Activation of mTORC1 is essential for β-adrenergic stimulation of adipose browning

Liu, Dianxin; Bordicchia, Marica; Zhang, Chaoying; Fang, Huafeng; Wei, Wan; Li, Jianliang; Guilherme, Adı́lson; Czech, Michael P.; Collins, Sheila

doi:10.1172/jci83532

Cited by 173 publications

(211 citation statements)

References 97 publications

Supporting

Mentioning

182

Contrasting

Unclassified

Order By: Relevance

“…In contrast to the prevailing view, we demonstrate that mTORC1 plays a positive role in the induction of beige adipocytes by β-adrenergic signaling, acting downstream of PKA and on expression of Adrb3 . While this article was in press, an independent report was published that confirms our central finding of a positive role for mTORC1 signaling in the beiging of white fat (47). Future experiments will further delineate the specific signaling mechanisms involved, which may open up new therapeutic avenues to promote beiging of WAT and avoid the detrimental side effects of rapamycin in humans.…”

Section: Discussionsupporting

confidence: 76%

Rapamycin Blocks Induction of the Thermogenic Program in White Adipose Tissue

Tran

Mukherjee

et al. 2016

Diabetes

View full text Add to dashboard Cite

Rapamycin extends life span in mice, yet paradoxically causes lipid dysregulation and glucose intolerance through mechanisms that remain incompletely understood. Whole-body energy balance can be influenced by beige/brite adipocytes, which are inducible by cold and other stimuli via β-adrenergic signaling in white adipose depots. Induction of beige adipocytes is considered a promising strategy to combat obesity because of their ability to metabolize glucose and lipids, dissipating the resulting energy as heat through uncoupling protein 1. Here, we report that rapamycin blocks the ability of β-adrenergic signaling to induce beige adipocytes and expression of thermogenic genes in white adipose depots. Rapamycin enhanced transcriptional negative feedback on the β3-adrenergic receptor. However, thermogenic gene expression remained impaired even when the receptor was bypassed with a cell-permeable cAMP analog, revealing the existence of a second inhibitory mechanism. Accordingly, rapamycin-treated mice are cold intolerant, failing to maintain body temperature and weight when shifted to 4°C. Adipocyte-specific deletion of the mTORC1 subunit Raptor recapitulated the block in β-adrenergic signaling. Our findings demonstrate a positive role for mTORC1 in the recruitment of beige adipocytes and suggest that inhibition of β-adrenergic signaling by rapamycin may contribute to its physiological effects.

show abstract

Section: Discussionsupporting

confidence: 76%

Rapamycin Blocks Induction of the Thermogenic Program in White Adipose Tissue

Tran

Mukherjee

et al. 2016

Diabetes

View full text Add to dashboard Cite

show abstract

“…5) In a recent study, mechanistic target of rapamycin complex 1 (mTORC1) was demonstrated to be a necessary component in the process of the browning of white adipose depots, and blocking of mTOR signaling by rapamycin treatment would abrogate the effect of WAT browning. 18) Our present data also suggested the inhibitory role of rapamycin treatment in WAT browning, for rapamycin treatment significantly decreased the expression levels of browning markers in the WAT of the mice. However, rapamycin's influence on brown fat browning has been poorly characterized thus far.…”

Section: Discussionsupporting

confidence: 80%

Chronic Rapamycin Treatment Improved Metabolic Phenotype but Inhibited Adipose Tissue Browning in High-Fat Diet-Fed C57BL/6J Mice

