1932

Abstract

The synthesis of lipids in response to food intake represents a key advantage that allows organisms to survive when energy availability is limited. In mammals, circulating levels of insulin and nutrients, which fluctuate between fasting and feeding, dictate whether lipids are synthesized or catabolized by tissues. The mechanistic target of rapamycin (mTOR), a kinase that is activated by anabolic signals, plays fundamental roles in regulating lipid biosynthesis and metabolism in response to nutrition. The mTOR kinase nucleates two large protein complexes named mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Following their activation, these complexes facilitate the accumulation of triglycerides by promoting adipogenesis and lipogenesis and by shutting down catabolic processes such as lipolysis and β-oxidation. Here, we review and discuss the roles of mTOR complexes in various aspects of lipid metabolism in mammals. We also use this opportunity to discuss the implication of these relations to the maintenance of systemic lipid homeostasis.

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2015-07-17
2024-03-29
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Literature Cited

  1. Abu-Elheiga L, Oh W, Kordari P, Wakil SJ. 1.  2003. Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/high-carbohydrate diets. PNAS 100:10207–12 [Google Scholar]
  2. Aggarwal D, Fernandez ML, Soliman GA. 2.  2006. Rapamycin, an mTOR inhibitor, disrupts triglyceride metabolism in guinea pigs. Metabolism 55:794–802 [Google Scholar]
  3. Bakan I, Laplante M. 3.  2012. Connecting mTORC1 signaling to SREBP-1 activation. Curr. Opin. Lipidol. 23:226–34 [Google Scholar]
  4. Bar-Peled L, Sabatini DM. 4.  2014. Regulation of mTORC1 by amino acids. Trends Cell Biol. 24:400–6 [Google Scholar]
  5. Bar-Peled L, Schweitzer LD, Zoncu R, Sabatini DM. 5.  2012. Ragulator is a GEF for the Rag GTPases that signal amino acid levels to mTORC1. Cell 150:1196–208 [Google Scholar]
  6. Bell A, Grunder L, Sorisky A. 6.  2000. Rapamycin inhibits human adipocyte differentiation in primary culture. Obes. Res. 8:249–54 [Google Scholar]
  7. Bengoechea-Alonso MT, Ericsson J. 7.  2009. A phosphorylation cascade controls the degradation of active SREBP1. J. Biol. Chem. 284:5885–95 [Google Scholar]
  8. Bentzinger CF, Romanino K, Cloetta D, Lin S, Mascarenhas JB. 8.  et al. 2008. Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab. 8:411–24 [Google Scholar]
  9. Birsoy K, Festuccia WT, Laplante M. 9.  2013. A comparative perspective on lipid storage in animals. J. Cell Sci. 126:1541–52 [Google Scholar]
  10. Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT. 10.  et al. 1994. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369:756–58 [Google Scholar]
  11. Brown NF, Stefanovic-Racic M, Sipula IJ, Perdomo G. 11.  2007. The mammalian target of rapamycin regulates lipid metabolism in primary cultures of rat hepatocytes. Metabolism 56:1500–7 [Google Scholar]
  12. Carnevalli LS, Masuda K, Frigerio F, Le Bacquer O, Um SH. 12.  et al. 2010. S6K1 plays a critical role in early adipocyte differentiation. Dev. Cell 18:763–74 [Google Scholar]
  13. Cawthorn WP, Scheller EL, MacDougald OA. 13.  2012. Adipose tissue stem cells meet preadipocyte commitment: going back to the future. J. Lipid Res. 53:227–46 [Google Scholar]
  14. Chakrabarti P, English T, Shi J, Smas CM, Kandror KV. 14.  2010. Mammalian target of rapamycin complex 1 suppresses lipolysis, stimulates lipogenesis, and promotes fat storage. Diabetes 59:775–81 [Google Scholar]
  15. Chakrabarti P, Kim JY, Singh M, Shin YK, Kim J. 15.  et al. 2013. Insulin inhibits lipolysis in adipocytes via the evolutionarily conserved mTORC1-Egr1-ATGL-mediated pathway. Mol. Cell. Biol. 33:3659–66 [Google Scholar]
