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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

Cold exposure promotes mTORC1 activity in BAT through the sympathetic nervous system.Mice were either kept at thermoneutrality (warm; 30 °C) or exposed to cold (10 °C) during 2 weeks. Acute cold exposure (6-hour at 10 °C) was performed following 2 weeks at thermoneutrality. (A) Gene expression of Pgc1a and Ucp1 in BAT (n = 8 for warm; n = 5 for acute cold; n = 8 for chronic cold; mean +/− SEM; ANOVA; *P < 0.05; ***P < 0.001). (B) (Left) Representative pictures of BAT collected from mice kept at thermoneutrality or exposed to cold for 2 weeks. (Right) BAT weight measured from the same animals (n = 14–22; mean +/− SEM; t-test; ***P < 0.001). (C) Representative H&E staining of representative BAT collected from mice kept at thermoneutrality or in cold for 2 weeks. (D) (Left) Total DNA content (n = 7–8; mean +/− SEM; t-test; *P < 0.05) and (right) mtDNA content measured in mice kept in warm or cold for 2 weeks. (n = 8; mean +/− SEM; t-test; ***P < 0.05). (E) Western blots performed on BAT collected from mice following warm or acute cold exposure. Mice were fasted during the cold exposure (6-hour period). (F) Western blots performed on BAT collected from mice following warm or acute cold exposure. A group of cold-exposed mice received an acute intraperitoneal injection of rapamycin (2 mg/kg) one-hour prior to the cold exposure (6-hour period). (G) Western blots performed on BAT collected from mice following warm or chronic cold exposure. Mice were fasted during the last 6 hours. (H) Representative pictures of unilateral BAT denervation. (Left) Sham mice kept at thermoneutrality, (middle) unilateral BAT denervation following acute cold or (right) chronic cold exposure. (I) BAT lobe weight following unilateral BAT denervation (n = 8 for Sham-Warm; n = 5 for acute cold; n = 10 for chronic cold; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Sham-Warm lobe; ###P < 0.001 vs. Innervated lobe). (J) Western blots performed on BAT collected from mice with unilateral BAT denervation. Mice were fasted during the last 6 hours. Each mouse was its own control. In this panel, (I) refers to the innervated lobe and and (D) refers to the denervated lobe. All gels have been run under the same experimental conditions.
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f1: Cold exposure promotes mTORC1 activity in BAT through the sympathetic nervous system.Mice were either kept at thermoneutrality (warm; 30 °C) or exposed to cold (10 °C) during 2 weeks. Acute cold exposure (6-hour at 10 °C) was performed following 2 weeks at thermoneutrality. (A) Gene expression of Pgc1a and Ucp1 in BAT (n = 8 for warm; n = 5 for acute cold; n = 8 for chronic cold; mean +/− SEM; ANOVA; *P < 0.05; ***P < 0.001). (B) (Left) Representative pictures of BAT collected from mice kept at thermoneutrality or exposed to cold for 2 weeks. (Right) BAT weight measured from the same animals (n = 14–22; mean +/− SEM; t-test; ***P < 0.001). (C) Representative H&E staining of representative BAT collected from mice kept at thermoneutrality or in cold for 2 weeks. (D) (Left) Total DNA content (n = 7–8; mean +/− SEM; t-test; *P < 0.05) and (right) mtDNA content measured in mice kept in warm or cold for 2 weeks. (n = 8; mean +/− SEM; t-test; ***P < 0.05). (E) Western blots performed on BAT collected from mice following warm or acute cold exposure. Mice were fasted during the cold exposure (6-hour period). (F) Western blots performed on BAT collected from mice following warm or acute cold exposure. A group of cold-exposed mice received an acute intraperitoneal injection of rapamycin (2 mg/kg) one-hour prior to the cold exposure (6-hour period). (G) Western blots performed on BAT collected from mice following warm or chronic cold exposure. Mice were fasted during the last 6 hours. (H) Representative pictures of unilateral BAT denervation. (Left) Sham mice kept at thermoneutrality, (middle) unilateral BAT denervation following acute cold or (right) chronic cold exposure. (I) BAT lobe weight following unilateral BAT denervation (n = 8 for Sham-Warm; n = 5 for acute cold; n = 10 for chronic cold; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Sham-Warm lobe; ###P < 0.001 vs. Innervated lobe). (J) Western blots performed on BAT collected from mice with unilateral BAT denervation. Mice were fasted during the last 6 hours. Each mouse was its own control. In this panel, (I) refers to the innervated lobe and and (D) refers to the denervated lobe. All gels have been run under the same experimental conditions.