Wang

2017

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Rapamycin (Rap) has been demonstrated to affect lipid metabolism through stimulating lipolysis, inhibiting de novo lipogenesis and reducing adiposity. In the present study, we investigated rapamycin exposure's influence on adipose tissue browning in high-fat diet-induced fatty mice. Four-week old C57BL/6J mice were fed normal chow or high-fat diet for a period of 6 weeks and then divided into three groups: (1) Nor group: mice fed with normal chow; (2) high fat diet (HFD) group: fatty mice fed with high-fat diet; (3) Rap group: high-fat diet-fed fatty mice treated intragastrically with rapamycin at a dose of 2.5 mg/kg per day for 5 weeks. Body weights and food intakes of the mice were recorded weekly. At the end of the study, blood samples were collected for glucose, lipid and insulin evaluations. Adipose tissues were weighed and lipid contents were monitored. Moreover, real-time PCR and Western blotting were applied to detect the expression levels of beige and brown fat marker genes in white adipose tissue (WAT) and brown adipose tissue (BAT). Our data demonstrated that Rap exposure significantly ameliorated metabolic defects including hyperglycaemia, dyslipidaemia and insulin resistance in the fatty mice. Furthermore, Rap treatment led to decreased tissue weights and lipid contents both in WAT and BAT. Remarkably, expression levels of BAT marker genes including uncoupling protein-1 (UCP-1), cell death-inducing DNA fragmentation factor-alpha-like effector A (CIDEA), PR-domain containing protein-16 (PRDM16) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) were significantly down-regulated in Rap-treated fatty mice. This report demonstrates Rap exposure is capable of inhibiting adipose tissue browning in high-fat diet-induced fatty mice, and provides evidence for deeper understanding of Rap's influence on lipid homeostasis.Key words rapamycin; beige fat; brown fat; uncoupling protein-1 (ucp-1); high fat diet mTOR, a highly conserved serine/threonine protein kinase and "target of rapamycin," serves as a primary regulator of protein synthesis and integrates diverse upstream signals that include amino acid and energy stress sensing to regulate cell proliferation, growth and survival.1,2) Rapamycin, the specific mTOR signaling blocker, is therefore widely used as immunosuppressant and anticancer agent due to its strong antiproliferative effect involved in immunosuppression. Recently, emerging evidence unveiled the profound role rapamycin played in lipid homeostasis. In high-fat diet-fed C57BL/6J mice, rapamycin treatment inhibits adipocyte differentiation and reduces fat mass, 3) and chronic rapamycin exposure exacerbates dyslipidemia in high-fat diet and streptozotocininduced diabetic mice. 4) Moreover, the mechanism underlying the effect of rapamycin on lipid metabolism are verified to increase lipolysis, inhibit lipid storage and down-regulate genes required for lipid uptake and storage in adipose tissue. 5,6) The global epidemic of obesity has drawn increasing attention worldwide. While whi...

show abstract

“…Loss of raptor and mTORC1 activity in fat leads to browning of WAT (Polak et al 2008;Tran et al 2016), while converse activation of mTOR via deletion of TSC1 leads to whitening of BAT (Xiang et al 2015), thus suggesting that mTOR suppresses adipose browning. In contrast, however, two reports now show that loss of raptor in fat or pharmacological inhibition of mTOR dramatically blocks cold-induced browning of WAT and that mTOR is a direct target of adrenergic signaling and protein kinase A (PKA) (Liu et al 2016;Tran et al 2016). Thus, mTOR appears to have paradoxical both positive and negative roles in adipose browning in vivo.…”

Section: Reconciling the Role Of Mtor In Adipocyte Browningmentioning

confidence: 99%

“…Loss of raptor in fat and portions of the brain leads to browning of WAT (Polak et al 2008), while activation of mTOR in the same tissue distribution via deletion of tuberous sclerosis complex-1 (TSC1) leads to whitening of BAT (Xiang et al 2015), suggesting that mTOR suppresses adipose browning in vivo. On the other hand, recent work shows that loss of raptor in fat or pharmacological inhibition of mTOR blocks cold-induced browning of WAT (Liu et al 2016;Tran et al 2016), demonstrating that mTOR can also promote adipose browning in vivo. A mechanistic reconciliation of these observations is lacking.…”

mentioning

confidence: 99%

The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue

et al. 2016

View full text Add to dashboard Cite

Noncanonical mechanistic target of rapamycin (mTOR) pathways remain poorly understood. Mutations in the tumor suppressor folliculin (FLCN) cause Birt-Hogg-Dubé syndrome, a hamartomatous disease marked by mitochondria-rich kidney tumors. FLCN functionally interacts with mTOR and is expressed in most tissues, but its role in fat has not been explored. We show here that FLCN regulates adipose tissue browning via mTOR and the transcription factor TFE3. Adipose-specific deletion of FLCN relieves mTOR-dependent cytoplasmic retention of TFE3, leading to direct induction of the PGC-1 transcriptional coactivators, drivers of mitochondrial biogenesis and the browning program. Cytoplasmic retention of TFE3 by mTOR is sensitive to ambient amino acids, is independent of growth factor and tuberous sclerosis complex (TSC) signaling, is driven by RagC/D, and is separable from canonical mTOR signaling to S6K. Codeletion of TFE3 in adipose-specific FLCN knockout animals rescues adipose tissue browning, as does codeletion of PGC-1β. Conversely, inducible expression of PGC-1β in white adipose tissue is sufficient to induce beige fat gene expression in vivo. These data thus unveil a novel FLCN-mTOR-TFE3-PGC-1β pathway-separate from the canonical TSC-mTOR-S6K pathway-that regulates browning of adipose tissue.

show abstract

Activation of mTORC1 is essential for β-adrenergic stimulation of adipose browning

Cited by 173 publications

References 97 publications

Rapamycin Blocks Induction of the Thermogenic Program in White Adipose Tissue

Rapamycin Blocks Induction of the Thermogenic Program in White Adipose Tissue

Chronic Rapamycin Treatment Improved Metabolic Phenotype but Inhibited Adipose Tissue Browning in High-Fat Diet-Fed C57BL/6J Mice

The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue

Contact Info

Product

Resources

About