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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.

No MeSH data available.


Related in: MedlinePlus

Loss of mTORC1 affects substrate partitioning in BAT.Control and Ad-RaptorKO mice were exposed to cold (10 °C) during 2 weeks and fasted for 6 hours before dynamic PET scan procedures. (A) Representative PET images of extraction coefficient uptake of the glucose analog 18FDG between 25–30 min post-injection (last frame). White arrows point to the interscapular BAT that is highlighted in the upper right insert. (B) (Left) Glucose extraction coefficient was determined using the Patlak graphical analysis following a 30-minutes dynamic scan. (Right) Total dynamic glucose uptake corrected for tissue weight was calculated from the extraction coefficient, BAT weight and plasma glucose levels (n = 4–5; mean +/− SEM; t-test; *P < 0.05; ***P < 0.001). (C) Gene expression (left) (n = 4; mean +/− SEM; Two-way ANOVA; ***P < 0.01 vs. Warm; ###P < 0.001 vs. Control) and circulating levels (right) of FGF21 (n = 8; mean +/− SEM; t-test; **P < 0.01). (D) Representative PET images of the uptake of the fatty acid analog 18FTHA between 25–30 min post-injection (last frame). White arrows point to the interscapular BAT that is highlighted in the upper right insert. (E) (Left) NEFA extraction coefficient was determined using the Patlak graphical analysis following a 30-minutes dynamic scan. (Right) Total dynamic NEFA uptake corrected for tissue weight was calculated from the extraction coefficient, BAT weight and plasma NEFA levels (n = 4; mean +/− SEM; t-test; *P < 0.05; ***P < 0.001).
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f3: Loss of mTORC1 affects substrate partitioning in BAT.Control and Ad-RaptorKO mice were exposed to cold (10 °C) during 2 weeks and fasted for 6 hours before dynamic PET scan procedures. (A) Representative PET images of extraction coefficient uptake of the glucose analog 18FDG between 25–30 min post-injection (last frame). White arrows point to the interscapular BAT that is highlighted in the upper right insert. (B) (Left) Glucose extraction coefficient was determined using the Patlak graphical analysis following a 30-minutes dynamic scan. (Right) Total dynamic glucose uptake corrected for tissue weight was calculated from the extraction coefficient, BAT weight and plasma glucose levels (n = 4–5; mean +/− SEM; t-test; *P < 0.05; ***P < 0.001). (C) Gene expression (left) (n = 4; mean +/− SEM; Two-way ANOVA; ***P < 0.01 vs. Warm; ###P < 0.001 vs. Control) and circulating levels (right) of FGF21 (n = 8; mean +/− SEM; t-test; **P < 0.01). (D) Representative PET images of the uptake of the fatty acid analog 18FTHA between 25–30 min post-injection (last frame). White arrows point to the interscapular BAT that is highlighted in the upper right insert. (E) (Left) NEFA extraction coefficient was determined using the Patlak graphical analysis following a 30-minutes dynamic scan. (Right) Total dynamic NEFA uptake corrected for tissue weight was calculated from the extraction coefficient, BAT weight and plasma NEFA levels (n = 4; mean +/− SEM; t-test; *P < 0.05; ***P < 0.001).

Mentions: Glucose uptake is rapidly increased in BAT of rodents144445 and humans92346 exposed to cold. Glycolytic intermediates are essential to support lipogenesis and thermogenesis in BAT47484950. Here, the dynamic uptake of glucose by tissues was assessed using the PET tracer 2-deoxy-2-[18F]-fluoro-D-glucose (18FDG). Upon an acute cold challenge, we observed that 18FDG uptake by BAT was significantly higher in Ad-RaptorKO mice versus controls (Figure S3A and S3B). In mice chronically exposed to cold, we noticed that the extraction coefficient (capacity for one gram of tissue to extract substrate from the circulation) was increased in response to mTORC1 loss (Fig. 3A and B left panel). Such increase in glucose uptake is likely the result of the elevation in Akt activation in BAT of Ad-RaptorKO mice (Fig. 2A), a kinase recognized to play a crucial role in promoting glucose transport in brown adipocytes3051. Interestingly, we also noted elevated expression of fibroblast growth factor 21 (Fgf21) in BAT of Ad-RaptorKO mice chronically exposed to cold (Fig. 3C), which may have contributed to drive glucose uptake, as reported525354. High circulating FGF21 was also detected in these mice (Fig. 3C). Despite the increase in glucose extraction coefficient, it is important to point out that the total uptake of glucose by the whole BAT was reduced in Ad-RaptorKO (Fig. 3B, right panel). This was likely caused by the severe reduction in BAT mass and by the elevation in glucose uptake in WAT in these mice (Figure S3C).


