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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 affects glucose metabolism in BAT following chronic cold exposure.Control and Ad-RaptorKO mice were cold exposed during 14 days and fasted for 6 hours before BAT collection. (A) Glycolytic intermediates 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) Glycolytic 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). (C) Genes expression of components of the pentose phosphate pathway 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) Nucleotides measured by metabolomics. Metabolites in bold are statistically different between control and Ad-RaptorKO mice (n = 3; mean +/− SEM; t-test; *P < 0.05). (E) Expression of genes involved in nucleotide synthesis 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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f4: mTORC1 loss affects glucose metabolism in BAT following chronic cold exposure.Control and Ad-RaptorKO mice were cold exposed during 14 days and fasted for 6 hours before BAT collection. (A) Glycolytic intermediates 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) Glycolytic 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). (C) Genes expression of components of the pentose phosphate pathway 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) Nucleotides measured by metabolomics. Metabolites in bold are statistically different between control and Ad-RaptorKO mice (n = 3; mean +/− SEM; t-test; *P < 0.05). (E) Expression of genes involved in nucleotide synthesis 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: To better define the importance of mTORC1 for BAT metabolic adaptation to cold, we have performed metabolomics and transcriptomics analyses on BAT samples isolated from control and Ad-RaptorKO mice. Supporting the elevation in glucose extraction in response to chronic mTORC1 inhibition (Fig. 3), BAT of Ad-RaptorKO mice markedly accumulated key glycolytic products (Fig. 4A, see also the metabolic map in Fig. 4F). Specifically, we observed a striking elevation in dihydroxyacetone-phosphate (DHAP) and pyruvate levels in Ad-RaptorKO mice (3.6 and 6.4 fold, respectively). Such elevations were observed despite a reduction in the expression of many glycolytic genes, indicating that these changes were not driven by a transcriptional modulation of the glycolytic machinery (Fig. 4B). Supporting the elevation in glucose flux in response to mTORC1 loss, we also measured an increase in the production of ribose/ribulose 5-phosphate and sedoheptulose 7-phosphate, which are key intermediates of the pentose phosphate pathway (PPP) (Fig. 4A). As observed in the case of glycolysis, the elevation in PPP metabolites was associated with a reduction rather than an increase in the expression of genes coding for proteins regulating this pathway (Fig. 4C). The PPP is a key metabolic pathway used for nucleotide biosynthesis and for the generation of NADPH for de novo lipogenesis. Interestingly, we observed a severe decrease in the levels of most nucleotides in BAT of Ad-RaptorKO mice, indicating an inability of the tissue to produce nucleotides despite the accumulation of the several molecules required for their production (Fig. 4D). At the transcriptional level, we observed a mixed profile regarding the expression of genes regulating nucleotide biosynthesis, some genes showing an elevation whereas others showing a reduction (Fig. 4E).


mTORC1 is Required for Brown Adipose Tissue Recruitment and Metabolic Adaptation to Cold
mTORC1 loss affects glucose metabolism in BAT following chronic cold exposure.Control and Ad-RaptorKO mice were cold exposed during 14 days and fasted for 6 hours before BAT collection. (A) Glycolytic intermediates 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) Glycolytic 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). (C) Genes expression of components of the pentose phosphate pathway 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) Nucleotides measured by metabolomics. Metabolites in bold are statistically different between control and Ad-RaptorKO mice (n = 3; mean +/− SEM; t-test; *P < 0.05). (E) Expression of genes involved in nucleotide synthesis 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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f4: mTORC1 loss affects glucose metabolism in BAT following chronic cold exposure.Control and Ad-RaptorKO mice were cold exposed during 14 days and fasted for 6 hours before BAT collection. (A) Glycolytic intermediates 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) Glycolytic 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). (C) Genes expression of components of the pentose phosphate pathway 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) Nucleotides measured by metabolomics. Metabolites in bold are statistically different between control and Ad-RaptorKO mice (n = 3; mean +/− SEM; t-test; *P < 0.05). (E) Expression of genes involved in nucleotide synthesis 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: To better define the importance of mTORC1 for BAT metabolic adaptation to cold, we have performed metabolomics and transcriptomics analyses on BAT samples isolated from control and Ad-RaptorKO mice. Supporting the elevation in glucose extraction in response to chronic mTORC1 inhibition (Fig. 3), BAT of Ad-RaptorKO mice markedly accumulated key glycolytic products (Fig. 4A, see also the metabolic map in Fig. 4F). Specifically, we observed a striking elevation in dihydroxyacetone-phosphate (DHAP) and pyruvate levels in Ad-RaptorKO mice (3.6 and 6.4 fold, respectively). Such elevations were observed despite a reduction in the expression of many glycolytic genes, indicating that these changes were not driven by a transcriptional modulation of the glycolytic machinery (Fig. 4B). Supporting the elevation in glucose flux in response to mTORC1 loss, we also measured an increase in the production of ribose/ribulose 5-phosphate and sedoheptulose 7-phosphate, which are key intermediates of the pentose phosphate pathway (PPP) (Fig. 4A). As observed in the case of glycolysis, the elevation in PPP metabolites was associated with a reduction rather than an increase in the expression of genes coding for proteins regulating this pathway (Fig. 4C). The PPP is a key metabolic pathway used for nucleotide biosynthesis and for the generation of NADPH for de novo lipogenesis. Interestingly, we observed a severe decrease in the levels of most nucleotides in BAT of Ad-RaptorKO mice, indicating an inability of the tissue to produce nucleotides despite the accumulation of the several molecules required for their production (Fig. 4D). At the transcriptional level, we observed a mixed profile regarding the expression of genes regulating nucleotide biosynthesis, some genes showing an elevation whereas others showing a reduction (Fig. 4E).

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