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The vagus nerve and the inflammatory reflex—linking immunity and metabolism

Abstract

The vagus nerve has an important role in regulation of metabolic homeostasis, and efferent vagus nerve-mediated cholinergic signalling controls immune function and proinflammatory responses via the inflammatory reflex. Dysregulation of metabolism and immune function in obesity are associated with chronic inflammation, a critical step in the pathogenesis of insulin resistance and type 2 diabetes mellitus. Cholinergic mechanisms within the inflammatory reflex have, in the past 2 years, been implicated in attenuating obesity-related inflammation and metabolic complications. This knowledge has led to the exploration of novel therapeutic approaches in the treatment of obesity-related disorders.

Key Points

  • The inflammatory reflex is a physiological mechanism through which the vagus nerve regulates immune function and inhibits excessive proinflammatory cytokine production

  • Vagus nerve signalling has an important role in the regulation of feeding behaviour and metabolic homeostasis

  • Disruption of metabolic and immune regulation in obesity results in inflammation, which mediates insulin resistance and the development of type 2 diabetes mellitus as well as other debilitating and life-threatening conditions

  • Activation of cholinergic signalling in the efferent arm of the inflammatory reflex alleviates obesity-associated inflammation and metabolic derangements

  • The inflammatory reflex can potentially be exploited for treatment of the metabolic syndrome, type 2 diabetes mellitus and other obesity-driven disorders

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Figure 1: The functional anatomy of the inflammatory reflex.
Figure 2: Molecular mechanisms of cholinergic control of inflammation.
Figure 3: The role of the vagus nerve in metabolic regulation.
Figure 4: Possible therapies based on cholinergic-based approaches for the treatment of obesity-driven disorders.

References

  1. 1

    Tracey, K. J. The inflammatory reflex. Nature 420, 853–859 (2002).

    Article  CAS  Google Scholar 

  2. 2

    Tracey, K. J. Reflex control of immunity. Nat. Rev. Immunol. 9, 418–428 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Andersson, U. & Tracey, K. J. Reflex principles of immunological homeostasis. Annu. Rev. Immunol. 30, 313–335 (2011).

    Article  CAS  Google Scholar 

  4. 4

    Baccala, R. et al. Sensors of the innate immune system: their mode of action. Nat. Rev. Rheumatol. 5, 448–456 (2009).

    Article  CAS  Google Scholar 

  5. 5

    Chen, G. Y. & Nunez, G. Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol. 10, 826–837 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Andersson, U. & Tracey, K. J. HMGB1 is a therapeutic target for sterile inflammation and infection. Annu. Rev. Immunol. 29, 139–162 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Medzhitov, R. Inflammation 2010: new adventures of an old flame. Cell 140, 771–776 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. 8

    Pavlov, V. A. & Tracey, K. J. The cholinergic anti-inflammatory pathway. Brain Behav. Immun. 19, 493–499 (2005).

    Article  CAS  Google Scholar 

  9. 9

    Tracey, K. J. Physiology and immunology of the cholinergic antiinflammatory pathway. J. Clin. Invest. 117, 289–296 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Pavlov, V. A. Cholinergic modulation of inflammation. Int. J. Clin. Exp. Med. 1, 203–212 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Bastard, J. P. et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur. Cytokine Netw. 17, 4–12 (2006).

    CAS  PubMed  Google Scholar 

  12. 12

    Donath, M. Y. & Shoelson, S. E. Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11, 98–107 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).

    Article  CAS  Google Scholar 

  14. 14

    Richter, W. O., Geiss, H. C., Aleksic, S. & Schwandt, P. Cardiac autonomic nerve function and insulin sensitivity in obese subjects. Int. J. Obes. Relat. Metab. Disord. 20, 966–969 (1996).

    CAS  PubMed  Google Scholar 

  15. 15

    Karason, K., Molgaard, H., Wikstrand, J. & Sjostrom, L. Heart rate variability in obesity and the effect of weight loss. Am. J. Cardiol. 83, 1242–1247 (1999).

