Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Metabolism of inflammation limited by AMPK and pseudo-starvation

Subjects

Abstract

Metabolic changes in cells that participate in inflammation, such as activated macrophages and T-helper 17 cells, include a shift towards enhanced glucose uptake, glycolysis and increased activity of the pentose phosphate pathway. Opposing roles in these changes for hypoxia-inducible factor 1β and AMP-activated protein kinase have been proposed. By contrast, anti-inflammatory cells, such as M2 macrophages, regulatory T cells and quiescent memory T cells, have lower glycolytic rates and higher levels of oxidative metabolism. Some anti-inflammatory agents might act by inducing, through activation of AMP-activated protein kinase, a state akin to pseudo-starvation. Altered metabolism may thus participate in the signal-directed programs that promote or inhibit inflammation.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Central metabolic pathways involved in the Warburg effect in tumour cells and inflammatory cells.
Figure 2: Metabolic changes in TLR4-activated M1 macrophages.
Figure 3: Metabolic regulation of M2 macrophages and TH17 cells.
Figure 4: Regulation of AMPK by drugs, including anti-inflammatory drugs, and the principal metabolic pathways it regulates.

Similar content being viewed by others

References

  1. Warburg, O. Metabolism of tumours. Biochem. Z. 142, 317–333 (1923).

    CAS  Google Scholar 

  2. Oren, P., Farnham, A. E., Milofsky, M. & Marnovsky, M. L. Metabolic patterns in three types of phagocytizing cells. J. Cell Biol. 17, 487–501 (1963).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bennett, W. E. & Cohn, Z. A. The isolation and selected properties of blood monocytes. J. Exp. Med. 123, 145–159 (1966).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Arwadi, M. S. & Newsholme, E. A. Maximum activities of some enzymes of glycolysis, the CS cycle and ketone body and glutamine utilization pathways in lymphocytes of the rat. Biochem. J. 208, 743–748 (1982).

    Article  Google Scholar 

  5. Newsholme, P., Curi, R., Gordon, S. & Newsholme, E. A. Metabolism of glucose, glutamine, long-chain fatty acids and ketone bodies by murine macrophages. Biochem. J. 239, 121–125 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Krawczyk, C. et al. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 115, 4742–4749 (2010). This paper describes for the first time how lipopolysaccharide induces aerobic glycolysis in dendritic cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rodriguez-Prados, J. C. et al. Substrate fate in activated macrophages: a comparison between innate, classic and alternative activation. J. Immunol. 185, 605–614 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Shi, L. Z. et al. HIF-1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 208, 1367–1379 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dang, E. V. et al. Control of TH17/Treg balance by hypoxia-inducible factor 1. Cell 146, 772–784 (2012). References 8 and 9 provide a detailed insight into the role of HIF-1α in T H 17 cells for the promotion of glycolysis and induction of RORγt.

    Article  CAS  Google Scholar 

  10. van der Windt, G. J. W. et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36, 68–78 (2012). This paper describes the predominance of mitochondrial metabolism in memory T lymphocytes.

    Article  CAS  PubMed  Google Scholar 

  11. Wang, R. et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35, 871–882 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Everts, B. et al. Commitment to glycolysis sustains survival of nitric oxide-producing inflammatory dendritic cells. Blood 120, 1422–1431 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Garedew, A., Henderson, S. O. & Moncada, S. Activated macrophages utilize glycolytic ATP to maintain mitochondrial membrane potential and prevent apoptotic death. Cell Death Differ. 17, 1540–1550 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. West, A. P. et al. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 472, 476–482 (2011). A key role for mitochondrial ROS activated by TLR4 in bactericidal activity is described.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sonoda, J. et al. Nuclear receptor ERRα and coactivator PGC-1β are effectors of IFN-γ-induced host defense. Genes Dev. 21, 1909–1920 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Vats, D. et al. Oxidative metabolism and PGC-1β attenuates macrophage-mediated inflammation. Cell Metab. 4, 13–24 (2006).

    Article  MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic co-activator PGC-1. Cell 98, 115–124 (2010).

    Article  Google Scholar 

  18. Schwer, B. & Verdin, E. Conserved metabolic regulatory functions of sirtuins. Cell Metab. 7, 104–112 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Liu, T. F., Vachharajani, V. T., Yoza, B. K. & McCall, C. E. NAD+-dependent sirtuin 1 and 6 proteins coordinate a switch from glucose to fatty acid oxidation during the acute inflammatory response. J. Biol. Chem. 287, 25758–25769 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yeung, F. et al. Modulation of NF-κB-dependent transcription and cell survival by Sirt1 deacetylase. EMBO J. 23, 2369–2380 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kelly, T. J., Lerin, C., Haas, W., Gygi, S. P. & Puigserver, P. GCN5-mediated transcriptional control of the metabolic coactivator PGC-1β through lysine acetylation. J. Biol. Chem. 284, 19945–19952 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lin, J., Handschin, C. & Spiegelman, B. M. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 1, 361–370 (2005).