mTORC1 is Required for Brown Adipose Tissue Recruitment and Metabolic Adaptation to Cold
Loss of mTORC1 affects substrate partitioning in BAT.Control and Ad-RaptorKO mice were exposed to cold (10 °C) during 2 weeks and fasted for 6 hours before dynamic PET scan procedures. (A) Representative PET images of extraction coefficient uptake of the glucose analog 18FDG between 25–30 min post-injection (last frame). White arrows point to the interscapular BAT that is highlighted in the upper right insert. (B) (Left) Glucose extraction coefficient was determined using the Patlak graphical analysis following a 30-minutes dynamic scan. (Right) Total dynamic glucose uptake corrected for tissue weight was calculated from the extraction coefficient, BAT weight and plasma glucose levels (n = 4–5; mean +/− SEM; t-test; *P < 0.05; ***P < 0.001). (C) Gene expression (left) (n = 4; mean +/− SEM; Two-way ANOVA; ***P < 0.01 vs. Warm; ###P < 0.001 vs. Control) and circulating levels (right) of FGF21 (n = 8; mean +/− SEM; t-test; **P < 0.01). (D) Representative PET images of the uptake of the fatty acid analog 18FTHA between 25–30 min post-injection (last frame). White arrows point to the interscapular BAT that is highlighted in the upper right insert. (E) (Left) NEFA extraction coefficient was determined using the Patlak graphical analysis following a 30-minutes dynamic scan. (Right) Total dynamic NEFA uptake corrected for tissue weight was calculated from the extraction coefficient, BAT weight and plasma NEFA levels (n = 4; mean +/− SEM; t-test; *P < 0.05; ***P < 0.001).
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f3: Loss of mTORC1 affects substrate partitioning in BAT.Control and Ad-RaptorKO mice were exposed to cold (10 °C) during 2 weeks and fasted for 6 hours before dynamic PET scan procedures. (A) Representative PET images of extraction coefficient uptake of the glucose analog 18FDG between 25–30 min post-injection (last frame). White arrows point to the interscapular BAT that is highlighted in the upper right insert. (B) (Left) Glucose extraction coefficient was determined using the Patlak graphical analysis following a 30-minutes dynamic scan. (Right) Total dynamic glucose uptake corrected for tissue weight was calculated from the extraction coefficient, BAT weight and plasma glucose levels (n = 4–5; mean +/− SEM; t-test; *P < 0.05; ***P < 0.001). (C) Gene expression (left) (n = 4; mean +/− SEM; Two-way ANOVA; ***P < 0.01 vs. Warm; ###P < 0.001 vs. Control) and circulating levels (right) of FGF21 (n = 8; mean +/− SEM; t-test; **P < 0.01). (D) Representative PET images of the uptake of the fatty acid analog 18FTHA between 25–30 min post-injection (last frame). White arrows point to the interscapular BAT that is highlighted in the upper right insert. (E) (Left) NEFA extraction coefficient was determined using the Patlak graphical analysis following a 30-minutes dynamic scan. (Right) Total dynamic NEFA uptake corrected for tissue weight was calculated from the extraction coefficient, BAT weight and plasma NEFA levels (n = 4; mean +/− SEM; t-test; *P < 0.05; ***P < 0.001).
Mentions: Glucose uptake is rapidly increased in BAT of rodents144445 and humans92346 exposed to cold. Glycolytic intermediates are essential to support lipogenesis and thermogenesis in BAT47484950. Here, the dynamic uptake of glucose by tissues was assessed using the PET tracer 2-deoxy-2-[18F]-fluoro-D-glucose (18FDG). Upon an acute cold challenge, we observed that 18FDG uptake by BAT was significantly higher in Ad-RaptorKO mice versus controls (Figure S3A and S3B). In mice chronically exposed to cold, we noticed that the extraction coefficient (capacity for one gram of tissue to extract substrate from the circulation) was increased in response to mTORC1 loss (Fig. 3A and B left panel). Such increase in glucose uptake is likely the result of the elevation in Akt activation in BAT of Ad-RaptorKO mice (Fig. 2A), a kinase recognized to play a crucial role in promoting glucose transport in brown adipocytes3051. Interestingly, we also noted elevated expression of fibroblast growth factor 21 (Fgf21) in BAT of Ad-RaptorKO mice chronically exposed to cold (Fig. 3C), which may have contributed to drive glucose uptake, as reported525354. High circulating FGF21 was also detected in these mice (Fig. 3C). Despite the increase in glucose extraction coefficient, it is important to point out that the total uptake of glucose by the whole BAT was reduced in Ad-RaptorKO (Fig. 3B, right panel). This was likely caused by the severe reduction in BAT mass and by the elevation in glucose uptake in WAT in these mice (Figure S3C).

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