  16. Chang GR, Chiu YS, Wu YY, Chen WY, Liao JW. 16.  et al. 2009. Rapamycin protects against high fat diet-induced obesity in C57BL/6J mice. J. Pharmacol. Sci. 109:496–503 [Google Scholar]
  17. Chang GR, Wu YY, Chiu YS, Chen WY, Liao JW. 17.  et al. 2009. Long-term administration of rapamycin reduces adiposity, but impairs glucose tolerance in high-fat diet-fed KK/HlJ mice. Basic Clin. Pharmacol. Toxicol. 105:188–98 [Google Scholar]
  18. Cho HJ, Park J, Lee HW, Lee YS, Kim JB. 18.  2004. Regulation of adipocyte differentiation and insulin action with rapamycin. Biochem. Biophys. Res. Commun. 321:942–48 [Google Scholar]
  19. Cornu M, Oppliger W, Albert V, Robitaille AM, Trapani F. 19.  et al. 2014. Hepatic mTORC1 controls locomotor activity, body temperature, and lipid metabolism through FGF21. PNAS 111:11592–99 [Google Scholar]
  20. Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P. 20.  2007. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature 450:736–40 [Google Scholar]
  21. Cybulski N, Polak P, Auwerx J, Ruegg MA, Hall MN. 21.  2009. mTOR complex 2 in adipose tissue negatively controls whole-body growth. PNAS 106:9902–7 [Google Scholar]
  22. Dibble CC, Elis W, Menon S, Qin W, Klekota J. 22.  et al. 2012. TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol. Cell 47:535–46 [Google Scholar]
  23. Dif N, Euthine V, Gonnet E, Laville M, Vidal H, Lefai E. 23.  2006. Insulin activates human sterol-regulatory-element-binding protein-1c (SREBP-1c) promoter through SRE motifs. Biochem. J. 400:179–88 [Google Scholar]
  24. Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI. 24.  et al. 2010. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39:171–83 [Google Scholar]
  25. Efeyan A, Comb WC, Sabatini DM. 25.  2015. Nutrient-sensing mechanisms and pathways. Nature 517:302–10 [Google Scholar]
  26. El-Chaar D, Gagnon A, Sorisky A. 26.  2004. Inhibition of insulin signaling and adipogenesis by rapamycin: effect on phosphorylation of p70 S6 kinase versus eIF4E-BP1. Int. J. Obes. Relat. Metab. Disord. 28:191–98 [Google Scholar]
  27. Festuccia WT, Pouliot P, Bakan I, Sabatini DM, Laplante M. 27.  2014. Myeloid-specific Rictor deletion induces M1 macrophage polarization and potentiates in vivo pro-inflammatory response to lipopolysaccharide. PLOS ONE 9:e95432 [Google Scholar]
  28. Foretz M, Pacot C, Dugail I, Lemarchand P, Guichard C. 28.  et al. 1999. ADD1/SREBP-1c is required in the activation of hepatic lipogenic gene expression by glucose. Mol. Cell. Biol. 19:3760–68 [Google Scholar]
  29. Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T. 29.  et al. 2006. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr. Biol. 16:1865–70 [Google Scholar]
  30. Gagnon A, Lau S, Sorisky A. 30.  2001. Rapamycin-sensitive phase of 3T3-L1 preadipocyte differentiation after clonal expansion. J. Cell. Physiol. 189:14–22 [Google Scholar]
  31. Guertin DA, Stevens DM, Saitoh M, Kinkel S, Crosby K. 31.  et al. 2009. mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell 15:148–59 [Google Scholar]
  32. Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY. 32.  et al. 2006. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCα, but not S6K1. Dev. Cell 11:859–71 [Google Scholar]
  33. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A. 33.  et al. 2008. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30:214–26 [Google Scholar]
  34. Hagiwara A, Cornu M, Cybulski N, Polak P, Betz C. 34.  et al. 2012. Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell Metab. 15:725–38 [Google Scholar]
  35. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N. 35.  et al. 2002. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110:177–89 [Google Scholar]
  36. Harrington LS, Findlay GM, Gray A, Tolkacheva T, Wigfield S. 36.  et al. 2004. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J. Cell Biol. 166:213–23 [Google Scholar]
  37. Hernandez TL, Sutherland JP, Wolfe P, Allian-Sauer M, Capell WH. 37.  et al. 2010. Lack of suppression of circulating free fatty acids and hypercholesterolemia during weight loss on a high-fat, low-carbohydrate diet. Am. J. Clin. Nutr. 91:578–85 [Google Scholar]
  38. Horton JD, Bashmakov Y, Shimomura I, Shimano H. 38.  1998. Regulation of sterol regulatory element binding proteins in livers of fasted and refed mice. PNAS 95:5987–92 [Google Scholar]
  39. Horton JD, Goldstein JL, Brown MS. 39.  2002. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109:1125–31 [Google Scholar]
  40. Houde VP, Brule S, Festuccia WT, Blanchard PG, Bellmann K. 40.  et al. 2010. Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue. Diabetes 59:1338–48 [Google Scholar]
  41. Hsu PP, Kang SA, Rameseder J, Zhang Y, Ottina KA. 41.  et al. 2011. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332:1317–22 [Google Scholar]
  42. Hung CM, Calejman CM, Sanchez-Gurmaches J, Li H, Clish CB. 42.  et al. 2014. Rictor/mTORC2 loss in the Myf5 lineage reprograms brown fat metabolism and protects mice against obesity and metabolic disease. Cell Rep. 8:256–71 [Google Scholar]
  43. Inoki K, Li Y, Xu T, Guan KL. 43.  2003. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 17:1829–34 [Google Scholar]
  44. Inoki K, Li Y, Zhu T, Wu J, Guan KL. 44.  2002. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 4:648–57 [Google Scholar]
  45. Inoki K, Zhu T, Guan KL. 45.  2003. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115:577–90 [Google Scholar]
  46. Jacinto E, Facchinetti V, Liu D, Soto N, Wei S. 46.  et al. 2006. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127:125–37 [Google Scholar]
  47. Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA. 47.  et al. 2004. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol. 6:1122–28 [Google Scholar]
  48. Kaizuka T, Hara T, Oshiro N, Kikkawa U, Yonezawa K. 48.  et al. 2010. Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. J. Biol. Chem. 285:20109–16 [Google Scholar]
  49. Kammoun HL, Chabanon H, Hainault I, Luquet S, Magnan C. 49.  et al. 2009. GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J. Clin. Invest. 119:1201–15 [Google Scholar]
  50. Kenerson HL, Yeh MM, Yeung RS. 50.  2011. Tuberous sclerosis complex-1 deficiency attenuates diet-induced hepatic lipid accumulation. PLOS ONE 6:e18075 [Google Scholar]
  51. Kersten S. 51.  2001. Mechanisms of nutritional and hormonal regulation of lipogenesis. EMBO Rep. 2:282–86 [Google Scholar]
  52. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR. 52.  et al. 2002. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110:163–75 [Google Scholar]
  53. Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV. 53.  et al. 2003. GβL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol. Cell 11:895–904 [Google Scholar]
  54. Kim E, Goraksha-Hicks P, Li L, Neufeld TP, Guan KL. 54.  2008. Regulation of TORC1 by Rag GTPases in nutrient response. Nat. Cell Biol. 10:935–45 [Google Scholar]
  55. Kim JB, Spiegelman BM. 55.  1996. ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. Genes Dev. 10:1096–107 [Google Scholar]
  56. Kim JB, Wright HM, Wright M, Spiegelman BM. 56.  1998. ADD1/SREBP1 activates PPARγ through the production of endogenous ligand. PNAS 95:4333–37 [Google Scholar]
  57. Kim JE, Chen J. 57.  2004. Regulation of peroxisome proliferator-activated receptor-γ activity by mammalian target of rapamycin and amino acids in adipogenesis. Diabetes 53:2748–56 [Google Scholar]
  58. Kim K, Pyo S, Um SH. 58.  2012. S6 kinase 2 deficiency enhances ketone body production and increases peroxisome proliferator-activated receptor alpha activity in the liver. Hepatology 55:1727–37 [Google Scholar]
  59. Kohn AD, Summers SA, Birnbaum MJ, Roth RA. 59.  1996. Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation. J. Biol. Chem. 271:31372–78 [Google Scholar]
  60. Koyanagi M, Asahara S, Matsuda T, Hashimoto N, Shigeyama Y. 60.  et al. 2011. Ablation of TSC2 enhances insulin secretion by increasing the number of mitochondria through activation of mTORC1. PLOS ONE 6:e23238 [Google Scholar]
  61. Kumar A, Harris TE, Keller SR, Choi KM, Magnuson MA, Lawrence JC Jr. 61.  2008. Muscle-specific deletion of rictor impairs insulin-stimulated glucose transport and enhances basal glycogen synthase activity. Mol. Cell. Biol. 28:61–70 [Google Scholar]
  62. Kumar A, Lawrence JC Jr, Jung DY, Ko HJ, Keller SR. 62.  et al. 2010. Fat cell–specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism. Diabetes 59:1397–406 [Google Scholar]
  63. Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M. 63.  et al. 2012. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335:1638–43 [Google Scholar]
  64. Laplante M, Horvat S, Festuccia WT, Birsoy K, Prevorsek Z. 64.  et al. 2012. DEPTOR cell-autonomously promotes adipogenesis, and its expression is associated with obesity. Cell Metab. 16:202–12 [Google Scholar]
  65. Laplante M, Sabatini DM. 65.  2009. mTOR signaling at a glance. J. Cell Sci. 122:3589–94 [Google Scholar]
  66. Laplante M, Sabatini DM. 66.  2012. mTOR signaling in growth control and disease. Cell 149:274–93 [Google Scholar]
  67. Laplante M, Sabatini DM. 67.  2013. Regulation of mTORC1 and its impact on gene expression at a glance. J. Cell Sci. 126:1713–19 [Google Scholar]
  68. Laplante M, Sell H, MacNaul KL, Richard D, Berger JP, Deshaies Y. 68.  2003. PPAR-γ activation mediates adipose depot–specific effects on gene expression and lipoprotein lipase activity: mechanisms for modulation of postprandial lipemia and differential adipose accretion. Diabetes 52:291–99 [Google Scholar]
  69. Le Bacquer O, Petroulakis E, Paglialunga S, Poulin F, Richard D. 69.  et al. 2007. Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2. J. Clin. Invest. 117:387–96 [Google Scholar]
  70. Lebrun-Julien F, Bachmann L, Norrmen C, Trotzmuller M, Kofeler H. 70.  et al. 2014. Balanced mTORC1 activity in oligodendrocytes is required for accurate CNS myelination. J. Neurosci. 34:8432–48 [Google Scholar]
  71. Lee KY, Russell SJ, Ussar S, Boucher J, Vernochet C. 71.  et al. 2013. Lessons on conditional gene targeting in mouse adipose tissue. Diabetes 62:864–74 [Google Scholar]
  72. Li S, Brown MS, Goldstein JL. 72.  2010. Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. PNAS 107:3441–46 [Google Scholar]
  73. Li S, Ogawa W, Emi A, Hayashi K, Senga Y. 73.  et al. 2011. Role of S6K1 in regulation of SREBP1c expression in the liver. Biochem. Biophys. Res. Commun. 412:197–202 [Google Scholar]
  74. Listenberger LL, Han X, Lewis SE, Cases S, Farese RV Jr. 74.  et al. 2003. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. PNAS 100:3077–82 [Google Scholar]
  75. Liu X, Yuan H, Niu Y, Niu W, Fu L. 75.  2012. The role of AMPK/mTOR/S6K1 signaling axis in mediating the physiological process of exercise-induced insulin sensitization in skeletal muscle of C57BL/6 mice. Biochim. Biophys. Acta 1822:1716–26 [Google Scholar]
  76. Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J. 76.  2005. Rheb binds and regulates the mTOR kinase. Curr. Biol. 15:702–13 [Google Scholar]
  77. Lopes PC, Fuhrmann A, Sereno J, Espinoza DO, Pereira MJ. 77.  et al. 2014. Short and long term in vivo effects of Cyclosporine A and Sirolimus on genes and proteins involved in lipid metabolism in Wistar rats. Metabolism 63:702–15 [Google Scholar]
  78. Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP. 78.  2005. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121:179–93 [Google Scholar]
  79. Magun R, Burgering BM, Coffer PJ, Pardasani D, Lin Y. 79.  et al. 1996. Expression of a constitutively activated form of protein kinase B (c-Akt) in 3T3-L1 preadipose cells causes spontaneous differentiation. Endocrinology 137:3590–93 [Google Scholar]
  80. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. 80.  2002. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/Akt pathway. Mol. Cell 10:151–62 [Google Scholar]
  81. Martens K, Bottelbergs A, Baes M. 81.  2010. Ectopic recombination in the central and peripheral nervous system by aP2/FABP4-Cre mice: implications for metabolism research. FEBS Lett. 584:1054–58 [Google Scholar]
  82. Matsuda M, Korn BS, Hammer RE, Moon YA, Komuro R. 82.  et al. 2001. SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation. Genes Dev. 15:1206–16 [Google Scholar]
  83. Mauvoisin D, Rocque G, Arfa O, Radenne A, Boissier P, Mounier C. 83.  2007. Role of the PI3-kinase/mTor pathway in the regulation of the stearoyl CoA desaturase (SCD1) gene expression by insulin in liver. J. Cell Commun. Signaling 1:113–25 [Google Scholar]
  84. Menendez JA, Lupu R. 84.  2007. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat. Rev. Cancer 7:763–77 [Google Scholar]
  85. Menghini R, Marchetti V, Cardellini M, Hribal ML, Mauriello A. 85.  et al. 2005. Phosphorylation of GATA2 by Akt increases adipose tissue differentiation and reduces adipose tissue-related inflammation: a novel pathway linking obesity to atherosclerosis. Circulation 111:1946–53 [Google Scholar]
  86. Morrisett JD, Abdel-Fattah G, Kahan BD. 86.  2003. Sirolimus changes lipid concentrations and lipoprotein metabolism in kidney transplant recipients. Transplant. Proc. 35:143–50S [Google Scholar]
  87. Nakae J, Kitamura T, Kitamura Y, Biggs WH 3rd, Arden KC, Accili D. 87.  2003. The forkhead transcription factor Foxo1 regulates adipocyte differentiation. Dev. Cell 4:119–29 [Google Scholar]
  88. Narayanan SP, Flores AI, Wang F, Macklin WB. 88.  2009. Akt signals through the mammalian target of rapamycin pathway to regulate CNS myelination. J. Neurosci. 29:6860–70 [Google Scholar]
  89. Nobukuni T, Joaquin M, Roccio M, Dann SG, Kim SY. 89.  et al. 2005. Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. PNAS 102:14238–43 [Google Scholar]
  90. Norrmen C, Figlia G, Lebrun-Julien F, Pereira JA, Trotzmuller M. 90.  et al. 2014. mTORC1 controls PNS myelination along the mTORC1-RXRgamma-SREBP-lipid biosynthesis axis in Schwann cells. Cell Rep. 9:646–60 [Google Scholar]
  91. Norrmén C, Suter U. 91.  2013. Akt/mTOR signalling in myelination. Biochem. Soc. Trans. 41:944–50 [Google Scholar]
  92. Ntambi JM, Miyazaki M, Stoehr JP, Lan H, Kendziorski CM. 92.  et al. 2002. Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. PNAS 99:11482–86 [Google Scholar]
  93. Owen JL, Zhang Y, Bae SH, Farooqi MS, Liang G. 93.  et al. 2012. Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase. PNAS 109:16184–89 [Google Scholar]
  94. Ozcan U, Ozcan L, Yilmaz E, Duvel K, Sahin M. 94.  et al. 2008. Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol. Cell 29:541–51 [Google Scholar]
  95. Pearce LR, Huang X, Boudeau J, Pawlowski R, Wullschleger S. 95.  et al. 2007. Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem. J. 405:513–22 [Google Scholar]