    Article  CAS  Google Scholar 

  16. 16

    Ziegler, D. et al. Selective contribution of diabetes and other cardiovascular risk factors to cardiac autonomic dysfunction in the general population. Exp. Clin. Endocrinol. Diabetes 114, 153–159 (2006).

    Article  CAS  Google Scholar 

  17. 17

    Carnethon, M. R., Jacobs, D. R. Jr, Sidney, S. & Liu, K. Influence of autonomic nervous system dysfunction on the development of type 2 diabetes: the CARDIA study. Diabetes Care 26, 3035–3041 (2003).

    Article  Google Scholar 

  18. 18

    Marrero, M. B. et al. An α7 nicotinic acetylcholine receptor-selective agonist reduces weight gain and metabolic changes in a mouse model of diabetes. J. Pharmacol. Exp. Ther. 332, 173–180 (2010).

    Article  CAS  Google Scholar 

  19. 19

    Wang, X., Yang, Z., Xue, B. & Shi, H. Activation of the cholinergic antiinflammatory pathway ameliorates obesity-induced inflammation and insulin resistance. Endocrinology 152, 836–846 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Satapathy, S. K. et al. Galantamine alleviates inflammation and other obesity-associated complications in high-fat diet-fed mice. Mol. Med. 17, 599–606 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Borovikova, L. V. et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405, 458–462 (2000).

    Article  CAS  Google Scholar 

  22. 22

    Wang, H. et al. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature 421, 384–388 (2003).

    Article  CAS  Google Scholar 

  23. 23

    Pavlov, V. A., Wang, H., Czura, C. J., Friedman, S. G. & Tracey, K. J. The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol. Med. 9, 125–134 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Goehler, L. E. et al. Vagal immune-to-brain communication: a visceral chemosensory pathway. Auton. Neurosci. 85, 49–59 (2000).

    Article  CAS  Google Scholar 

  25. 25

    Niijima, A. The afferent discharges from sensors for interleukin 1β in the hepatoportal system in the anesthetized rat. J. Auton. Nerv. Syst. 61, 287–291 (1996).

    Article  CAS  Google Scholar 

  26. 26

    Ek, M., Kurosawa, M., Lundeberg, T. & Ericsson, A. Activation of vagal afferents after intravenous injection of interleukin-1β: role of endogenous prostaglandins. J. Neurosci. 18, 9471–9479 (1998).

    Article  CAS  Google Scholar 

  27. 27

    Goehler, L. E. et al. Interleukin-1β in immune cells of the abdominal vagus nerve: a link between the immune and nervous systems? J. Neurosci. 19, 2799–2806 (1999).

    Article  CAS  Google Scholar 

  28. 28

    Hansen, M. K., O'Connor, K. A., Goehler, L. E., Watkins, L. R. & Maier, S. F. The contribution of the vagus nerve in interleukin-1β-induced fever is dependent on dose. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280, R929–R934 (2001).

    Article  CAS  Google Scholar 

  29. 29

    Pavlov, V. A. & Tracey, K. J. Neural regulators of innate immune responses and inflammation. Cell. Mol. Life Sci. 61, 2322–2331 (2004).

    Article  CAS  Google Scholar 

  30. 30

    Hosoi, T., Okuma, Y., Matsuda, T. & Nomura, Y. Novel pathway for LPS-induced afferent vagus nerve activation: possible role of nodose ganglion. Auton. Neurosci. 120, 104–107 (2005).

    Article  CAS  Google Scholar 

  31. 31

    de Lartigue, G., Barbier, de la Serre, C., Espero, E., Lee, J. & Raybould, H. E. Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons. Am. J. Physiol. Endocrinol. Metab. 301, E187–E195 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Guarini, S. et al. Adrenocorticotropin reverses hemorrhagic shock in anesthetized rats through the rapid activation of a vagal anti-inflammatory pathway. Cardiovasc. Res. 63, 357–365 (2004).

    Article  CAS  Google Scholar 

  33. 33

    Pavlov, V. A. et al. Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia. Proc. Natl. Acad. Sci. USA 103, 5219–5223 (2006).

