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Nutrient-sensing mechanisms and pathways

Abstract

The ability to sense and respond to fluctuations in environmental nutrient levels is a requisite for life. Nutrient scarcity is a selective pressure that has shaped the evolution of most cellular processes. Different pathways that detect intracellular and extracellular levels of sugars, amino acids, lipids and surrogate metabolites are integrated and coordinated at the organismal level through hormonal signals. During food abundance, nutrient-sensing pathways engage anabolism and storage, whereas scarcity triggers homeostatic mechanisms, such as the mobilization of internal stores through autophagy. Nutrient-sensing pathways are commonly deregulated in human metabolic diseases.

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Figure 1: Lipid-sensing mechanism.
Figure 2: Amino-acid-sensing mechanisms.
Figure 3: Glucose-sensing mechanisms.
Figure 4: Nutrients and autophagy.

References

  1. Wu, G. & Morris, S. M. Arginine metabolism: nitric oxide and beyond. Biochem. J. 336, 1–17 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. Reeds, P. J. Dispensable and indispensable amino acids for humans. J. Nutr. 130, 1835S–1840S (2000).

    CAS  PubMed  Article  Google Scholar 

  3. Richieri, G. V. & Kleinfeld, A. M. Unbound free fatty acid levels in human serum. J. Lipid Res. 36, 229–240 (1995).

    CAS  PubMed  Article  Google Scholar 

  4. Itoh, Y. et al. Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40. Nature 422, 173–176 (2003).

    CAS  PubMed  Article  ADS  Google Scholar 

  5. Hirasawa, A. et al. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nature Med. 11, 90–94 (2005).

    CAS  PubMed  Article  Google Scholar 

  6. Oh, D. Y. et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142, 687–698 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. Ichimura, A. et al. Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 483, 350–354 (2012).

    CAS  PubMed  Article  ADS  Google Scholar 

  8. Oh, D. Y. et al. A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice. Nature Med. 20, 942–947 (2014).

    CAS  PubMed  Article  Google Scholar 

  9. Pepino, M. Y., Kuda, O., Samovski, D. & Abumrad, N. A. Structure-function of CD36 and importance of fatty acid signal transduction in fat metabolism. Annu. Rev. Nutr. 34, 281–303 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. Laugerette, F. et al. CD36 involvement in orosensory detection of dietary lipids, spontaneous fat preference, and digestive secretions. J. Clin. Invest. 115, 3177–3184 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. Cartoni, C. et al. Taste preference for fatty acids is mediated by GPR40 and GPR120. J. Neurosci. 30, 8376–8382 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Martin, C. et al. The lipid-sensor candidates CD36 and GPR120 are differentially regulated by dietary lipids in mouse taste buds: impact on spontaneous fat preference. PLoS ONE 6, e24014 (2011).

    CAS  PubMed  PubMed Central  Article  ADS  Google Scholar 

  13. Pepino, M. Y., Love-Gregory, L., Klein, S. & Abumrad, N. A. The fatty acid translocase gene CD36 and lingual lipase influence oral sensitivity to fat in obese subjects. J. Lipid Res. 53, 561–566 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. Brown, M. S. & Goldstein, J. L. A receptor-mediated pathway for cholesterol homeostasis. Science 232, 34–47 (1986).

    CAS  PubMed  Article  ADS  Google Scholar 

  15. Brown, A. J., Sun, L., Feramisco, J. D., Brown, M. S. & Goldstein, J. L. Cholesterol addition to ER membranes alters conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolism. Mol. Cell 10, 237–245 (2002). This paper demonstrates the functional regulation of SCAP-protein conformation by cholesterol levels within the ER membrane, providing strong support for its cholesterol-sensing ability.

    CAS  PubMed  Article  Google Scholar 

  16. Radhakrishnan, A., Sun, L.-P., Kwon, H. J., Brown, M. S. & Goldstein, J. L. Direct binding of cholesterol to the purified membrane region of SCAP: mechanism for a sterol-sensing domain. Mol. Cell 15, 259–268 (2004).

    CAS  PubMed  Article  Google Scholar 

  17. Feramisco, J. D. et al. Intramembrane aspartic acid in SCAP protein governs cholesterol-induced conformational change. Proc. Natl Acad. Sci. USA 102, 3242–3247 (2005).

