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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 impairs cold-induced BAT expansion, mitochondrial biogenesis, and oxidative metabolism.Control and Ad-RaptorKO mice were either kept at thermoneutrality (warm; 30 °C) or exposed to cold (10 °C) for 2 weeks. (A) Western blots performed on BAT following warm or acute cold exposure. All gels have been run under the same experimental conditions. (B) Representative pictures of BAT and (C) H&E staining of representative BAT collected after warm or chronic cold exposure. (D) Total BAT mass (n = 13–17; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; ###P < 0.001 vs. Control). (E) Total DNA content (n = 7–9; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; ###P < 0.001 vs. Control). (F) mtDNA content (n = 7–9; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; ###P < 0.001 vs. Control). (G) Gene expression of Pgc1a (n = 4; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; ###P < 0.001 vs. Control). (H) Western blots performed on BAT collected from control and Ad-RaptorKO mice following chronic cold exposure. All gels were run under the same experimental conditions. (I) Oxygen consumption at thermoneutrality (warm) and during the transition to cold. (n = 6–8; mean +/− SEM; t-test; *P < 0.05; ***P < 0.001). White section: thermoneutrality, when the lights were on; Grey section: thermoneutrality, when the lights were off; Light blue section: cold, when the lights were on; Dark blue section: cold, when the lights were off. (J) Mean SUV time-activity curves of 11C-acetate during (left) acute and (right) chronic cold exposure (n = 4–5; mean +/− SEM). (K) Total BAT oxidative activity index corrected for tissue weight (n = 6–8; mean +/−SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; #P < 0.05 vs. Control; ###P < 0.001 vs. Control). (L) Total BAT blood flow index corrected for tissue weight (n = 4–5; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; #P < 0.05 vs. Control; ###P < 0.001 vs. Control). (M) Plasma CK activity (n = 10–13; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; ###P < 0.001 vs. Control).
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f2: Loss of mTORC1 impairs cold-induced BAT expansion, mitochondrial biogenesis, and oxidative metabolism.Control and Ad-RaptorKO mice were either kept at thermoneutrality (warm; 30 °C) or exposed to cold (10 °C) for 2 weeks. (A) Western blots performed on BAT following warm or acute cold exposure. All gels have been run under the same experimental conditions. (B) Representative pictures of BAT and (C) H&E staining of representative BAT collected after warm or chronic cold exposure. (D) Total BAT mass (n = 13–17; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; ###P < 0.001 vs. Control). (E) Total DNA content (n = 7–9; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; ###P < 0.001 vs. Control). (F) mtDNA content (n = 7–9; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; ###P < 0.001 vs. Control). (G) Gene expression of Pgc1a (n = 4; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; ###P < 0.001 vs. Control). (H) Western blots performed on BAT collected from control and Ad-RaptorKO mice following chronic cold exposure. All gels were run under the same experimental conditions. (I) Oxygen consumption at thermoneutrality (warm) and during the transition to cold. (n = 6–8; mean +/− SEM; t-test; *P < 0.05; ***P < 0.001). White section: thermoneutrality, when the lights were on; Grey section: thermoneutrality, when the lights were off; Light blue section: cold, when the lights were on; Dark blue section: cold, when the lights were off. (J) Mean SUV time-activity curves of 11C-acetate during (left) acute and (right) chronic cold exposure (n = 4–5; mean +/− SEM). (K) Total BAT oxidative activity index corrected for tissue weight (n = 6–8; mean +/−SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; #P < 0.05 vs. Control; ###P < 0.001 vs. Control). (L) Total BAT blood flow index corrected for tissue weight (n = 4–5; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; #P < 0.05 vs. Control; ###P < 0.001 vs. Control). (M) Plasma CK activity (n = 10–13; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; ###P < 0.001 vs. Control).

Mentions: In order to test the importance of mTORC1 in regulating BAT function and expansion in response to cold, we crossed RaptorLox/Lox mice36 with mice expressing the Cre-recombinase under the control of the Adiponectin promoter37. This method was efficient to specifically delete Raptor, an essential component of mTORC1, in adipose tissues (Ad-RaptorKO) (Fig. 2A and Figure S2A). At thermoneutrality and following chronic cold exposure, Ad-RaptorKO mice were slightly heavier than control animals, despite a significant reduction in WAT masses (Figure S2B). Consistent with the reduction in WAT size, Ad-RaptorKO mice showed lower levels of circulating leptin and NEFAs (Figure S2C).


