Glucose uptake in brown fat cells is dependent on mTOR complex 2–promoted GLUT1 translocation

Olsen, Jessica M.; Sato, Masaaki; Dallner, Olof S.; Sandström, Anna L.; Pisani, Didier F.; Chambard, Jean-Claude; Amri, Ez-Zoubir; Hutchinson, Dana S.; Bengtsson, Tore

doi:10.1083/jcb.201403080

Cited by 143 publications

(149 citation statements)

References 44 publications

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“…The 2117-LMP1 was reported to have more potent activity in NF-B activation but lower cellular toxicity than the B95.8-derived LMP1 sequences commonly used in B cell lymphoma studies (34). Moreover, dual mechanisms of activation of Glut-1 involving direct activation and membrane relocation of Glut-1 are involved in the glucose uptake in brown adipose tissue upon stimulation of ␤ 3 adrenoceptors involving cAMP1 and mTOR activation, respectively (35). More studies are warranted to further dissect the mechanisms involved in the upregulation of Glut-1 transcription and membrane translocation in LMP1 activation of glucose uptake in nasopharyngeal epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus-Encoded Latent Membrane Protein 1 Upregulates Glucose Transporter 1 Transcription via the mTORC1/NF-κB Signaling Pathways

Zhang

Jia

Lin

et al. 2017

J Virol

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Accumulating evidence indicates that oncogenic viral protein plays a crucial role in activating aerobic glycolysis during tumorigenesis, but the underlying mechanisms are largely undefined. Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is a transmembrane protein with potent cell signaling properties and has tumorigenic transformation property. Activation of NF-B is a major signaling pathway mediating many downstream transformation properties of LMP1. Here we report that activation of mTORC1 by LMP1 is a key modulator for activation of NF-B signaling to mediate aerobic glycolysis. NF-B activation is involved in the LMP1-induced upregulation of glucose transporter 1 (Glut-1) transcription and growth of nasopharyngeal carcinoma (NPC) cells. Blocking the activity of mTORC1 signaling effectively suppressed LMP1-induced NF-B activation and Glut-1 transcription. Interfering NF-B signaling had no effect on mTORC1 activity but effectively altered Glut-1 transcription. Luciferase promoter assay of Glut-1 also confirmed that the Glut-1 gene is a direct target gene of NF-B signaling. Furthermore, we demonstrated that C-terminal activating region 2 (CTAR2) of LMP1 is the key domain involved in mTORC1 activation, mainly through IKK␤-mediated phosphorylation of TSC2 at Ser 939 . Depletion of Glut-1 effectively led to suppression of aerobic glycolysis, inhibition of cell proliferation, colony formation, and attenuation of tumorigenic growth property of LMP1-expressing nasopharyngeal epithelial (NPE) cells. These findings suggest that targeting the signaling axis of mTORC1/NF-B/Glut-1 represents a novel therapeutic target against NPC.IMPORTANCE Aerobic glycolysis is one of the hallmarks of cancer, including NPC. Recent studies suggest a role for LMP1 in mediating aerobic glycolysis. LMP1 expression is common in NPC. The delineation of essential signaling pathways induced by LMP1 in aerobic glycolysis contributes to the understanding of NPC pathogenesis. This study provides evidence that LMP1 upregulates Glut-1 transcription to control aerobic glycolysis and tumorigenic growth of NPC cells through mTORC1/NF-B signaling. Our results reveal novel therapeutic targets against the mTORC1/NF-B/ Glut-1 signaling axis in the treatment of EBV-infected NPC.

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Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus-Encoded Latent Membrane Protein 1 Upregulates Glucose Transporter 1 Transcription via the mTORC1/NF-κB Signaling Pathways

Zhang

Jia

Lin

et al. 2017

J Virol

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“…KU-63794 is known to inhibit the phosphorylation of mTOR at the Ser2448/2481. 38,39 Inhibition of mTOR phosphorylation was confirmed with immunoblot and effects of mTOR inhibition on MB-induced protection against OGD-reoxygenation was monitored with Calcein AM assay.…”

Section: Methodsmentioning

confidence: 99%

Methylene blue-induced neuronal protective mechanism against hypoxia-reoxygenation stress

