically different between control and Ad-RaptorKO mice (n = 4; mean +/− SEM; SAM t-test; *FDR < 0.05). (D) Lipogenic metabolites produced from the TCA cycle measured by metabolomics (n = 3; mean +/− SEM; t-test). (E) Lipogenic gene expression extracted from the microarray dataset. Genes in bold are statistically different between control and Ad-RaptorKO mice (n = 4; mean +/− SEM; SAM t-test; *FDR < 0.05). (F) Schematic summary of transcriptomics and metabolomics data.
Mentions: The metabolomics data presented above showed that Ad-RaptorKO mice accumulated high levels of DHAP, a key glycolytic intermediate used for the synthesis of glycerolipids. Downstream of DHAP, we observed an elevation in glycerol 3-phosphate and lysophosphatidic acid (LPA) accumulation in BAT of Ad-RaptorKO mice (Fig. 5A, see also the metabolic map in Fig. 5G). This effect was linked to a dramatic increase in the content of various diacylglycerols (DG) (Fig. 5B). Although several TG species were also higher in BAT of Ad-RaptorKO mice than in control animals, this trend was not as striking as what was observed for DG (Figure S4). Nevertheless, these results indicate that an important fraction of glycolytic intermediates are shuttled onto the glycerol moiety of glycerolipids in Ad-RaptorKO mice. As reported above for glycolysis and PPP, these effects were not caused by an elevation in the expression of genes coding for proteins regulating this process. Indeed, we observed that several genes promoting glycerolipid synthesis were decreased rather than increased in BAT of Ad-RaptorKO mice (Fig. 5C). Triacylglycerol synthesis involves the sequential esterification of acyl-CoA on glycerol 3-phosphate, phosphatidic acid, and DG respectively. The acyl-CoA molecules are provided either by circulating lipids or can be synthesized de novo from the conversion of citrate to malonyl-CoA (see the metabolic map in Fig. 5F). Here, we observed a reduction in citrate and acetyl-CoA levels in BAT of Ad-RaptorKO (Fig. 5D). We also measured a profound defect in the expression of genes coding for proteins required for de novo fatty acid synthesis (Fig. 5E). These results suggest that the fatty acids contributing to the elevation in glycerolipid synthesis in BAT of Ad-RaptorKO mice are most likely derived from circulating lipids rather than de novo lipogenesis.

View Article: PubMed Central - PubMed

ABSTRACT

In response to cold, brown adipose tissue (BAT) increases its metabolic rate and expands its mass to produce heat required for survival, a process known as BAT recruitment. The mechanistic target of rapamycin complex 1 (mTORC1) controls metabolism, cell growth and proliferation, but its role in regulating BAT recruitment in response to chronic cold stimulation is unknown. Here, we show that cold activates mTORC1 in BAT, an effect that depends on the sympathetic nervous system. Adipocyte-specific mTORC1 loss in mice completely blocks cold-induced BAT expansion and severely impairs mitochondrial biogenesis. Accordingly, mTORC1 loss reduces oxygen consumption and causes a severe defect in BAT oxidative metabolism upon cold exposure. Using in vivo metabolic imaging, metabolomics and transcriptomics, we show that mTORC1 deletion impairs glucose and lipid oxidation, an effect linked to a defect in tricarboxylic acid (TCA) cycle activity. These analyses also reveal a severe defect in nucleotide synthesis in the absence of mTORC1. Overall, these findings demonstrate an essential role for mTORC1 in the regulation of BAT recruitment and metabolism in response to cold.

No MeSH data available.


Related in: MedlinePlus