Rapamycin Blocks Induction of the Thermogenic Program in White Adipose Tissue

Tran, Cassie M.; Mukherjee, Sarmistha; Ye, Lan; Frederick, David W.; Kissig, Megan; Davis, James G.; Lamming, Dudley W.; Seale, Patrick; Baur, Joseph A.

doi:10.2337/db15-0502

Cited by 70 publications

(75 citation statements)

References 49 publications

(51 reference statements)

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“…1E, we observed that acute cold exposure induced a robust increase in the phosphorylation levels of ribosomal protein S6, a readout of mTORC1 activity. These results confirm the findings of two recent reports showing that adrenergic stimulation and cold both activate mTORC1 in WAT and BAT2829. Interestingly, pre-treating mice with the mTORC1 inhibitor rapamycin was sufficient to block cold-induced phosphorylation of S6 (Fig.…”

Section: Resultssupporting

confidence: 92%

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: Resultssupporting

confidence: 92%

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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“…This phenotype could be reversed both in vivo and in vitro in cultured brown adipocytes by treatment with rapamycin, which rescued the normal brown phenotype. Intriguingly, rapamycin treatment also promotes a brown phenotype in white adipocytes; treatment with rapamycin blocks white adipocyte beiging in response to acute β3-adrenergic receptor agonist stimulation, and suppresses cold-induced beiging of white adipose tissue, decreasing cold tolerance (Tran et al, 2016). Subsequent work determined that β3-adrenergic signaling stimulates PKA-mediated phosphorylation of both mTOR and Raptor, leading to activation of mTORC1 and expression of uncoupling protein-1 (Ucp1) (Liu et al, 2016).…”

Section: Mtor a Metabolic Master Regulatormentioning

confidence: 99%

The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging

2016

Self Cite

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Summary Since the discovery that rapamycin, a small molecule inhibitor of the protein kinase mTOR (mechanistic Target Of Rapamycin), can extend the lifespan of model organisms including mice, interest in understanding the physiological role and molecular targets of this pathway has surged. While mTOR was already well known as a regulator of growth and protein translation, it is now clear that mTOR functions as a central coordinator of organismal metabolism in response to both environmental and hormonal signals. This review discusses recent developments in our understanding of how mTOR signaling is regulated by nutrients and the role of the mTOR signaling pathway in key metabolic tissues. Finally, we discuss the molecular basis for the negative metabolic side effects associated with rapamycin treatment, which may serve as barriers to the adoption of rapamycin or similar compounds for the treatment of diseases of aging and metabolism.

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“…Insulin activates TORC1 via the PI 3-kinase/Akt pathway. Importantly, adipocyte-specific ablation of raptor, an essential component of the TORC1 complex, inhibits β adrenergic-stimulated beige adipogenesis in mice (306). Thus, the IRS1/PI 3-kinase/Akt/TORC1 pathway appears to be indispensable for insulin to promote BAT and beige fat function.…”

Section: Humoral Regulation Of Brown and Beige Fat Thermogenesismentioning

confidence: 99%

Brown and Beige Adipose Tissues in Health and Disease

Rui

2017

Comprehensive Physiology

137

106

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Brown and beige adipocytes arise from distinct developmental origins. Brown adipose tissue (BAT) develops embryonically from precursors that also give to skeletal muscle. Beige fat develops postnatally and is highly inducible. Beige fat recruitment is mediated by multiple mechanisms, including de novo beige adipogenesis and white-to-brown adipocyte transdifferentiaiton. Beige precursors reside around vasculatures, and proliferate and differentiate into beige adipocytes. PDGFRα+Ebf2+ precursors are restricted to beige lineage cells, while another PDGFRα+ subset gives rise to beige adipocytes, white adipocytes, or fibrogenic cells. White adipocytes can be reprogramed and transdifferentiated into beige adipocytes. Brown and beige adipocytes display many similar properties, including multilocular lipid droplets, dense mitochondria, and expression of UCP1. UCP1-mediated thermogenesis is a hallmark of brown/beige adipocytes, albeit UCP1-independent thermogenesis also occurs. Development, maintenance, and activation of BAT/beige fat are guided by genetic and epigenetic programs. Numerous transcriptional factors and coactivators act coordinately to promote BAT/beige fat thermogenesis. Epigenetic reprograming also influences expression of brown/beige adipocyte-selective genes. BAT/beige fat is regulated by neuronal, hormonal, and immune mechanisms. Hypothalamic thermal circuits define the temperature setpoint that guides BAT/beige fat activity. Metabolic hormones, paracrine/autocrine factors, and various immune cells also play a critical role in regulating BAT/beige fat functions. BAT and beige fat defend temperature homeostasis, and regulate body weight and glucose and lipid metabolism. Obesity is associated with brown/beige fat deficiency, and reactivation of brown/beige fat provides metabolic health benefits in some patients. Pharmacological activation of BAT/beige fat may hold promise for combating metabolic diseases.

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Rapamycin Blocks Induction of the Thermogenic Program in White Adipose Tissue

Cited by 70 publications

References 49 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

The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging

Brown and Beige Adipose Tissues in Health and Disease

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