    Article  PubMed  CAS  Google Scholar 

  23. Liu, T. F. et al. NAD+-dependent SIRT1 deacetylase participates in epigenetic reprogramming during endotoxin tolerance. J. Biol. Chem. 286, 9856–9864 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Haschemi, A. et al. The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. Cell Metab. 15, 813–826 (2012). This paper describes the role of CARKL in M2 macrophage function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nishi, T. et al. Spatial redox regulation of a critical cysteine residue in NF-κB in vivo. J. Biol. Chem. 277, 44548–44556 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Newsholme, P. & Newsholme, E. A. Rates of utilization of glucose, glutamine and oleate and formation of end-products by mouse peritoneal macrophages in culture. Biochem. J. 261, 211–218 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Infantino, V. et al. The mitochondrial citrate carrier: a new player in inflammation. Biochem. J. 438, 433–436 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Hedesov, C. J. & Esmann, V. Respiration and glycolysis of normal human lymphocytes. Blood 28, 163–174 (1966).

    Article  Google Scholar 

  29. Frauwirth K. A. et al. The CD28 signalling pathway regulates glucose metabolism. Immunity 16, 769–777 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Michalek, R. D. et al. Distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 186, 3299–3303 (2011). This paper gives the first detailed description of the metabolic features of effector and regulatory T cells.

    Article  CAS  PubMed  Google Scholar 

  31. Huo, Y. et al. Stable isotope-labelling analysis of the impact of inhibition of the mammalian target of rapamycin on protein synthesis. Biochem. J. 444, 141–151 (2012).

    Article  CAS  PubMed  Google Scholar 

  32. Duvel, K. et al. Activation of a metabolic gene regulatory network downstream of mTOR complex. Mol. Cell 39, 171–183 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Powell, J. D. et al. Regulation of immune responses by mTOR. Annu. Rev. Immunol. 30, 39–68 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Delgoffe, G. M. et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30, 832–844 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Battaglia, M. et al. Rapamycin selectively expands CD4+CD25+Foxp3+ regulatory T cells. Blood 105, 4743–4748 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Degoffe, G. M. et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signalling by mTORC1 and mTORC2. Nature Immunol. 12, 295–303 (2011). This article highlights the role of mTOR in metabolic regulation in T H cells.

    Article  CAS  Google Scholar 

  37. Peyssonnaux, C. et al. Essential role of hypoxia inducible factor-1α in development of lipopolysaccharide-induced sepsis. J. Immunol. 178, 7516–7519 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Nizet, V. & Johnson, R. S. Interdependence of hypoxic and innate immune responses. Nature Rev. Immunol. 9, 609–617 (2009).

    Article  CAS  Google Scholar 

  39. Cramer, T. et al. HIF-1α is essential for myeloid cell-mediated inflammation. Cell 112, 645–657 (2003). This paper describes the crucial function of HIF-1α in inflammation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Imtiyaz, H. Z. et al. Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation. J. Clin. Invest. 120, 2699–2714 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pearce, E. L. et al. Enhancing CD8 T cell memory by modulating fatty acid oxidation. Nature 460, 103–107 (2009). This article is the first report on the key role of fatty-acid oxidation in mitochondria in memory T cells.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  42. Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hawley, S. A. et al. Complexes between the LKB1 tumor suppressor, STRADα/β and MO25α/β are upstream kinases in the AMP-activated protein kinase cascade. J. Biol. 2, 28 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Woods, A. et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 13, 2004–2008 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Shaw, R. J. et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl Acad. Sci. USA 101, 3329–3335 (2004).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  46. Alessi, D. R., Sakamoto, K. & Bayascas, J. R. Lkb1-dependent signaling pathways. Annu. Rev. Biochem. 75, 137–163 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Lizcano, J. M. et al. LKB1 is a master kinase that activates 13 protein kinases of the AMPK subfamily, including the MARK/PAR-1 kinases. EMBO J. 23, 833–843 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hawley, S. A. et al. 5′-AMP activates the AMP-activated protein kinase cascade, and Ca2+/calmodulin the calmodulin-dependent protein kinase I cascade, via three independent mechanisms. J. Biol. Chem. 270, 27186–27191 (1995).

    Article  CAS  PubMed  Google Scholar 

  49. Davies, S. P., Helps, N. R., Cohen, P. T. W. & Hardie, D. G. 5′-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2Cα and native bovine protein phosphatase-2AC. FEBS Lett. 377, 421–425 (1995).

