Constitutive adipocyte mTORC1 activation enhances mitochondrial activity and reduces visceral adiposity in mice

Magdalon, Juliana; Chimin, Patrícia; Belchior, Thiago; Neves, R. F.; Vieira-Lara, Marcel A.; Andrade, Mauro Figueiredo Carvalho de; Farias, Talita S. M.; Lopes, Andressa Bolsoni; Paschoal, Vivian A.; Yamashita, Alex Shimura; Kowaltowski, Alicia J.; Festuccia, William T.

doi:10.1016/j.bbalip.2016.02.023

Cited by 37 publications

(32 citation statements)

References 38 publications

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“…Recent studies reported the impact of tuberous sclerosis complex 1 (Tsc1 ) loss on WAT and BAT7879. Because the loss of TSC1 constitutively activates mTORC1, it would be expected that these studies would show results that oppose our findings.…”

Section: Discussioncontrasting

confidence: 69%

“…Because the loss of TSC1 constitutively activates mTORC1, it would be expected that these studies would show results that oppose our findings. Accordingly, Adiponectin-cre mediated recombination of Tsc1 increased BAT mass, an effect associated with a trend towards higher BAT DNA content78. The impact of cold on BAT mass expansion and metabolism was not tested in this report.…”

Section: Discussionmentioning

confidence: 79%

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

Labbé

Mouchiroud

Caron

et al. 2016

Sci Rep

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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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Section: Discussioncontrasting

confidence: 69%

Section: Discussionmentioning

confidence: 79%

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

Labbé

Mouchiroud

Caron

et al. 2016

Sci Rep

Self Cite

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“…Elevated mTORC1 signaling resulting from the deletion of tuberous sclerosis complex 2 (Tsc2), a complex made up of Tsc1 and Tsc2 proteins that inhibits mTORC1 signaling, led to increased adipogenesis in mouse fibroblasts and 3T3-L1 adipocytes ). However, in vivo constitutive activation of mTORC1 in adipocytes by Tsc1 deletion did not induce adipocyte hypertrophy, but instead led to reduced VAT mass, reduced VAT adipocyte number and reduced VAT adipocytes diameter without affecting SAT, pointing to the complex nature of mTORC1 signaling in adipocytes (Magdalon et al, 2016). Taken together, these results show that mTORC1 depletion leads to adipose atrophy, although conclusive evidence of a role for mTORC1 in adipocyte hypertrophy has not been fully elucidated.…”

Section: Cellular Mechanisms Hypothesized To Regulate Adipose Morphologysupporting

confidence: 54%

Adipose morphology and metabolic disease

Tandon

Wafer

Minchin

2018

Journal of Experimental Biology

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Adipose morphology is defined as the number and size distribution of adipocytes (fat cells) within adipose tissue. Adipose tissue with fewer but larger adipocytes is said to have a 'hypertrophic' morphology, whereas adipose with many adipocytes of a smaller size is said to have a 'hyperplastic' morphology. Hypertrophic adipose morphology is positively associated with insulin resistance, diabetes and cardiovascular disease. By contrast, hyperplastic morphology is associated with improved metabolic parameters. These phenotypic associations suggest that adipose morphology influences risk of cardiometabolic disease. Intriguingly, monozygotic twin studies have determined that adipose morphology is in part determined genetically. Therefore, identifying the genetic regulation of adipose morphology may help us to predict, prevent and ameliorate insulin resistance and associated metabolic diseases. Here, we review the current literature regarding adipose morphology in relation to: (1) metabolic and medical implications; (2) the methods used to assess adipose morphology; and (3) transcriptional differences between morphologies. We further highlight three mechanisms that have been hypothesized to promote adipocyte hypertrophy and thus to regulate adipose morphology.

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“…To address the specificity of rapamycin’s effect in vivo, both studies used Raptor Adipoq-Cre mice to show that Ucp1 cannot be induced by cold [76, 77] or βAR3-agonists [76, 77] without functional mTORC1 in WAT. In agreement, another recent study finds that activating mTORC1 in WAT by deleting its negative regulator TSC1 ( Tsc1 Adipoq-Cre mice) elevates Ucp1, PGC-1α, and PPARα levels [81]. In cultured adipocytes, βAR agonists were also shown to stimulate S6K but not AKT phosphorylation, suggesting a link between mTORC1 and protein kinase A (PKA) signaling [77].…”

Section: Mtorc1 In Brown Adipocytes and The “Browning Of Wat”mentioning

confidence: 69%

The Complex Roles of Mechanistic Target of Rapamycin in Adipocytes and Beyond

Lee

Jung

Guertin

2017

Trends in Endocrinology & Metabolism

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Having healthy adipose tissue is essential for metabolic fitness. This is clear from the obesity epidemic, which is unveiling a myriad of comorbidities associated with excess adipose tissue including type 2 diabetes, cardiovascular disease, and cancer. Lipodystrophy also causes insulin resistance emphasizing the importance of having a balanced amount fat. In cells, the mammalian target of rapamycin (mTOR) complexes (mTORC1 and mTORC2) link nutrient and hormonal signaling with metabolism, and recent studies are shedding new light on their in vivo roles in adipocytes. Here, we discuss how recent advances in adipose tissue and mTOR biology are converging to reveal new mechanisms that maintain healthy adipose tissue, and discuss ongoing mysteries of mTOR signaling, particularly for the less understood complex mTORC2.

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Constitutive adipocyte mTORC1 activation enhances mitochondrial activity and reduces visceral adiposity in mice

Cited by 37 publications

References 38 publications

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

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

Adipose morphology and metabolic disease

The Complex Roles of Mechanistic Target of Rapamycin in Adipocytes and Beyond

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