Ryou¹,

Choudhury²,

Li³

et al. 2015

Neuroscience

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Brain ischemia and reperfusion (I/R) injury occurs in various pathological conditions, but there is no effective treatment currently available in clinical practice. Methylene blue (MB) is a century old drug with a newly discovered protective function in the ischemic stroke model. In the current investigation we studied the MB-induced neuroprotective mechanism focusing on stabilization and activation of hypoxia inducible factor-1α (HIF-1α) in an in vitro oxygen and glucose deprivation (OGD)-reoxygenation model. Methods HT22 cells were exposed to OGD (0.1% O2, 6h) and reoxygenation (21% O2, 24h). Cell viability was determined with the calcein AM assay. The dynamic change of intracellular O2 concentration was monitored by fluorescence lifetime imaging microscopy (FLTIM). Glucose uptake was quantified using the 2-[N-(7-Nitrobenz-2-Oxa- 1,3-Diazol-4-yl)Amino]- 2-Deoxy-D-Glucose (2-NBDG) assay. ATP concentration and glycolytic enzyme activity were examined by spectrophotometry. Protein content changes were measured by immunoblot: HIF-1α, prolyl hydroxylase 2(PHD2), erythropoietin (EPO), Akt, mTOR, and PIP5K. The contribution of HIF-1α activation in the MB-induced neuroprotective mechanism was confirmed by blocking HIF-1α activation with 2-methoxyestradiol-2 (2-MeOE2) and by transiently transfecting constitutively active HIF-1α. Results MB increases cell viability by about 50% vs. OGD control. Compared to the corresponding control, MB increases intracellular O2 concentration and glucose uptake as well as the activities of hexokinase and G-6-PDH, and ATP concentration. MB activates the EPO signaling pathway with a corresponding increase in HIF-1α. Phosphorylation of Akt was significantly increased with MB treatment followed by activation of the mTOR pathway. Importantly, we observed, MB increased nuclear translocation of HIF-1α vs. control (about 3 folds), which was shown by a ratio of nuclear:cytoplasmic HIF-1α protein content. Conclusion We conclude that MB protects the hippocampus derived neuronal cells against OGD-reoxygenation injury by enhancing energy metabolism and increasing HIF-1α protein content accompanied by an activation of the EPO signaling pathway.

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“…Upon cold exposure or adrenergic stimulation the glucose uptake in BAT is also greatly enhanced [84, 85]. Interestingly, mTORC2 but not mTORC1 has a novel role in β 3-adrenoceptor-stimulated glucose uptake in BAT, in which mTORC2 stimulates translocation of GLUT1 to the plasma membrane and increases glucose uptake, independent of classic insulin-PI3K-Akt pathway [86]. Fatty acids stimulate UCP-1 activity and supply fuel for BAT thermogenesis.…”

Section: Effect Of Mtor Signaling On Thermogenesismentioning

confidence: 99%

Recent Advances in Adipose mTOR Signaling and Function: Therapeutic Prospects

Cai

Dong

Liu

2016

Trends in Pharmacological Sciences

113

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The increasing epidemic of obesity and its comorbidities has spurred research interest in adipose biology and its regulatory functions. Recent studies have revealed that the mechanistic target of rapamycin (mTOR) signaling pathway plays a critical role in the regulation of adipose tissue function, including adipogenesis, lipid metabolism, thermogenesis, and adipokine synthesis/secretion. Given the extreme importance of mTOR signaling in controlling energy homeostasis, it is not unexpected that deregulated mTOR signaling is associated with obesity and related metabolic disorders. In this review, we highlight the current advances in the roles of the mTOR signaling pathway in adipose tissue. We also provide a more nuanced view of how the mTOR signaling pathway regulates adipose tissue biology and function. Finally, we describe approaches to modulate the activity and tissue specific function of mTOR that may pave the way towards counteracting obesity and related metabolic diseases.

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Glucose uptake in brown fat cells is dependent on mTOR complex 2–promoted GLUT1 translocation

Abstract: β3-Adrenoceptors promote glucose uptake in brown adipose tissue via both cAMP-mediated increases in GLUT1 transcription and mTORC2-stimulated translocation of newly synthesized GLUT1 to the plasma membrane.

Cited by 143 publications

References 44 publications

Epstein-Barr Virus-Encoded Latent Membrane Protein 1 Upregulates Glucose Transporter 1 Transcription via the mTORC1/NF-κB Signaling Pathways

Epstein-Barr Virus-Encoded Latent Membrane Protein 1 Upregulates Glucose Transporter 1 Transcription via the mTORC1/NF-κB Signaling Pathways

Methylene blue-induced neuronal protective mechanism against hypoxia-reoxygenation stress

Recent Advances in Adipose mTOR Signaling and Function: Therapeutic Prospects

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