    Article  CAS  PubMed  Google Scholar 

  50. Oakhill, J. S. et al. AMPK is a direct adenylate charge-regulated protein kinase. Science 332, 1433–1435 (2011).

    Article  ADS  CAS  PubMed  Google Scholar 

  51. Woods, A. et al. Yeast SNF1 is functionally related to mammalian AMP-activated protein kinase and regulates acetyl-CoA carboxylase in vivo. J. Biol. Chem. 269, 19509–19515 (1994).

    Article  CAS  PubMed  Google Scholar 

  52. Wilson, W. A., Hawley, S. A. & Hardie, D. G. The mechanism of glucose repression/derepression in yeast: SNF1 protein kinase is activated by phosphorylation under derepressing conditions, and this correlates with a high AMP:ATP ratio. Curr. Biol. 6, 1426–1434 (1996).

    Article  CAS  PubMed  Google Scholar 

  53. Gancedo, J. M. Carbon catabolite repression in yeast. Eur. J. Biochem. 206, 297–313 (1992).

    Article  CAS  PubMed  Google Scholar 

  54. Haurie, V., Sagliocco, F. & Boucherie, H. Dissecting regulatory networks by means of two-dimensional gel electrophoresis: application to the study of the diauxic shift in the yeast Saccharomyces cerevisiae. Proteomics 4, 364–373 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Imamura, K., Ogura, T., Kishimoto, A., Kaminishi, M. & Esumi, H. Cell cycle regulation via p53 phosphorylation by a 5′-AMP activated protein kinase activator, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, in a human hepatocellular carcinoma cell line. Biochem. Biophys. Res. Commun. 287, 562–567 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Jones, R. G. et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 18, 283–293 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Lin, J., Handschin, C. & Spiegelman, B. M. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 1, 361–370 (2005).

    Article  PubMed  CAS  Google Scholar 

  58. Jager, S., Handschin, C., St-Pierre, J. & Spiegelman, B. M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc. Natl Acad. Sci. USA 104, 12017–12022 (2007).

    Article  ADS  PubMed  CAS  PubMed Central  Google Scholar 

  59. Inoki, K., Zhu, T. & Guan, K. L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Gwinn, D. M. et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214–226 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Shackelford, D. B. et al. mTOR and HIF-1α-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome. Proc. Natl. Acad. Sci. USA 106, 11137–11142 (2009).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  62. MacIver, N. J. et al. The liver kinase B1 is a central regulator of T cell development, activation, and metabolism. J. Immunol. 187, 4187–4198 (2011).

    Article  CAS  PubMed  Google Scholar 

  63. Sanchez-Cespedes, M. et al. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res. 62, 3659–3662 (2002).

    CAS  PubMed  Google Scholar 

  64. Corton, J. M., Gillespie, J. G., Hawley, S. A. & Hardie, D. G. 5-Aminoimidazole-4-carboxamide ribonucleoside: a specific method for activating AMP-activated protein kinase in intact cells? Eur. J. Biochem. 229, 558–565 (1995).

    Article  CAS  PubMed  Google Scholar 

  65. Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167–1174 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Lee, Y. S. et al. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes 55, 2256–2264 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Cool, B. et al. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab. 3, 403–416 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Owen, M. R., Doran, E. & Halestrap, A. P. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J. 348, 607–614 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. El-Mir, M. Y. et al. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem. 275, 223–228 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Goransson, O. et al. Mechanism of action of A-769662, a valuable tool for activation of AMP-activated protein kinase. J. Biol. Chem. 282, 32549–32560 (2007).

    Article  PubMed  CAS  Google Scholar 

  71. Hawley, S. A. et al. Use of cells expressing γ-subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab. 11, 554–565 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Soranna, D. et al. Cancer risk associated with use of metformin and sulfonylurea in type 2 diabetes: a meta-analysis. Oncologist 17, 813–822 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Pilon, G., Dallaire, P. & Marette, A. Inhibition of inducible nitric-oxide synthase by activators of AMP-activated protein kinase: a new mechanism of action of insulin-sensitizing drugs. J. Biol. Chem. 279, 20767–20774 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Nath, N. et al. 5-Aminoimidazole-4-carboxamide ribonucleoside: a novel immunomodulator with therapeutic efficacy in experimental autoimmune encephalomyelitis. J. Immunol. 175, 566–574 (2005). This is the first report to give a detailed account of the anti-inflammatory effects of the AMPK activator AICA riboside.

    Article  CAS  PubMed  Google Scholar 

  75. Nath, N. et al. Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis. J. Immunol. 182, 8005–8014 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Bai, A. et al. AMPK agonist downregulates innate and adaptive immune responses in TNBS-induced murine acute and relapsing colitis. Biochem. Pharmacol. 80, 1708–1717 (2010).