    CAS  PubMed  Article  ADS  PubMed Central  Google Scholar 

  18. Yang, T. et al. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 110, 489–500 (2002).

    CAS  PubMed  Article  Google Scholar 

  19. Radhakrishnan, A., Goldstein, J. L., McDonald, J. G. & Brown, M. S. Switch-like control of SREBP-2 transport triggered by small changes in ER cholesterol: a delicate balance. Cell Metab. 8, 512–521 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Motamed, M. et al. Identification of luminal Loop 1 of Scap protein as the sterol sensor that maintains cholesterol homeostasis. J. Biol. Chem. 286, 18002–18012 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Zhang, Y., Motamed, M., Seemann, J., Brown, M. S. & Goldstein, J. L. Point mutation in luminal loop 7 of Scap protein blocks interaction with loop 1 and abolishes movement to Golgi. J. Biol. Chem. 288, 14059–14067 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. Jeon, T.-I. & Osborne, T. F. SREBPs: metabolic integrators in physiology and metabolism. Trends Endocrinol. Metab. 23, 65–72 (2012).

    CAS  PubMed  Article  Google Scholar 

  23. Sever, N., Yang, T., Brown, M. S., Goldstein, J. L. & DeBose-Boyd, R. A. Accelerated degradation of HMG CoA reductase mediated by binding of insig-1 to its sterol-sensing domain. Mol. Cell 11, 25–33 (2003).

    CAS  PubMed  Article  Google Scholar 

  24. Song, B.-L., Sever, N. & DeBose-Boyd, R. A. Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase. Mol. Cell 19, 829–840 (2005).

    CAS  PubMed  Article  Google Scholar 

  25. Birsoy, K. et al. Cellular program controlling the recovery of adipose tissue mass: an in vivo imaging approach. Proc. Natl Acad. Sci. USA 105, 12985–12990 (2008).

    CAS  PubMed  Article  ADS  PubMed Central  Google Scholar 

  26. Wrann, C. D. et al. FOSL2 promotes leptin gene expression in human and mouse adipocytes. J. Clin. Invest. 122, 1010–1021 (2012).

    CAS  PubMed  PubMed Central  Article  ADS  Google Scholar 

  27. Clément, K. et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392, 398–401 (1998).

    PubMed  Article  ADS  Google Scholar 

  28. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994). In this seminal paper, the mouse Ob gene and its human homologue LEP are identified.

    CAS  PubMed  Article  ADS  Google Scholar 

  29. Lee, G. H. et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632–635 (1996).

    CAS  PubMed  Article  ADS  Google Scholar 

  30. Scherer, P. E., Williams, S., Fogliano, M., Baldini, G. & Lodish, H. F. A novel serum protein similar to C1q, produced exclusively in adipocytes. J. Biol. Chem. 270, 26746–26749 (1995).

    CAS  PubMed  Article  Google Scholar 

  31. Hu, E., Liang, P. & Spiegelman, B. M. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J. Biol. Chem. 271, 10697–10703 (1996).

    CAS  PubMed  Article  Google Scholar 

  32. Shehzad, A., Iqbal, W., Shehzad, O. & Lee, Y. S. Adiponectin: regulation of its production and its role in human diseases. Hormones (Athens) 11, 8–20 (2012).

    Article  Google Scholar 

  33. Maeda, N. et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nature Med. 8, 731–737 (2002).

    CAS  PubMed  Article  ADS  Google Scholar 

  34. Kadowaki, T. et al. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J. Clin. Invest. 116, 1784–1792 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Waki, H. & Tontonoz, P. Endocrine functions of adipose tissue. Annu. Rev. Pathol. 2, 31–56 (2007).

    CAS  PubMed  Article  Google Scholar 

  36. Takahashi, M. et al. Genomic structure and mutations in adipose-specific gene, adiponectin. Int. J. Obes. Relat. Metab. Disord. 24, 861–868 (2000).

    CAS  PubMed  Article  Google Scholar 

  37. Hara, K. et al. Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population. Diabetes 51, 536–540 (2002).

    CAS  PubMed  Article  Google Scholar 

  38. Kondo, H. et al. Association of adiponectin mutation with type 2 diabetes: a candidate gene for the insulin resistance syndrome. Diabetes 51, 2325–2328 (2002).

    CAS  PubMed  Article  Google Scholar 

  39. Ibba, M. & Soll, D. Aminoacyl-tRNA synthesis. Annu. Rev. Biochem. 69, 617–650 (2000).

    CAS  PubMed  Article  Google Scholar 

  40. Dong, J., Qiu, H., Garcia-Barrio, M., Anderson, J. & Hinnebusch, A. G. Uncharged tRNA activates GCN2 by displacing the protein kinase moiety from a bipartite tRNA-binding domain. Mol. Cell 6, 269–279 (2000).

    CAS  PubMed  Article  Google Scholar 

  41. Berlanga, J. J., Santoyo, J. & De Haro, C. Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2α kinase. Eur. J. Biochem. 265, 754–762 (1999).