    Article  CAS  Google Scholar 

  34. 34

    Pavlov, V. A. et al. Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway. Brain Behav. Immun. 23, 41–45 (2009).

    Article  CAS  Google Scholar 

  35. 35

    Lee, S. T. et al. Cholinergic anti-inflammatory pathway in intracerebral hemorrhage. Brain Res. 1309, 164–171 (2010).

    Article  CAS  Google Scholar 

  36. 36

    Pavlov, V. A. et al. Selective α7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis. Crit. Care Med. 35, 1139–1144 (2007).

    Article  CAS  Google Scholar 

  37. 37

    Parrish, W. R. et al. Modulation of TNF release by choline requires α7 subunit nicotinic acetylcholine receptor-mediated signaling. Mol. Med. 14, 567–574 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Gallowitsch-Puerta, M. & Pavlov, V. A. Neuro-immune interactions via the cholinergic anti-inflammatory pathway. Life Sci. 80, 2325–2329 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Olofsson, P. S. et al. α7 nicotinic acetylcholine receptor (α7nAChR) expression in bone marrow-derived non-T cells is required for the inflammatory reflex. Mol. Med. 18, 539–543 (2012).

    Article  CAS  Google Scholar 

  40. 40

    Hamano, R. et al. Stimulation of α7 nicotinic acetylcholine receptor inhibits CD14 and the toll-like receptor 4 expression in human monocytes. Shock 26, 358–364 (2006).

    Article  CAS  Google Scholar 

  41. 41

    Guarini, S. et al. Efferent vagal fibre stimulation blunts nuclear factor-κB activation and protects against hypovolemic hemorrhagic shock. Circulation 107, 1189–1194 (2003).

    Article  Google Scholar 

  42. 42

    Pavlov, V. A. & Tracey, K. J. Controlling inflammation: the cholinergic anti-inflammatory pathway. Biochem. Soc. Trans. 34, 1037–1040 (2006).

    Article  CAS  Google Scholar 

  43. 43

    de Jonge, W. J. et al. Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat. Immunol. 6, 844–851 (2005).

    Article  CAS  Google Scholar 

  44. 44

    Rosas-Ballina, M. et al. Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia. Proc. Natl Acad. Sci. USA 105, 11008–11013 (2008).

    Article  Google Scholar 

  45. 45

    Rosas-Ballina, M. et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 334, 98–101 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Ghia, J. E., Blennerhassett, P., Kumar-Ondiveeran, H., Verdu, E. F. & Collins, S. M. The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology 131, 1122–1130 (2006).

    Article  Google Scholar 

  47. 47

    Bonaz, B. The cholinergic anti-inflammatory pathway and the gastrointestinal tract. Gastroenterology 133, 1370–1373 (2007).

    Article  CAS  Google Scholar 

  48. 48

    Leib, C. et al. Role of the cholinergic antiinflammatory pathway in murine autoimmune myocarditis. Circ. Res. 109, 130–140 (2011).

    Article  CAS  Google Scholar 

  49. 49

    van Maanen, M. A., Vervoordeldonk, M. J. & Tak, P. P. The cholinergic anti-inflammatory pathway: towards innovative treatment of rheumatoid arthritis. Nat. Rev. Rheumatol. 5, 229–232 (2009).

    Article  CAS  Google Scholar 

  50. 50

    Koopman, F. A. et al. Restoring the balance of the autonomic nervous system as an innovative approach to the treatment of rheumatoid arthritis. Mol. Med. 17, 937–948 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Huston, J. M. & Tracey, K. J. The pulse of inflammation: heart rate variability, the cholinergic anti-inflammatory pathway and implications for therapy. J. Intern. Med. 269, 45–53 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Yi, C. X., la Fleur, S. E., Fliers, E. & Kalsbeek, A. The role of the autonomic nervous liver innervation in the control of energy metabolism. Biochim. Biophys. Acta. 1802, 416–431 (2010).