  96. Pearce LR, Sommer EM, Sakamoto K, Wullschleger S, Alessi DR. 96.  2011. Protor-1 is required for efficient mTORC2-mediated activation of SGK1 in the kidney. Biochem. J. 436:169–79 [Google Scholar]
  97. Peng T, Golub TR, Sabatini DM. 97.  2002. The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation. Mol. Cell. Biol. 22:5575–84 [Google Scholar]
  98. Peng XD, Xu PZ, Chen ML, Hahn-Windgassen A, Skeen J. 98.  et al. 2003. Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2. Genes Dev. 17:1352–65 [Google Scholar]
  99. Pereira MJ, Palming J, Rizell M, Aureliano M, Carvalho E. 99.  et al. 2013. The immunosuppressive agents rapamycin, cyclosporin A and tacrolimus increase lipolysis, inhibit lipid storage and alter expression of genes involved in lipid metabolism in human adipose tissue. Mol. Cell. Endocrinol. 365:260–69 [Google Scholar]
  100. Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA. 100.  et al. 2009. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137:873–86 [Google Scholar]
  101. Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA. 100a.  et al. 2011. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146:408–20 [Google Scholar]
  102. Polak P, Cybulski N, Feige JN, Auwerx J, Ruegg MA, Hall MN. 101.  2008. Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration. Cell Metab. 8:399–410 [Google Scholar]
  103. Porstmann T, Santos CR, Griffiths B, Cully M, Wu M. 102.  et al. 2008. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 8:224–36 [Google Scholar]
  104. Potter CJ, Pedraza LG, Xu T. 103.  2002. Akt regulates growth by directly phosphorylating Tsc2. Nat. Cell Biol. 4:658–65 [Google Scholar]
  105. Reue K. 104.  2009. The lipin family: mutations and metabolism. Curr. Opin. Lipidol. 20:165–70 [Google Scholar]
  106. Romanino K, Mazelin L, Albert V, Conjard-Duplany A, Lin S. 105.  et al. 2011. Myopathy caused by mammalian target of rapamycin complex 1 (mTORC1) inactivation is not reversed by restoring mitochondrial function. PNAS 108:20808–13 [Google Scholar]
  107. Rosen ED, MacDougald OA. 106.  2006. Adipocyte differentiation from the inside out. Nat. Rev. Mol. Cell Biol. 7:885–96 [Google Scholar]
  108. Rosen ED, Spiegelman BM. 107.  2014. What we talk about when we talk about fat. Cell 156:20–44 [Google Scholar]
  109. Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J. 108.  2004. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. PNAS 101:13489–94 [Google Scholar]
  110. Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH. 109.  1994. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78:35–43 [Google Scholar]
  111. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. 110.  2010. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141:290–303 [Google Scholar]
  112. Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC. 111.  et al. 2008. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320:1496–501 [Google Scholar]
  113. Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA. 112.  et al. 2007. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell 25:903–15 [Google Scholar]
  114. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR. 113.  et al. 2004. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14:1296–302 [Google Scholar]
  115. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP. 114.  et al. 2006. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22:159–68 [Google Scholar]
  116. Sengupta S, Peterson TR, Laplante M, Oh S, Sabatini DM. 115.  2010. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 468:1100–4 [Google Scholar]
  117. Shen WJ, Patel S, Natu V, Kraemer FB. 116.  1998. Mutational analysis of structural features of rat hormone-sensitive lipase. Biochemistry 37:8973–79 [Google Scholar]
  118. Shende P, Plaisance I, Morandi C, Pellieux C, Berthonneche C. 117.  et al. 2011. Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice. Circulation 123:1073–82 [Google Scholar]
  119. Shimomura I, Bashmakov Y, Ikemoto S, Horton JD, Brown MS, Goldstein JL. 118.  1999. Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. PNAS 96:13656–61 [Google Scholar]
  120. Shiota C, Woo JT, Lindner J, Shelton KD, Magnuson MA. 119.  2006. Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability. Dev. Cell 11:583–89 [Google Scholar]
  121. Sipula IJ, Brown NF, Perdomo G. 120.  2006. Rapamycin-mediated inhibition of mammalian target of rapamycin in skeletal muscle cells reduces glucose utilization and increases fatty acid oxidation. Metabolism 55:1637–44 [Google Scholar]
  122. Soliman GA, Acosta-Jaquez HA, Fingar DC. 121.  2010. mTORC1 inhibition via rapamycin promotes triacylglycerol lipolysis and release of free fatty acids in 3T3-L1 adipocytes. Lipids 45:1089–100 [Google Scholar]
  123. Stylianou IM, Clinton M, Keightley PD, Pritchard C, Tymowska-Lalanne Z. 122.  et al. 2005. Microarray gene expression analysis of the Fob3b obesity QTL identifies positional candidate gene Sqle and perturbed cholesterol and glycolysis pathways. Physiol. Genomics 20:224–32 [Google Scholar]
  124. Sundqvist A, Bengoechea-Alonso MT, Ye X, Lukiyanchuk V, Jin J. 123.  et al. 2005. Control of lipid metabolism by phosphorylation-dependent degradation of the SREBP family of transcription factors by SCFFbw7. Cell Metab. 1:379–91 [Google Scholar]
  125. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J. 124.  2003. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 13:1259–68 [Google Scholar]
  126. Thedieck K, Polak P, Kim ML, Molle KD, Cohen A. 125.  et al. 2007. PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis. PLOS ONE 2:e1217 [Google Scholar]
  127. Toh SY, Gong J, Du G, Li JZ, Yang S. 126.  et al. 2008. Up-regulation of mitochondrial activity and acquirement of brown adipose tissue-like property in the white adipose tissue of fsp27 deficient mice. PLOS ONE 3:e2890 [Google Scholar]
  128. Tontonoz P, Spiegelman BM. 127.  2008. Fat and beyond: the diverse biology of PPARγ. Annu. Rev. Biochem. 77:289–312 [Google Scholar]
  129. Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M. 128.  et al. 2004. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431:200–5 [Google Scholar]
  130. Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH. 129.  2007. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat. Cell Biol. 9:316–23 [Google Scholar]
  131. Wan M, Leavens KF, Saleh D, Easton RM, Guertin DA. 130.  et al. 2011. Postprandial hepatic lipid metabolism requires signaling through Akt2 independent of the transcription factors FoxA2, FoxO1, and SREBP1c. Cell Metab. 14:516–27 [Google Scholar]
  132. Wang BT, Ducker GS, Barczak AJ, Barbeau R, Erle DJ, Shokat KM. 131.  2011. The mammalian target of rapamycin regulates cholesterol biosynthetic gene expression and exhibits a rapamycin-resistant transcriptional profile. PNAS 108:15201–6 [Google Scholar]
  133. Wang L, Harris TE, Roth RA, Lawrence JC Jr. 132.  2007. PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J. Biol. Chem. 282:20036–44 [Google Scholar]
  134. Wang QA, Scherer PE. 133.  2014. The AdipoChaser mouse: a model tracking adipogenesis in vivo. Adipocyte 3:146–50 [Google Scholar]
  135. Werstuck GH, Lentz SR, Dayal S, Hossain GS, Sood SK. 134.  et al. 2001. Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J. Clin. Invest. 107:1263–73 [Google Scholar]
  136. Yabe D, Komuro R, Liang G, Goldstein JL, Brown MS. 135.  2003. Liver-specific mRNA for Insig-2 down-regulated by insulin: implications for fatty acid synthesis. PNAS 100:3155–60 [Google Scholar]
  137. Yahagi N, Shimano H, Hasty AH, Matsuzaka T, Ide T. 136.  et al. 2002. Absence of sterol regulatory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lepob/Lepob mice. J. Biol. Chem. 277:19353–57 [Google Scholar]
  138. Yang J, Goldstein JL, Hammer RE, Moon YA, Brown MS, Horton JD. 137.  2001. Decreased lipid synthesis in livers of mice with disrupted Site-1 protease gene. PNAS 98:13607–12 [Google Scholar]
  139. Yao Y, Suraokar M, Darnay BG, Hollier BG, Shaiken TE. 138.  et al. 2013. BSTA promotes mTORC2-mediated phosphorylation of Akt1 to suppress expression of FoxC2 and stimulate adipocyte differentiation. Sci. Signal. 6:ra2 [Google Scholar]
  140. Ye L, Varamini B, Lamming DW, Sabatini DM, Baur JA. 139.  2012. Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2. Front. Genet. 3:177 [Google Scholar]
  141. Yecies JL, Zhang HH, Menon S, Liu S, Yecies D. 140.  et al. 2011. Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metab. 14:21–32 [Google Scholar]
  142. Yeh WC, Bierer BE, McKnight SL. 141.  1995. Rapamycin inhibits clonal expansion and adipogenic differentiation of 3T3-L1 cells. PNAS 92:11086–90 [Google Scholar]
  143. Yellaturu CR, Deng X, Cagen LM, Wilcox HG, Mansbach CM 2nd. 142.  et al. 2009. Insulin enhances post-translational processing of nascent SREBP-1c by promoting its phosphorylation and association with COPII vesicles. J. Biol. Chem. 284:7518–32 [Google Scholar]
  144. Yellaturu CR, Deng X, Park EA, Raghow R, Elam MB. 143.  2009. Insulin enhances the biogenesis of nuclear sterol regulatory element-binding protein (SREBP)-1c by posttranscriptional down-regulation of Insig-2A and its dissociation from SREBP cleavage-activating protein (SCAP)·SREBP-1c complex. J. Biol. Chem. 284:31726–34 [Google Scholar]
  145. Yoon MS, Zhang C, Sun Y, Schoenherr CJ, Chen J. 144.  2013. Mechanistic target of rapamycin controls homeostasis of adipogenesis. J. Lipid Res. 54:2166–73 [Google Scholar]
  146. Yu W, Chen Z, Zhang J, Zhang L, Ke H. 145.  et al. 2008. Critical role of phosphoinositide 3-kinase cascade in adipogenesis of human mesenchymal stem cells. Mol. Cell. Biochem. 310:11–18 [Google Scholar]
  147. Yu Y, Yoon SO, Poulogiannis G, Yang Q, Ma XM. 146.  et al. 2011. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 332:1322–26 [Google Scholar]
  148. Yuan M, Pino E, Wu L, Kacergis M, Soukas AA. 147.  2012. Identification of Akt-independent regulation of hepatic lipogenesis by mammalian target of rapamycin (mTOR) complex 2. J. Biol. Chem. 287:29579–88 [Google Scholar]
  149. Zechner R, Zimmermann R, Eichmann TO, Kohlwein SD, Haemmerle G. 148.  et al. 2012. FAT SIGNALS—lipases and lipolysis in lipid metabolism and signaling. Cell Metab. 15:279–91 [Google Scholar]
  150. Zhang HH, Huang J, Duvel K, Boback B, Wu S. 149.  et al. 2009. Insulin stimulates adipogenesis through the Akt-TSC2-mTORC1 pathway. PLOS ONE 4:e6189 [Google Scholar]
  151. Zinzalla V, Stracka D, Oppliger W, Hall MN. 150.  2011. Activation of mTORC2 by association with the ribosome. Cell 144:757–68 [Google Scholar]
  152. Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM. 151.  2011. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase. Science 334:678–83 [Google Scholar]
  153. Zoncu R, Efeyan A, Sabatini DM. 152.  2011. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 12:21–35 [Google Scholar]
  154. Zou J, Zhou L, Du XX, Ji Y, Xu J. 153.  et al. 2011. Rheb1 is required for mTORC1 and myelination in postnatal brain development. Dev. Cell 20:97–108 [Google Scholar]
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