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

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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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The defects in BAT expansion and metabolism in Ad-RaptorKO are not mediated by a reduction in adrenergic signalling.Control and Ad-RaptorKO mice were cold exposed for 14 days and fasted during 6 hours before BAT collection. (A) Gene expression of Adrb3 (n = 4; mean +/− SEM; Two-way ANOVA; **P < 0.01 vs. Warm; ###P < 0.001 vs. Control). (B) Western blots performed on BAT collected from control and Ad-RaptorKO mice following chronic cold exposure. All gels have been run under the same experimental conditions. (C) Model summarizing the role of mTORC1 in BAT during cold adaptation. (D) Model summarizing the impact of mTORC1 loss in BAT during cold adaptation. Bold and dashed lines indicate increase and decrease respectively, in comparison to the model presented in (C).
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f7: The defects in BAT expansion and metabolism in Ad-RaptorKO are not mediated by a reduction in adrenergic signalling.Control and Ad-RaptorKO mice were cold exposed for 14 days and fasted during 6 hours before BAT collection. (A) Gene expression of Adrb3 (n = 4; mean +/− SEM; Two-way ANOVA; **P < 0.01 vs. Warm; ###P < 0.001 vs. Control). (B) Western blots performed on BAT collected from control and Ad-RaptorKO mice following chronic cold exposure. All gels have been run under the same experimental conditions. (C) Model summarizing the role of mTORC1 in BAT during cold adaptation. (D) Model summarizing the impact of mTORC1 loss in BAT during cold adaptation. Bold and dashed lines indicate increase and decrease respectively, in comparison to the model presented in (C).

Mentions: It was recently shown that chronic mTORC1 inhibition with rapamycin reduces the transcription of the β3-adrenergic receptor (Adrb3) in WAT and BAT29. To determine whether a reduction in adrenergic signaling could have contributed to the defect in BAT expansion and metabolism in Ad-RaptorKO mice, we measured mRNA expression of Adrb3. Although mTORC1 loss did not affect Adrb3 expression in BAT of mice kept at thermoneutrality, we observed a severe reduction in the expression of this gene when animals were chronically exposed to cold (Fig. 7A). To evaluate whether this effect was associated with changes in adrenergic signaling, we next performed western blot analyses to measure the phosphorylation status of hormone sensitive lipase (HSL) on S563 and S660, which are key residues phosphorylated downstream of ADRB3. Surprisingly, we observed that, despite a severe reduction in Adrb3 mRNA expression, the phosphorylation of HSL on S563 and S660 was massively increased in Ad-RaptorKO mice. On the other hand, the phosphorylation of HSL on S565, a site phosphorylated by AMP kinase that negatively regulates the activity of HSL, was not modulated in these conditions. These results indicate that defects in BAT observed in response to chronic mTORC1 inhibition are not a consequence of a reduction in adrenergic signaling. In fact, these changes occurred in the face of elevated adrenergic signaling, which further highlights the importance of mTORC1 for BAT recruitment and metabolic adaptation to cold. How mTORC1 inhibition drives adrenergic signaling is unknown, but does not involve any elevation in Adrb1 or Adrb2 expression (Figure S7). A model recapitulating our findings is presented in Fig. 7C,D.


mTORC1 is Required for Brown Adipose Tissue Recruitment and Metabolic Adaptation to Cold
The defects in BAT expansion and metabolism in Ad-RaptorKO are not mediated by a reduction in adrenergic signalling.Control and Ad-RaptorKO mice were cold exposed for 14 days and fasted during 6 hours before BAT collection. (A) Gene expression of Adrb3 (n = 4; mean +/− SEM; Two-way ANOVA; **P < 0.01 vs. Warm; ###P < 0.001 vs. Control). (B) Western blots performed on BAT collected from control and Ad-RaptorKO mice following chronic cold exposure. All gels have been run under the same experimental conditions. (C) Model summarizing the role of mTORC1 in BAT during cold adaptation. (D) Model summarizing the impact of mTORC1 loss in BAT during cold adaptation. Bold and dashed lines indicate increase and decrease respectively, in comparison to the model presented in (C).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5120333&req=5

f7: The defects in BAT expansion and metabolism in Ad-RaptorKO are not mediated by a reduction in adrenergic signalling.Control and Ad-RaptorKO mice were cold exposed for 14 days and fasted during 6 hours before BAT collection. (A) Gene expression of Adrb3 (n = 4; mean +/− SEM; Two-way ANOVA; **P < 0.01 vs. Warm; ###P < 0.001 vs. Control). (B) Western blots performed on BAT collected from control and Ad-RaptorKO mice following chronic cold exposure. All gels have been run under the same experimental conditions. (C) Model summarizing the role of mTORC1 in BAT during cold adaptation. (D) Model summarizing the impact of mTORC1 loss in BAT during cold adaptation. Bold and dashed lines indicate increase and decrease respectively, in comparison to the model presented in (C).
Mentions: It was recently shown that chronic mTORC1 inhibition with rapamycin reduces the transcription of the β3-adrenergic receptor (Adrb3) in WAT and BAT29. To determine whether a reduction in adrenergic signaling could have contributed to the defect in BAT expansion and metabolism in Ad-RaptorKO mice, we measured mRNA expression of Adrb3. Although mTORC1 loss did not affect Adrb3 expression in BAT of mice kept at thermoneutrality, we observed a severe reduction in the expression of this gene when animals were chronically exposed to cold (Fig. 7A). To evaluate whether this effect was associated with changes in adrenergic signaling, we next performed western blot analyses to measure the phosphorylation status of hormone sensitive lipase (HSL) on S563 and S660, which are key residues phosphorylated downstream of ADRB3. Surprisingly, we observed that, despite a severe reduction in Adrb3 mRNA expression, the phosphorylation of HSL on S563 and S660 was massively increased in Ad-RaptorKO mice. On the other hand, the phosphorylation of HSL on S565, a site phosphorylated by AMP kinase that negatively regulates the activity of HSL, was not modulated in these conditions. These results indicate that defects in BAT observed in response to chronic mTORC1 inhibition are not a consequence of a reduction in adrenergic signaling. In fact, these changes occurred in the face of elevated adrenergic signaling, which further highlights the importance of mTORC1 for BAT recruitment and metabolic adaptation to cold. How mTORC1 inhibition drives adrenergic signaling is unknown, but does not involve any elevation in Adrb1 or Adrb2 expression (Figure S7). A model recapitulating our findings is presented in Fig. 7C,D.

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