    Article  CAS  Google Scholar 

  53. 53

    Owyang, C. & Heldsinger, A. Vagal control of satiety and hormonal regulation of appetite. J. Neurogastroenterol. Motil. 17, 338–348 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Kreier, F. et al. Selective parasympathetic innervation of subcutaneous and intra-abdominal fat—functional implications. J. Clin. Invest. 110, 1243–1250 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Giordano, A. et al. White adipose tissue lacks significant vagal innervation and immunohistochemical evidence of parasympathetic innervation. Am. J. Physiol. Regul. Integr. Comp. Physiol 291, R1243–R1255 (2006).

    Article  CAS  Google Scholar 

  56. 56

    Wang, P. Y. et al. Upper intestinal lipids trigger a gut–brain–liver axis to regulate glucose production. Nature 452, 1012–1016 (2008).

    Article  CAS  Google Scholar 

  57. 57

    Cheung, G. W., Kokorovic, A., Lam, C. K., Chari, M. & Lam, T. K. Intestinal cholecystokinin controls glucose production through a neuronal network. Cell Metab. 10, 99–109 (2009).

    Article  CAS  Google Scholar 

  58. 58

    Lam, C. K. et al. Activation of N-methyl-D-aspartate (NMDA) receptors in the dorsal vagal complex lowers glucose production. J. Biol. Chem. 285, 21913–21921 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Nakabayashi, H., Nishizawa, M., Nakagawa, A., Takeda, R. & Niijima, A. Vagal hepatopancreatic reflex effect evoked by intraportal appearance of tGLP-1. Am. J. Physiol. 271, E808–E813 (1996).

    CAS  PubMed  Google Scholar 

  60. 60

    Balkan, B. & Li, X. Portal GLP-1 administration in rats augments the insulin response to glucose via neuronal mechanisms. Am. J. Physiol. Regul. Integr. Comp. Physiol. 279, R1449–R1454 (2000).

    Article  CAS  Google Scholar 

  61. 61

    Vincent, K. M., Sharp, J. W. & Raybould, H. E. Intestinal glucose-induced calcium–calmodulin kinase signaling in the gut–brain axis in awake rats. Neurogastroenterol. Motil. 23, e282–e293 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Obici, S., Zhang, B. B., Karkanias, G. & Rossetti, L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat. Med. 8, 1376–1382 (2002).

    Article  CAS  Google Scholar 

  63. 63

    Pocai, A. et al. Hypothalamic K(ATP) channels control hepatic glucose production. Nature 434, 1026–1031 (2005).

    Article  CAS  Google Scholar 

  64. 64

    Pocai, A., Obici, S., Schwartz, G. J. & Rossetti, L. A brain–liver circuit regulates glucose homeostasis. Cell Metab. 1, 53–61 (2005).

    Article  CAS  Google Scholar 

  65. 65

    Shimazu, T., Matsushita, H. & Ishikawa, K. Cholinergic stimulation of the rat hypothalamus: effects of liver glycogen synthesis. Science 194, 535–536 (1976).

    Article  CAS  Google Scholar 

  66. 66

    Matsushita, H., Ishikawa, K. & Shimazu, T. Chemical coding of the hypothalamic neurones in metabolic control. I. Acetylcholine-sensitive neurones and glycogen synthesis in liver. Brain Res. 163, 253–261 (1979).

    Article  CAS  Google Scholar 

  67. 67

    Ruiz, d. A. I, Gautam, D., Guettier, J. M. & Wess, J. Novel insights into the function of β-cell M3 muscarinic acetylcholine receptors: therapeutic implications. Trends Endocrinol. Metab. 22, 74–80 (2011).

    Article  CAS  Google Scholar 

  68. 68

    Kampe, J., Tschop, M. H., Hollis, J. H. & Oldfield, B. J. An anatomic basis for the communication of hypothalamic, cortical and mesolimbic circuitry in the regulation of energy balance. Eur. J. Neurosci. 30, 415–430 (2009).

    Article  CAS  Google Scholar 

  69. 69

    Morton, G. J., Cummings, D. E., Baskin, D. G., Barsh, G. S. & Schwartz, M. W. Central nervous system control of food intake and body weight. Nature 443, 289–295 (2006).

    Article  CAS  Google Scholar 

  70. 70

    Saper, C. B., Chou, T. C. & Elmquist, J. K. The need to feed: homeostatic and hedonic control of eating. Neuron 36, 199–211 (2002).

    Article  CAS  Google Scholar 

  71. 71

    Erridge, C., Attina, T., Spickett, C. M. & Webb,D. J. A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Am. J. Clin. Nutr. 86, 1286–1292 (2007).

    Article  CAS  Google Scholar 

  72. 72

    Ghanim, H. et al. Increase in plasma endotoxin concentrations and the expression of Toll-like receptors and suppressor of cytokine signaling-3 in mononuclear cells after a high-fat, high-carbohydrate meal: implications for insulin resistance. Diabetes Care 32, 2281–2287 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Lundman, P. et al. A high-fat meal is accompanied by increased plasma interleukin-6 concentrations. Nutr. Metab. Cardiovasc. Dis. 17, 195–202 (2007).

    Article  CAS  Google Scholar 

  74. 74

    Laugerette, F. et al. Emulsified lipids increase endotoxemia: possible role in early postprandial low-grade inflammation. J. Nutr. Biochem. 22, 53–59 (2011).

    Article  CAS  Google Scholar 

  75. 75

    Luyer, M. D. et al. Nutritional stimulation of cholecystokinin receptors inhibits inflammation via the vagus nerve. J. Exp. Med. 202, 1023–1029 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Bucinskaite, V., Kurosawa, M., Miyasaka, K., Funakoshi, A. & Lundeberg, T. Interleukin-1β sensitizes the response of the gastric vagal afferent to cholecystokinin in rat. Neurosci. Lett. 229, 33–36 (1997).

    Article  CAS  Google Scholar 

  77. 77

    Gaige, S., Abou, E., Abysique, A. & Bouvier, M. Effects of interactions between interleukin-1β and leptin on cat intestinal vagal mechanoreceptors. J. Physiol. 555, 297–310 (2004).

    Article  CAS  Google Scholar 

  78. 78

    Doganay, M. et al. The effects of vagotomy on bacterial translocation: an experimental study. J. Surg. Res. 71, 166–171 (1997).

    Article  CAS  Google Scholar 

  79. 79

    Eckel, R. H. Mechanisms of the components of the metabolic syndrome that predispose to diabetes and atherosclerotic CVD. Proc. Nutr. Soc. 66, 82–95 (2007).

    Article  CAS  Google Scholar 

  80. 80

    Shoelson, S. E., Herrero, L. & Naaz, A. Obesity, inflammation, and insulin resistance. Gastroenterology 132, 2169–2180 (2007).

    Article  CAS  Google Scholar 

  81. 81

    Sutherland, J. P., McKinley, B. & Eckel, R. H. The metabolic syndrome and inflammation. Metab. Syndr. Relat. Disord. 2, 82–104 (2004).

    Article  CAS  Google Scholar 

  82. 82

    Gregor, M. F. & Hotamisligil, G. S. Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 29, 415–445 (2010).

    Article  CAS  Google Scholar 

  83. 83

    Ouchi, N., Parker, J. L., Lugus, J. J. & Walsh, K. Adipokines in inflammation and metabolic disease. Nat. Rev. Immunol. 11, 85–97 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Tilg, H. & Moschen, A. R. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat. Rev. Immunol. 6, 772–783 (2006).

    Article  CAS  Google Scholar 

  85. 85

    Olefsky, J. M. & Glass, C. K. Macrophages, inflammation, and insulin resistance. Annu. Rev. Physiol. 72, 219–246 (2010).

    Article  CAS  Google Scholar 

  86. 86

    Nishimura, S. et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 15, 914–920 (2009).

    Article  CAS  Google Scholar 

  87. 87

    Nathan, C. Epidemic inflammation: pondering obesity. Mol. Med. 14, 485–492 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Baker, R. G., Hayden, M. S. & Ghosh, S. NF-κB, inflammation, and metabolic disease. Cell Metab. 13, 11–22 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–188 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Masters, S. L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat. Immunol. 11, 897–904 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Musso, G., Gambino, R. & Cassader, M. Interactions between gut microbiota and host metabolism predisposing to obesity and diabetes. Annu. Rev. Med. 62, 361–380 (2011).

    Article  CAS  Google Scholar 

  92. 92

    Delzenne, N. M., Neyrinck, A. M., Backhed, F. & Cani, P. D. Targeting gut microbiota in obesity: effects of prebiotics and probiotics. Nat. Rev. Endocrinol. 7, 639–646 (2011).

    Article  CAS  Google Scholar 

  93. 93

    Cani, P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).

    Article  CAS  Google Scholar 

  94. 94

    Tilg, H. The role of cytokines in non-alcoholic fatty liver disease. Dig. Dis. 28, 179–185 (2010).

    Article  CAS  Google Scholar 

  95. 95

    Tilg, H. & Moschen, A. R. Inflammatory mechanisms in the regulation of insulin resistance. Mol. Med. 14, 222–231 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Ridker, P. M. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 107, 363–369 (2003).

    Article  Google Scholar 

  97. 97

    Scherer, T. et al. Brain insulin controls adipose tissue lipolysis and lipogenesis. Cell Metab. 13, 183–194 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Howard, J. K. & Flier, J. S. Attenuation of leptin and insulin signaling by SOCS proteins. Trends Endocrinol. Metab. 17, 365–371 (2006).

    Article  CAS  Google Scholar 

  99. 99

    de La Serre, C. B. et al. Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 299, G440–G448 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Lee, J. et al. Glucose-sensing by gut endocrine cells and activation of the vagal afferent pathway is impaired in a rodent model of type 2 diabetes mellitus. Am. J. Physiol. Regul. Integr. Comp. Physiol. 302, R657–R666 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Lam, T. K. et al. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat. Med. 11, 320–327 (2005).

    Article  CAS  Google Scholar 

  102. 102

    Morgan, K., Obici, S. & Rossetti, L. Hypothalamic responses to long-chain fatty acids are nutritionally regulated. J. Biol. Chem. 279, 31139–31148 (2004).

    Article  CAS  Google Scholar 

  103. 103

    Ribeiro, R. T., Lautt, W. W., Legare, D. J. & Macedo, M. P. Insulin resistance induced by sucrose feeding in rats is due to an impairment of the hepatic parasympathetic nerves. Diabetologia 48, 976–983 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Miller, A. W., Sims, J. J., Canavan, A., Hsu, T. & Ujhelyi, M. R. Impaired vagal reflex activity in insulin-resistant rats. J. Cardiovasc. Pharmacol. 33, 698–702 (1999).

    Article  CAS  Google Scholar 

  105. 105

    Gautam, D. et al. A critical role for β cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo. Cell Metab. 3, 449–461 (2006).

    Article  CAS  Google Scholar 

  106. 106

    Liu, R. H., Mizuta, M. & Matsukura, S. The expression and functional role of nicotinic acetylcholine receptors in rat adipocytes. J. Pharmacol. Exp. Ther. 310, 52–58 (2004).

    Article  CAS  Google Scholar 

  107. 107

    Cancello, R. et al. The nicotinic acetylcholine receptor α7 in subcutaneous mature adipocytes: downregulation in human obesity and modulation by diet-induced weight loss. Int. J. Obes. (Lond.) http://dx.doi.org/10.1038/ijo.2011.275.

  108. 108

    Waldburger, J. M. et al. Spinal p38 MAP kinase regulates peripheral cholinergic outflow. Arthritis Rheum. 58, 2919–2921 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  109. 109

    Albuquerque, E. X., Santos, M. D., Alkondon, M., Pereira, E. F. & Maelicke, A. Modulation of nicotinic receptor activity in the central nervous system: a novel approach to the treatment of Alzheimer disease. Alzheimer Dis. Assoc. Disord. 15 (Suppl. 1), S19–S25 (2001).

    Article  CAS  Google Scholar 

  110. 110

    Jo, Y. H., Wiedl, D. & Role, L. W. Cholinergic modulation of appetite-related synapses in mouse lateral hypothalamic slice. J. Neurosci. 25, 11133–11144 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Mineur, Y. S. et al. Nicotine decreases food intake through activation of POMC neurons. Science 332, 1330–1332 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Grundy, S. M. Metabolic syndrome pandemic. Arterioscler. Thromb. Vasc. Biol. 28, 629–636 (2008).

    Article  CAS  Google Scholar 

  113. 113

    James, W. P. The epidemiology of obesity: the size of the problem. J. Intern. Med. 263, 336–352 (2008).

    Article  CAS  Google Scholar 

  114. 114

    Vetter, M. L., Faulconbridge, L. F., Webb, V. L. & Wadden, T. A. Behavioral and pharmacologic therapies for obesity. Nat. Rev. Endocrinol. 6, 578–588 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007).

    Article  CAS  Google Scholar 

  116. 116

    Goldfine, A. B., Fonseca, V. & Shoelson, S. E. Therapeutic approaches to target inflammation in type 2 diabetes. Clin. Chem. 57, 162–167 (2011).

    Article  CAS  Google Scholar 

  117. 117

    Cohen, J. C., Horton, J. D. & Hobbs, H. H. Human fatty liver disease: old questions and new insights. Science 332, 1519–1523 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Kitagawa, H. et al. Safety, pharmacokinetics, and effects on cognitive function of multiple doses of GTS-21 in healthy, male volunteers. Neuropsychopharmacology 28, 542–551 (2003).

    Article  CAS  Google Scholar 

  119. 119

    US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  120. 120

    Inanaga, K. et al. Acetylcholinesterase inhibitors attenuate atherogenesis in apolipoprotein E-knockout mice. Atherosclerosis 213, 52–58 (2010).

    Article  CAS  Google Scholar 

  121. 121

    Handa, T. et al. Anti-Alzheimer's drug, donepezil, markedly improves long-term survival after chronic heart failure in mice. J. Card. Fail. 15, 805–811 (2009).

    Article  CAS  Google Scholar 

  122. 122

    Rodriguez-Diaz, R. et al. α cells secrete acetylcholine as a non-neuronal paracrine signal priming β cell function in humans. Nat. Med. 17, 888–892 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Citrome, L. & Volavka, J. Consensus development conference on antipsychotic drugs and obesity and diabetes: response to consensus statement. J. Clin. Psychiatry 66, 1073–1074 (2005).

    Article  Google Scholar 

  124. 124

    Victoriano, M. et al. Olanzapine-induced accumulation of adipose tissue is associated with an inflammatory state. Brain Res. 1350, 167–175 (2010).

    Article  CAS  Google Scholar 

  125. 125

    Teff, K. L. & Kim, S. F. Atypical antipsychotics and the neural regulation of food intake and peripheral metabolism. Physiol. Behav. 104, 590–598 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Weston-Green, K., Huang, X. F., Lian, J. & Deng, C. Effects of olanzapine on muscarinic M3 receptor binding density in the brain relates to weight gain, plasma insulin and metabolic hormone levels. Eur. Neuropsychopharmacol. 22, 364–373 (2011).

    Article  CAS  Google Scholar 

  127. 127

    Ribeiz, S. R. et al. Cholinesterase inhibitors as adjunctive therapy in patients with schizophrenia and schizoaffective disorder: a review and meta-analysis of the literature. CNS Drugs 24, 303–317 (2010).

    Article  CAS  Google Scholar 

  128. 128

    Strachan, M. W., Reynolds, R. M., Marioni, R. E. & Price, J. F. Cognitive function, dementia and type 2 diabetes mellitus in the elderly. Nat. Rev. Endocrinol. 7, 108–114 (2011).

    Article  CAS  PubMed  Google Scholar 

  129. 129

    Maser, R. E., Lenhard, M. J., Irgau, I. & Wynn, G. M. Impact of surgically induced weight loss on cardiovascular autonomic function: one-year follow-up. Obesity (Silver Spring) 15, 364–369 (2007).