    Article  CAS  PubMed  Google Scholar 

  77. Bai, A. et al. Novel anti-inflammatory action of 5-aminoimidazole-4-carboxamide ribonucleoside with protective effect in dextran sulfate sodium-induced acute and chronic colitis. J. Pharmacol. Exp. Ther. 333, 717–725 (2010).

    Article  CAS  PubMed  Google Scholar 

  78. Myerburg, M. M. et al. AMPK agonists ameliorate sodium and fluid transport and inflammation in cystic fibrosis airway epithelial cells. Am. J. Respir. Cell Mol. Biol. 42, 676–684 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Zhao, X. et al. Activation of AMPK attenuates neutrophil proinflammatory activity and decreases the severity of acute lung injury. Am. J. Physiol. Lung Cell. Mol. Physiol. 295, L497–L504 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Labuzek, K., Liber, S., Gabryel, B. & Okopien, B. AICAR (5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside) increases the production of toxic molecules and affects the profile of cytokines release in LPS-stimulated rat primary microglial cultures. Neurotoxicology 31, 134–146 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Nath, N. et al. Loss of AMPK exacerbates experimental autoimmune encephalomyelitis disease severity. Biochem. Biophys. Res. Comm. 386, 16–20 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. Sag, D., Carling, D., Stout, R. D. & Suttles, J. Adenosine 5′-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J. Immunol. 181, 8633–8641 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Salminen, A., Hyttinen, J. M. & Kaarniranta, K. AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan. J. Mol. Med. 89, 667–676 (2011).

    Article  CAS  PubMed  Google Scholar 

  84. Marsin, A. S., Bouzin, C., Bertrand, L. & Hue, L. The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible phosphofructo-2-kinase. J. Biol. Chem. 277, 30778–30783 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. Hawley, S. A. et al. The ancient drug salicylate directly activates AMP-activated protein kinase. Science 336, 918–922 (2012). This paper describes how salicylates might mediate their anti-inflammatory effects through AMPK activation.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  86. Higgs, G. A., Salmon, J. A., Henderson, B. & Vane, J. R. Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate cyclooxygenase and anti-inflammatory activity. Proc. Natl Acad. Sci. USA 84, 1417–1420 (1987).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  87. Yin, M. J., Yamamoto, Y. & Gaynor, R. B. The anti-inflammatory agents aspirin and salicylate inhibit the activity of IκB kinase-β. Nature 396, 77–80 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  88. Beckers, A. et al. Methotrexate enhances the anti-anabolic and antiproliferative effects of 5-aminoimidazole-4-carboxamide riboside. Mol. Cancer Ther. 5, 2211–2217 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Racanelli, A. C., Rothbart, S. B., Heyer, C. L. & Moran, R. G. Therapeutics by cytotoxic metabolite accumulation: pemetrexed causes ZMP accumulation, AMPK activation, and mammalian target of rapamycin inhibition. Cancer Res. 69, 5467–5474 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Rolf, J., Zarrouk, M., Finlay, D. K., Foretz, M., Viollet, B., Cantrell, D. A. AMPKα1: a glucose sensor that controls CD8 T-cell memory. Eur. J. Immunol. (in the press).

  91. Greer, E. L. et al. An AMPK–FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr. Biol. 17, 1646–1656 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Baur, J. A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342 (2006).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  93. Canto, C. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056–1060 (2009).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  94. Rothwell, P. M. et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet 379, 1602–1612 (2012).

    Article  CAS  PubMed  Google Scholar 

  95. Soranna, D. et al. Cancer risk associated with use of metformin and sulfonylurea in type 2 diabetes: a meta-analysis. Oncologist 17, 813–822 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Horman, S. et al. Insulin antagonizes ischemia-induced Thr172 phosphorylation of AMP-activated protein kinase α-subunits in heart via hierarchical phosphorylation of Ser485/491. J. Biol. Chem. 281, 5335–5340 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Yamauchi, T. et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nature Med. 6, 1288–1295 (2002).

    Article  CAS  Google Scholar 

  98. Matsui, T. et al. Inflammatory cytokines and hypoxia contribute to 18F-FDG uptake by cells involved in pannus formation in rheumatoid arthritis. J. Nucl. Med. 50, 920–926 (2009).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Work in the D.G.H. laboratory is supported by the Wellcome Trust and Cancer Research UK. Work in the L.O.N. laboratory is supported by Science Foundation Ireland and the European Research Council.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Luke A. J. O'Neill.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Reprints and permissions information is available at www.nature.com/reprints.

Rights and permissions

Reprints and permissions

About this article

Cite this article

O'Neill, L., Hardie, D. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 493, 346–355 (2013). https://doi.org/10.1038/nature11862

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11862

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing