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.
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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Tracey, K. J. The inflammatory reflex. Nature 420, 853–859 (2002).
Tracey, K. J. Reflex control of immunity. Nat. Rev. Immunol. 9, 418–428 (2009).
Andersson, U. & Tracey, K. J. Reflex principles of immunological homeostasis. Annu. Rev. Immunol. 30, 313–335 (2011).
Baccala, R. et al. Sensors of the innate immune system: their mode of action. Nat. Rev. Rheumatol. 5, 448–456 (2009).
Chen, G. Y. & Nunez, G. Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol. 10, 826–837 (2010).
Andersson, U. & Tracey, K. J. HMGB1 is a therapeutic target for sterile inflammation and infection. Annu. Rev. Immunol. 29, 139–162 (2011).
Medzhitov, R. Inflammation 2010: new adventures of an old flame. Cell 140, 771–776 (2010).
Pavlov, V. A. & Tracey, K. J. The cholinergic anti-inflammatory pathway. Brain Behav. Immun. 19, 493–499 (2005).
Tracey, K. J. Physiology and immunology of the cholinergic antiinflammatory pathway. J. Clin. Invest. 117, 289–296 (2007).
Pavlov, V. A. Cholinergic modulation of inflammation. Int. J. Clin. Exp. Med. 1, 203–212 (2008).
Bastard, J. P. et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur. Cytokine Netw. 17, 4–12 (2006).
Donath, M. Y. & Shoelson, S. E. Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11, 98–107 (2011).
Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).
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).
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).
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).
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).
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).
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).
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).
Borovikova, L. V. et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405, 458–462 (2000).
Wang, H. et al. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature 421, 384–388 (2003).
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).
Goehler, L. E. et al. Vagal immune-to-brain communication: a visceral chemosensory pathway. Auton. Neurosci. 85, 49–59 (2000).
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).
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).
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).
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).
Pavlov, V. A. & Tracey, K. J. Neural regulators of innate immune responses and inflammation. Cell. Mol. Life Sci. 61, 2322–2331 (2004).
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).
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).
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).
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).
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).
Lee, S. T. et al. Cholinergic anti-inflammatory pathway in intracerebral hemorrhage. Brain Res. 1309, 164–171 (2010).
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).
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).
Gallowitsch-Puerta, M. & Pavlov, V. A. Neuro-immune interactions via the cholinergic anti-inflammatory pathway. Life Sci. 80, 2325–2329 (2007).
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).
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).
Guarini, S. et al. Efferent vagal fibre stimulation blunts nuclear factor-κB activation and protects against hypovolemic hemorrhagic shock. Circulation 107, 1189–1194 (2003).
Pavlov, V. A. & Tracey, K. J. Controlling inflammation: the cholinergic anti-inflammatory pathway. Biochem. Soc. Trans. 34, 1037–1040 (2006).
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).
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).
Rosas-Ballina, M. et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 334, 98–101 (2011).
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).
Bonaz, B. The cholinergic anti-inflammatory pathway and the gastrointestinal tract. Gastroenterology 133, 1370–1373 (2007).
Leib, C. et al. Role of the cholinergic antiinflammatory pathway in murine autoimmune myocarditis. Circ. Res. 109, 130–140 (2011).
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).
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).
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).
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).
Owyang, C. & Heldsinger, A. Vagal control of satiety and hormonal regulation of appetite. J. Neurogastroenterol. Motil. 17, 338–348 (2011).
Kreier, F. et al. Selective parasympathetic innervation of subcutaneous and intra-abdominal fat—functional implications. J. Clin. Invest. 110, 1243–1250 (2002).
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).
Wang, P. Y. et al. Upper intestinal lipids trigger a gut–brain–liver axis to regulate glucose production. Nature 452, 1012–1016 (2008).
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).
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).
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).
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).
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).
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).
Pocai, A. et al. Hypothalamic K(ATP) channels control hepatic glucose production. Nature 434, 1026–1031 (2005).
Pocai, A., Obici, S., Schwartz, G. J. & Rossetti, L. A brain–liver circuit regulates glucose homeostasis. Cell Metab. 1, 53–61 (2005).
Shimazu, T., Matsushita, H. & Ishikawa, K. Cholinergic stimulation of the rat hypothalamus: effects of liver glycogen synthesis. Science 194, 535–536 (1976).
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).
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).
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).
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).
Saper, C. B., Chou, T. C. & Elmquist, J. K. The need to feed: homeostatic and hedonic control of eating. Neuron 36, 199–211 (2002).
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).
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).
Lundman, P. et al. A high-fat meal is accompanied by increased plasma interleukin-6 concentrations. Nutr. Metab. Cardiovasc. Dis. 17, 195–202 (2007).