mTORC1 is Required for Brown Adipose Tissue Recruitment and Metabolic Adaptation to Cold
Loss of mTORC1 impairs cold-induced BAT expansion, mitochondrial biogenesis, and oxidative metabolism.Control and Ad-RaptorKO mice were either kept at thermoneutrality (warm; 30 °C) or exposed to cold (10 °C) for 2 weeks. (A) Western blots performed on BAT following warm or acute cold exposure. All gels have been run under the same experimental conditions. (B) Representative pictures of BAT and (C) H&E staining of representative BAT collected after warm or chronic cold exposure. (D) Total BAT mass (n = 13–17; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; ###P < 0.001 vs. Control). (E) Total DNA content (n = 7–9; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; ###P < 0.001 vs. Control). (F) mtDNA content (n = 7–9; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; ###P < 0.001 vs. Control). (G) Gene expression of Pgc1a (n = 4; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; ###P < 0.001 vs. Control). (H) Western blots performed on BAT collected from control and Ad-RaptorKO mice following chronic cold exposure. All gels were run under the same experimental conditions. (I) Oxygen consumption at thermoneutrality (warm) and during the transition to cold. (n = 6–8; mean +/− SEM; t-test; *P < 0.05; ***P < 0.001). White section: thermoneutrality, when the lights were on; Grey section: thermoneutrality, when the lights were off; Light blue section: cold, when the lights were on; Dark blue section: cold, when the lights were off. (J) Mean SUV time-activity curves of 11C-acetate during (left) acute and (right) chronic cold exposure (n = 4–5; mean +/− SEM). (K) Total BAT oxidative activity index corrected for tissue weight (n = 6–8; mean +/−SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; #P < 0.05 vs. Control; ###P < 0.001 vs. Control). (L) Total BAT blood flow index corrected for tissue weight (n = 4–5; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; #P < 0.05 vs. Control; ###P < 0.001 vs. Control). (M) Plasma CK activity (n = 10–13; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; ###P < 0.001 vs. Control).
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f2: Loss of mTORC1 impairs cold-induced BAT expansion, mitochondrial biogenesis, and oxidative metabolism.Control and Ad-RaptorKO mice were either kept at thermoneutrality (warm; 30 °C) or exposed to cold (10 °C) for 2 weeks. (A) Western blots performed on BAT following warm or acute cold exposure. All gels have been run under the same experimental conditions. (B) Representative pictures of BAT and (C) H&E staining of representative BAT collected after warm or chronic cold exposure. (D) Total BAT mass (n = 13–17; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; ###P < 0.001 vs. Control). (E) Total DNA content (n = 7–9; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; ###P < 0.001 vs. Control). (F) mtDNA content (n = 7–9; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; ###P < 0.001 vs. Control). (G) Gene expression of Pgc1a (n = 4; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; ###P < 0.001 vs. Control). (H) Western blots performed on BAT collected from control and Ad-RaptorKO mice following chronic cold exposure. All gels were run under the same experimental conditions. (I) Oxygen consumption at thermoneutrality (warm) and during the transition to cold. (n = 6–8; mean +/− SEM; t-test; *P < 0.05; ***P < 0.001). White section: thermoneutrality, when the lights were on; Grey section: thermoneutrality, when the lights were off; Light blue section: cold, when the lights were on; Dark blue section: cold, when the lights were off. (J) Mean SUV time-activity curves of 11C-acetate during (left) acute and (right) chronic cold exposure (n = 4–5; mean +/− SEM). (K) Total BAT oxidative activity index corrected for tissue weight (n = 6–8; mean +/−SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; #P < 0.05 vs. Control; ###P < 0.001 vs. Control). (L) Total BAT blood flow index corrected for tissue weight (n = 4–5; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; #P < 0.05 vs. Control; ###P < 0.001 vs. Control). (M) Plasma CK activity (n = 10–13; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Warm; ###P < 0.001 vs. Control).
Mentions: In order to test the importance of mTORC1 in regulating BAT function and expansion in response to cold, we crossed RaptorLox/Lox mice36 with mice expressing the Cre-recombinase under the control of the Adiponectin promoter37. This method was efficient to specifically delete Raptor, an essential component of mTORC1, in adipose tissues (Ad-RaptorKO) (Fig. 2A and Figure S2A). At thermoneutrality and following chronic cold exposure, Ad-RaptorKO mice were slightly heavier than control animals, despite a significant reduction in WAT masses (Figure S2B). Consistent with the reduction in WAT size, Ad-RaptorKO mice showed lower levels of circulating leptin and NEFAs (Figure S2C).

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