Mentions: Cold exposure rapidly activates thermogenesis in BAT126. The rapid induction of BAT thermogenic capacity is highly dependent on peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a key transcriptional regulator that promotes the expression of several thermogenic genes, including Ucp127. Confirming previous findings, we observed that both acute (6 hours) and chronic (2 weeks) cold exposure (10 °C) strongly enhance the expression of Pgc1a and Ucp1 in BAT (Fig. 1A). Other genes known to participate in the metabolic adaptation to cold were also induced in these conditions (Figure S1A).


mTORC1 is Required for Brown Adipose Tissue Recruitment and Metabolic Adaptation to Cold
Cold exposure promotes mTORC1 activity in BAT through the sympathetic nervous system.Mice were either kept at thermoneutrality (warm; 30 °C) or exposed to cold (10 °C) during 2 weeks. Acute cold exposure (6-hour at 10 °C) was performed following 2 weeks at thermoneutrality. (A) Gene expression of Pgc1a and Ucp1 in BAT (n = 8 for warm; n = 5 for acute cold; n = 8 for chronic cold; mean +/− SEM; ANOVA; *P < 0.05; ***P < 0.001). (B) (Left) Representative pictures of BAT collected from mice kept at thermoneutrality or exposed to cold for 2 weeks. (Right) BAT weight measured from the same animals (n = 14–22; mean +/− SEM; t-test; ***P < 0.001). (C) Representative H&E staining of representative BAT collected from mice kept at thermoneutrality or in cold for 2 weeks. (D) (Left) Total DNA content (n = 7–8; mean +/− SEM; t-test; *P < 0.05) and (right) mtDNA content measured in mice kept in warm or cold for 2 weeks. (n = 8; mean +/− SEM; t-test; ***P < 0.05). (E) Western blots performed on BAT collected from mice following warm or acute cold exposure. Mice were fasted during the cold exposure (6-hour period). (F) Western blots performed on BAT collected from mice following warm or acute cold exposure. A group of cold-exposed mice received an acute intraperitoneal injection of rapamycin (2 mg/kg) one-hour prior to the cold exposure (6-hour period). (G) Western blots performed on BAT collected from mice following warm or chronic cold exposure. Mice were fasted during the last 6 hours. (H) Representative pictures of unilateral BAT denervation. (Left) Sham mice kept at thermoneutrality, (middle) unilateral BAT denervation following acute cold or (right) chronic cold exposure. (I) BAT lobe weight following unilateral BAT denervation (n = 8 for Sham-Warm; n = 5 for acute cold; n = 10 for chronic cold; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Sham-Warm lobe; ###P < 0.001 vs. Innervated lobe). (J) Western blots performed on BAT collected from mice with unilateral BAT denervation. Mice were fasted during the last 6 hours. Each mouse was its own control. In this panel, (I) refers to the innervated lobe and and (D) refers to the denervated lobe. All gels have been run under the same experimental conditions.
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Related In: Results  -  Collection

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f1: Cold exposure promotes mTORC1 activity in BAT through the sympathetic nervous system.Mice were either kept at thermoneutrality (warm; 30 °C) or exposed to cold (10 °C) during 2 weeks. Acute cold exposure (6-hour at 10 °C) was performed following 2 weeks at thermoneutrality. (A) Gene expression of Pgc1a and Ucp1 in BAT (n = 8 for warm; n = 5 for acute cold; n = 8 for chronic cold; mean +/− SEM; ANOVA; *P < 0.05; ***P < 0.001). (B) (Left) Representative pictures of BAT collected from mice kept at thermoneutrality or exposed to cold for 2 weeks. (Right) BAT weight measured from the same animals (n = 14–22; mean +/− SEM; t-test; ***P < 0.001). (C) Representative H&E staining of representative BAT collected from mice kept at thermoneutrality or in cold for 2 weeks. (D) (Left) Total DNA content (n = 7–8; mean +/− SEM; t-test; *P < 0.05) and (right) mtDNA content measured in mice kept in warm or cold for 2 weeks. (n = 8; mean +/− SEM; t-test; ***P < 0.05). (E) Western blots performed on BAT collected from mice following warm or acute cold exposure. Mice were fasted during the cold exposure (6-hour period). (F) Western blots performed on BAT collected from mice following warm or acute cold exposure. A group of cold-exposed mice received an acute intraperitoneal injection of rapamycin (2 mg/kg) one-hour prior to the cold exposure (6-hour period). (G) Western blots performed on BAT collected from mice following warm or chronic cold exposure. Mice were fasted during the last 6 hours. (H) Representative pictures of unilateral BAT denervation. (Left) Sham mice kept at thermoneutrality, (middle) unilateral BAT denervation following acute cold or (right) chronic cold exposure. (I) BAT lobe weight following unilateral BAT denervation (n = 8 for Sham-Warm; n = 5 for acute cold; n = 10 for chronic cold; mean +/− SEM; Two-way ANOVA; ***P < 0.001 vs. Sham-Warm lobe; ###P < 0.001 vs. Innervated lobe). (J) Western blots performed on BAT collected from mice with unilateral BAT denervation. Mice were fasted during the last 6 hours. Each mouse was its own control. In this panel, (I) refers to the innervated lobe and and (D) refers to the denervated lobe. All gels have been run under the same experimental conditions.
Mentions: Cold exposure rapidly activates thermogenesis in BAT126. The rapid induction of BAT thermogenic capacity is highly dependent on peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a key transcriptional regulator that promotes the expression of several thermogenic genes, including Ucp127. Confirming previous findings, we observed that both acute (6 hours) and chronic (2 weeks) cold exposure (10 °C) strongly enhance the expression of Pgc1a and Ucp1 in BAT (Fig. 1A). Other genes known to participate in the metabolic adaptation to cold were also induced in these conditions (Figure S1A).

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