Laugerette, F. et al. Emulsified lipids increase endotoxemia: possible role in early postprandial low-grade inflammation. J. Nutr. Biochem. 22, 53–59 (2011).
Luyer, M. D. et al. Nutritional stimulation of cholecystokinin receptors inhibits inflammation via the vagus nerve. J. Exp. Med. 202, 1023–1029 (2005).
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).
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).
Doganay, M. et al. The effects of vagotomy on bacterial translocation: an experimental study. J. Surg. Res. 71, 166–171 (1997).
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).
Shoelson, S. E., Herrero, L. & Naaz, A. Obesity, inflammation, and insulin resistance. Gastroenterology 132, 2169–2180 (2007).
Sutherland, J. P., McKinley, B. & Eckel, R. H. The metabolic syndrome and inflammation. Metab. Syndr. Relat. Disord. 2, 82–104 (2004).
Gregor, M. F. & Hotamisligil, G. S. Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 29, 415–445 (2010).
Ouchi, N., Parker, J. L., Lugus, J. J. & Walsh, K. Adipokines in inflammation and metabolic disease. Nat. Rev. Immunol. 11, 85–97 (2011).
Tilg, H. & Moschen, A. R. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat. Rev. Immunol. 6, 772–783 (2006).
Olefsky, J. M. & Glass, C. K. Macrophages, inflammation, and insulin resistance. Annu. Rev. Physiol. 72, 219–246 (2010).
Nishimura, S. et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 15, 914–920 (2009).
Nathan, C. Epidemic inflammation: pondering obesity. Mol. Med. 14, 485–492 (2008).
Baker, R. G., Hayden, M. S. & Ghosh, S. NF-κB, inflammation, and metabolic disease. Cell Metab. 13, 11–22 (2011).
Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–188 (2011).
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).
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).
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).
Cani, P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).
Tilg, H. The role of cytokines in non-alcoholic fatty liver disease. Dig. Dis. 28, 179–185 (2010).
Tilg, H. & Moschen, A. R. Inflammatory mechanisms in the regulation of insulin resistance. Mol. Med. 14, 222–231 (2008).
Ridker, P. M. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 107, 363–369 (2003).
Scherer, T. et al. Brain insulin controls adipose tissue lipolysis and lipogenesis. Cell Metab. 13, 183–194 (2011).
Howard, J. K. & Flier, J. S. Attenuation of leptin and insulin signaling by SOCS proteins. Trends Endocrinol. Metab. 17, 365–371 (2006).
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).
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).
Lam, T. K. et al. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat. Med. 11, 320–327 (2005).
Morgan, K., Obici, S. & Rossetti, L. Hypothalamic responses to long-chain fatty acids are nutritionally regulated. J. Biol. Chem. 279, 31139–31148 (2004).
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).
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).
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).
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).
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.
Waldburger, J. M. et al. Spinal p38 MAP kinase regulates peripheral cholinergic outflow. Arthritis Rheum. 58, 2919–2921 (2008).
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).
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).
Mineur, Y. S. et al. Nicotine decreases food intake through activation of POMC neurons. Science 332, 1330–1332 (2011).
Grundy, S. M. Metabolic syndrome pandemic. Arterioscler. Thromb. Vasc. Biol. 28, 629–636 (2008).
James, W. P. The epidemiology of obesity: the size of the problem. J. Intern. Med. 263, 336–352 (2008).
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).
Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007).
Goldfine, A. B., Fonseca, V. & Shoelson, S. E. Therapeutic approaches to target inflammation in type 2 diabetes. Clin. Chem. 57, 162–167 (2011).
Cohen, J. C., Horton, J. D. & Hobbs, H. H. Human fatty liver disease: old questions and new insights. Science 332, 1519–1523 (2011).
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).
US National Library of Medicine. ClinicalTrials.gov [online], (2012).
Inanaga, K. et al. Acetylcholinesterase inhibitors attenuate atherogenesis in apolipoprotein E-knockout mice. Atherosclerosis 213, 52–58 (2010).
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).
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).
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).
Victoriano, M. et al. Olanzapine-induced accumulation of adipose tissue is associated with an inflammatory state. Brain Res. 1350, 167–175 (2010).
Teff, K. L. & Kim, S. F. Atypical antipsychotics and the neural regulation of food intake and peripheral metabolism. Physiol. Behav. 104, 590–598 (2011).
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).
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).
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).
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).
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).
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.
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).
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).
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).
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).
Friedman, J. M. & Halaas, J. L. Leptin and the regulation of body weight in mammals. Nature 395, 763–770 (1998).
La Cava, A. & Matarese, G. The weight of leptin in immunity. Nat. Rev. Immunol. 4, 371–379 (2004).
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).
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).
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).
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).
Steppan, C. M. et al. The hormone resistin links obesity to diabetes. Nature 409, 307–312 (2001).
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.
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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