    Article  Google Scholar 

  130. 130

    Bueter, M. et al. Vagal sparing surgical technique but not stoma size affects body weight loss in rodent model of gastric bypass. Obes. Surg. 20, 616–622 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  131. 131

    Clancy, J. A., Deuchars, S. A. & Deuchars, J. 2012 GL Brown Lecture 'The Wonders of the Wanderer'. Exp. Physiol. http://dx.doi.org/10.1113/expphysiol.2012.064543.

  132. 132

    Pardo, J. V. et al. Weight loss during chronic, cervical vagus nerve stimulation in depressed patients with obesity: an observation. Int. J. Obes. (Lond.) 31, 1756–1759 (2007).

    Article  CAS  Google Scholar 

  133. 133

    Bugajski, A. J. et al. Effect of long-term vagal stimulation on food intake and body weight during diet induced obesity in rats. J. Physiol. Pharmacol. 58 (Suppl. 1), 5–12 (2007).

    PubMed  Google Scholar 

  134. 134

    Val-Laillet, D., Biraben, A., Randuineau, G. & Malbert, C. H. Chronic vagus nerve stimulation decreased weight gain, food consumption and sweet craving in adult obese minipigs. Appetite 55, 245–252 (2010).

    Article  CAS  Google Scholar 

  135. 135

    Schwartz, P. J. et al. Long term vagal stimulation in patients with advanced heart failure: first experience in man. Eur. J. Heart Fail. 10, 884–891 (2008).

    Article  Google Scholar 

  136. 136

    Friedman, J. M. & Halaas, J. L. Leptin and the regulation of body weight in mammals. Nature 395, 763–770 (1998).

    Article  CAS  Google Scholar 

  137. 137

    La Cava, A. & Matarese, G. The weight of leptin in immunity. Nat. Rev. Immunol. 4, 371–379 (2004).

    Article  CAS  Google Scholar 

  138. 138

    Maedler, K. et al. Leptin modulates β cell expression of IL-1 receptor antagonist and release of IL-1β in human islets. Proc. Natl Acad. Sci. USA 101, 8138–8143 (2004).

    Article  CAS  Google Scholar 

  139. 139

    Hotamisligil, G. S., Arner, P., Caro, J. F., Atkinson, R. L. & Spiegelman, B. M. Increased adipose tissue expression of tumor necrosis factor-α in human obesity and insulin resistance. J. Clin. Invest. 95, 2409–2415 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Leinonen, E. et al. Insulin resistance and adiposity correlate with acute-phase reaction and soluble cell adhesion molecules in type 2 diabetes. Atherosclerosis 166, 387–394 (2003).

    Article  CAS  Google Scholar 

  141. 141

    Kanda, H. et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Invest. 116, 1494–1505 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Steppan, C. M. et al. The hormone resistin links obesity to diabetes. Nature 409, 307–312 (2001).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors' research work is supported in part by grants from the National Institute of General Medical Sciences, NIH. The authors thank Peder S. Olofsson for critical reading of the manuscript.

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Both authors contributed equally to researching data for the article, writing the manuscript, discussions of the content, and review or editing of the manuscript before submission.

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Correspondence to Valentin A. Pavlov.

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K. J. Tracey is a cofounder of and consultant to SetPoint Medical, Inc. Both authors are inventors on the following patent: “Cholinesterase inhibitors for treating inflammation” (patent number 8,003,632). K. J. Tracey also is an inventor of other patents related to the content of this review: “Treatment of inflammation using α7 receptor-binding cholinergic agonists” (patent number 7,785,808); “Inhibition of inflammatory cytokine production by cholinergic agonists and vagus nerve stimulation” (patent number 6,838,471).

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Pavlov, V., Tracey, K. The vagus nerve and the inflammatory reflex—linking immunity and metabolism. Nat Rev Endocrinol 8, 743–754 (2012). https://doi.org/10.1038/nrendo.2012.189

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