    CAS  PubMed  Article  Google Scholar 

  42. Scheuner, D. et al. Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol. Cell 7, 1165–1176 (2001).

    CAS  PubMed  Article  Google Scholar 

  43. Zhang, P. et al. The GCN2 eIF2α kinase is required for adaptation to amino acid deprivation in mice. Mol. Cell. Biol. 22, 6681–6688 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Maurin, A.-C. et al. The GCN2 kinase biases feeding behavior to maintain amino acid homeostasis in omnivores. Cell Metab. 1, 273–277 (2005).

    CAS  PubMed  Article  Google Scholar 

  45. Hao, S. et al. Uncharged tRNA and sensing of amino acid deficiency in mammalian piriform cortex. Science 307, 1776–1778 (2005).

    CAS  PubMed  Article  ADS  Google Scholar 

  46. Guo, F. & Cavener, D. R. The GCN2 eIF2α kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid. Cell Metab. 5, 103–114 (2007).

    CAS  PubMed  Article  Google Scholar 

  47. Thoreen, C. C. et al. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 485, 109–113 (2012).

    CAS  PubMed  PubMed Central  Article  ADS  Google Scholar 

  48. Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Garami, A. et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol. Cell 11, 1457–1466 (2003).

    CAS  PubMed  Article  Google Scholar 

  50. Inoki, K., Li, Y., Xu, T. & Guan, K.-L. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 17, 1829–1834 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Tee, A. R., Manning, B. D., Roux, P. P., Cantley, L. C. & Blenis, J. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 13, 1259–1268 (2003).

    CAS  PubMed  Article  Google Scholar 

  52. Zhang, Y. et al. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nature Cell Biol. 5, 578–581 (2003).

    CAS  PubMed  Article  Google Scholar 

  53. Hara, K. et al. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J. Biol. Chem. 273, 14484–14494 (1998). This paper explores the amino-acid essentiality for mTORC1 activation, and specific amino-acid requirements independent of the growth-factor-mediated regulation of activity.

    CAS  PubMed  Article  Google Scholar 

  54. Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T. P. & Guan, K.-L. Regulation of TORC1 by Rag GTPases in nutrient response. Nature Cell Biol. 10, 935–945 (2008).

    CAS  PubMed  Article  Google Scholar 

  55. Sancak, Y. et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496–1501 (2008). References 54 and 55 report the identification of the Rag GTPases as the direct link between amino-acids levels and mTORC1, regulating mTORC1's subcellular localization.

    CAS  PubMed  PubMed Central  Article  ADS  Google Scholar 

  56. Sancak, Y. et al. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141, 290–303 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Bar-Peled, L., Schweitzer, L. D., Zoncu, R. & Sabatini, D. M. Ragulator is a GEF for the Rag GTPases that signal amino acid levels to mTORC1. Cell 150, 1196–1208 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Bar-Peled, L. et al. A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340, 1100–1106 (2013).

    CAS  PubMed  PubMed Central  Article  ADS  Google Scholar 

  59. Panchaud, N., Péli-Gulli, M.-P. & De Virgilio, C. Amino acid deprivation inhibits TORC1 through a GTPase-activating protein complex for the Rag family GTPase Gtr1. Sci. Signal. 6, ra42 (2013).

    PubMed  Article  CAS  Google Scholar 

  60. Tsun, Z.-Y. et al. The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol. Cell 52, 495–505 (2013).

    CAS  PubMed  Article  Google Scholar 

  61. Petit, C. S., Roczniak-Ferguson, A. & Ferguson, S. M. Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases. J. Cell Biol. 202, 1107–1122 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Chantranupong, L. et al. The sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell Rep. 9, 1–8 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Peng, M., Yin, N. & Li, M. O. Sestrins function as guanine nucleotide dissociation inhibitors for Rag GTPases to control mTORC1 signaling. Cell 159, 122–133 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Kitamoto, K., Yoshizawa, K., Ohsumi, Y. & Anraku, Y. Dynamic aspects of vacuolar and cytosolic amino acid pools of Saccharomyces cerevisiae. J. Bacteriol. 170, 2683–2686 (1988).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. Binda, M. et al. The Vam6 GEF controls TORC1 by activating the EGO complex. Mol. Cell 35, 563–573 (2009).

    CAS  PubMed  Article  Google Scholar 

  66. Harms, E., Gochman, N. & Schneider, J. A. Lysosomal pool of free-amino acids. Biochem. Biophys. Res. Commun. 99, 830–836 (1981).

    CAS  PubMed  Article  Google Scholar 

  67. Neuhaus, E. M., Almers, W. & Soldati, T. Morphology and dynamics of the endocytic pathway in Dictyostelium discoideum. Mol. Biol. Cell 13, 1390–1407 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Lee, J. H. et al. De novo somatic mutations in components of the PI(3)K–AKT3-mTOR pathway cause hemimegalencephaly. Nature Genet. 44, 941–945 (2012).

    CAS  PubMed  Article  Google Scholar 

  69. Bohn, G. et al. A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14. Nature Med. 13, 38–45 (2007).

    CAS  PubMed  Article  Google Scholar 

  70. Efeyan, A., Zoncu, R. & Sabatini, D. M. Amino acids and mTORC1: from lysosomes to disease. Trends Mol. Med. 18, 524–533 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. Bachmanov, A. A. & Beauchamp, G. K. Taste receptor genes. Annu. Rev. Nutr. 27, 389–414 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. Damak, S. et al. Detection of sweet and umami taste in the absence of taste receptor T1r3. Science 301, 850–853 (2003).

    CAS  PubMed  Article  ADS  Google Scholar 

  73. Nelson, G. et al. An amino-acid taste receptor. Nature 416, 199–202 (2002).

    CAS  PubMed  Article  ADS  Google Scholar 

  74. Chaudhari, N. & Roper, S. D. The cell biology of taste. J. Cell Biol. 190, 285–296 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. Wu, S. V. et al. Expression of bitter taste receptors of the T2R family in the gastrointestinal tract and enteroendocrine STC-1 cells. Proc. Natl Acad. Sci. USA 99, 2392–2397 (2002).

    CAS  PubMed  Article  ADS  PubMed Central  Google Scholar 

  76. Wauson, E. M. et al. The G protein-coupled taste receptor T1R1/T1R3 regulates mTORC1 and autophagy. Mol. Cell 47, 851–862 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. Printz, R. L., Magnuson, M. A. & Granner, D. K. Mammalian glucokinase. Annu. Rev. Nutr. 13, 463–496 (1993).

    CAS  PubMed  Article  Google Scholar 

  78. Nordlie, R. C., Foster, J. D. & Lange, A. J. Regulation of glucose production by the liver. Annu. Rev. Nutr. 19, 379–406 (1999).

    CAS  PubMed  Article  Google Scholar 

  79. Ogunnowo-Bada, E. O., Heeley, N., Brochard, L. & Evans, M. L. Brain glucose sensing, glucokinase and neural control of metabolism and islet function. Diabetes Obes. Metab. 16 (Suppl 1), 26–32 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. Gloyn, A. L. Glucokinase (GCK) mutations in hyper- and hypoglycemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy. Hum. Mutat. 22, 353–362 (2003).

    CAS  PubMed  Article  Google Scholar 

  81. Postic, C. et al. Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic β cell-specific gene knock-outs using Cre recombinase. J. Biol. Chem. 274, 305–315 (1999).

    CAS  PubMed  Article  Google Scholar 

  82. Thorens, B. & Mueckler, M. Glucose transporters in the 21st Century. Am. J. Physiol. Endocrinol. Metab. 298, E141–E145 (2010).

    CAS  PubMed  Article  Google Scholar 

  83. Santer, R. et al. Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome. Nature Genet. 17, 324–326 (1997).

    CAS  PubMed  Article  Google Scholar 

  84. De Vos, A. et al. Human and rat β cells differ in glucose transporter but not in glucokinase gene expression. J. Clin. Invest. 96, 2489–2495 (1995).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. Chang-Chen, K. J., Mullur, R. & Bernal-Mizrachi, E. β-Cell failure as a complication of diabetes. Rev. Endocr. Metab. Disord. 9, 329–343 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. Leto, D. & Saltiel, A. R. Regulation of glucose transport by insulin: traffic control of GLUT4. Nature Rev. Mol. Cell Biol. 13, 383–396 (2012).

    CAS  Article  Google Scholar 

  87. Hardie, D. G. AMP-activated protein kinase — an energy sensor that regulates all aspects of cell function. Genes Dev. 25, 1895–1908 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. Hardie, D. G., Ross, F. A. & Hawley, S. A. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nature Rev. Mol. Cell Biol. 13, 251–262 (2012).

    CAS  Article  Google Scholar 

  89. Efeyan, A. et al. Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival. Nature 493, 679–683 (2013).

    CAS  PubMed  Article  ADS  Google Scholar 

  90. Zoncu, R. et al. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase. Science 334, 678–683 (2011).

    CAS  PubMed  PubMed Central  Article  ADS  Google Scholar 

  91. Zhang, F. et al. Molecular mechanism for the umami taste synergism. Proc. Natl Acad. Sci. USA 105, 20930–20934 (2008).

    CAS  PubMed  Article  ADS  PubMed Central  Google Scholar 

  92. Nelson, G. et al. Mammalian sweet taste receptors. Cell 106, 381–390 (2001). This paper reports the identification of T1R2–T1R3 as the sweet taste receptor by means of mouse transgenesis and heterologous expression in cultured cells.

    CAS  PubMed  Article  Google Scholar 

  93. Mace, O. J., Affleck, J., Patel, N. & Kellett, G. L. Sweet taste receptors in rat small intestine stimulate glucose absorption through apical GLUT2. J. Physiol. 582, 379–392 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. Dyer, J., Salmon, K. S. H., Zibrik, L. & Shirazi-Beechey, S. P. Expression of sweet taste receptors of the T1R family in the intestinal tract and enteroendocrine cells. Biochem. Soc. Trans. 33, 302–305 (2005).

    CAS  PubMed  Article  Google Scholar 

  95. Nettleton, J. A. et al. Diet soda intake and risk of incident metabolic syndrome and type 2 diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA). Diabetes Care 32, 688–694 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. Klionsky, D. J. Autophagy as a regulated pathway of cellular degradation. Science 290, 1717–1721 (2000).

    CAS  PubMed  PubMed Central  Article  ADS  Google Scholar 

  97. Egan, D. F. et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456–461 (2011).

    CAS  PubMed  Article  ADS  Google Scholar 

  98. Kim, J., Kundu, M., Viollet, B. & Guan, K.-L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nature Cell Biol. 13, 132–141 (2011).

    CAS  PubMed  Article  ADS  Google Scholar 

  99. Mammucari, C. et al. FOXO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 6, 458–471 (2007).

    CAS  PubMed  Article  Google Scholar 

  100. He, C. & Klionsky, D. J. Regulation mechanisms and signaling pathways of autophagy. Annu. Rev. Genet. 43, 67–93 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. Thoreen, C. C. et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J. Biol. Chem. 284, 8023–8032 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. Kuma, A. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004). This paper demonstrates the essentiality of autophagy as a crucial mechanism to mobilize internal energy stores and to adapt to the interruption of transplacental nutrient supply in neonates.

    CAS  PubMed  Article  ADS  Google Scholar 

  103. Komatsu, M. et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425–434 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. Yu, L. et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465, 942–946 (2010).

    CAS  PubMed  PubMed Central  Article  ADS  Google Scholar 

  105. Naito, T., Kuma, A. & Mizushima, N. Differential contribution of insulin and amino acids to the mTORC1-autophagy pathway in the liver and muscle. J. Biol. Chem. 288, 21074–21081 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. Kroemer, G., Mariño, G. & Levine, B. Autophagy and the integrated stress response. Mol. Cell 40, 280–293 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. Tsukamoto, S. et al. Autophagy is essential for preimplantation development of mouse embryos. Science 321, 117–120 (2008).

    CAS  PubMed  Article  ADS  Google Scholar 

  108. Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006).

    CAS  Article  ADS  PubMed  Google Scholar 

  109. Karsli-Uzunbas, G. et al. Autophagy is required for glucose homeostasis and lung tumor maintenance. Cancer Discov. 4, 914–927 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. Singh, R. et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135 (2009).

    CAS  PubMed  PubMed Central  Article  ADS  Google Scholar 

  111. Mizushima, N. & Komatsu, M. Autophagy: renovation of cells and tissues. Cell 147, 728–741 (2011).

    CAS  PubMed  Article  Google Scholar 

  112. de Cabo, R., Carmona-Gutierrez, D., Bernier, M., Hall, M. N. & Madeo, F. The search for antiaging interventions: from elixirs to fasting regimens. Cell 157, 1515–1526 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

D.M.S. is supported by grants from the National Institutes of Health (R01 CA129105, CA103866 and AI047389; R21 AG042876) and awards from the American Federation for Aging, Starr Foundation, Koch Institute Frontier Research Program, and the Ellison Medical Foundation. A.E. is supported by the Charles King's Trust Foundation/Simeon J. Fortin Fellowship. W.C.C. is supported by American Cancer Society – Ellison Foundation Postdoctoral Fellowship (PF-13-356-01-TBE). D.M.S. is an investigator of the Howard Hughes Medical Institute.

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Efeyan, A., Comb, W. & Sabatini, D. Nutrient-sensing mechanisms and pathways. Nature 517, 302–310 (2015). https://doi.org/10.1038/nature14190

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