Vagus and Inflamation

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Nat Rev Endocrinol. Author manuscript; available in PMC 2014 July 04.
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Nat Rev Endocrinol. 2012 December ; 8(12): 743754. doi:10.1038/nrendo.2012.189.
The vagus nerve and the inflammatory reflexlinking immunity

and metabolism
Valentin A. Pavlov and Kevin J. Tracey
Center for Biomedical Science, The Feinstein Institute for Medical Research, 350 Community
Drive, Manhasset, NY 11030, USA
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.
Introduction
The vagus nerve (cranial nerve X) is the main nerve of the parasympathetic division of the
autonomic nervous system. The vagus nerve regulates metabolic homeostasis by controlling
heart rate, gastrointestinal motility and secretion, pancreatic endocrine and exocrine
secretion, hepatic glucose production, and other visceral functions. In addition, the vagus
nerve is a major constituent of a neural reflex mechanismthe inflammatory reflexthat
controls innate immune responses and inflammation during pathogen invasion and tissue
injury.13
Innate immune responses are activated by pathogen-associated and danger-associated

molecular patterns that are recognized by sensors on the immune cell surface or in
intracellular compartments. These cellular sensors include Toll-like receptors (TLRs),
nucleotide-binding oligomerization domain-like receptors (NLRs) and other patternrecognition receptors (Figure 1).46 Activation of signalling cascades downstream of TLRs
results in increased production and release of tumour necrosis factor (TNF), IL-6 and other
2012 Macmillan Publishers Limited. All rights reserved

Correspondence to: V. A. Pavlov [email protected].
Competing interests
The authors declare that they are inventors on patents related to the content of this manuscript. K. J. Tracey also declares an
association with the following company: SetPoint Medical. See the article online for the full details of the relationships.
Author contributions
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.
Pavlov and Tracey
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proinflammatory cytokines.1,7 In addition, activation of NLRs is associated with the

formation of multimeric protein complexes, termed inflammasomes, which regulate
maturation and release of the proinflammatory cytokines IL-1 and IL-18.5 Proinflammatory
cytokines, along with chemo-kines, reactive oxygen species, nitrogen inter mediates and
other inflammatory molecules, are critically implicated in extracellular pathogen clearance,
vasodilatation, neutrophil recruitment, increased vascular permeability and induction of
acute-phase proteins, such as C-reactive protein (CRP), and coagulation molecules.1,5,7
Proinflammatory progression is balanced by the release of IL-10, TGF-, soluble cytokine
receptors and other anti-inflammatory molecules.
Inflammation is normally a local and temporary event and, upon its resolution, immune and
physiological homeostasis is restored. However, disrupted innate immune regulation can
result in continual pro-inflammatory cytokine activity and excessive or chronic
inflammation. This state underlies the pathogenesis of a range of disease syndromes,
including sepsis, rheumatoid arthritis, inflammatory bowel disease and other inflammatory
and autoimmune disorders.810 Understanding endogenous mechanisms that prevent or
neutralize excessive proinflammatory responses could lead to novel therapeutic options for
diseases associated with an excessive or chronic inflammatory state.
Chronic inflammation as a result of immune and metabolic dysregulation is a characteristic

feature in patients with obesity and is causally linked with insulin resistance and other
metabolic complications.1113 Decreased vagus nerve activity in the context of obesity has
been reported.1417 Selective cholinergic activation within the efferent vagus nervemediated arm of the inflammatory reflex can suppress obesity-associated inflammation and
reverse metabolic complications.1820 These findings raise the intriguing possibility that
dysregulation of vagus nerve-mediated signalling might contribute to the pathogenes is of
obesity and its related comorbidities.
In this Review, we provide a conceptual view of the inflammatory reflex as a physiological
mechanism that functions on the path between immunity and metabolism and could be
exploited in the treatment of obesity-associated inflammation and obesity-related disorders.
The inflammatory reflex

Communication between the immune system and the brain is vital for controlling
inflammation. The inflammatory reflex is a centrally integrated physiological mechanism in
which afferent vagus nerve signalling, activated by cytokines or pathogen-derived products,
is functionally associated with efferent vagus nerve-mediated output to regulate
proinflammatory cytokine production and inflammation (Figure 1). The absence of this
inflammatory reflexresulting from neural lesions or genetic ablation of essential
componentsresults in excessive innate immune responses and cytokine toxicity.21,22 The
inflammatory reflex has been comprehensively reviewed elsewhere.13,9,23
Afferent arm
Afferent vagus nerve fibres sense peripheral inflammatory molecules and convey signals to
the brain and are, therefore, important for immune-to-brain communication (Figure 1).1,24
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Afferent vagus neurons, residing in the nodose and jugular ganglia, terminate primarily in
the nucleus tractus solitarius in the brainstem medulla oblongata (Figure 1).24 Afferent
signalling is further communicated through neural contacts between brainstem nuclei, the
hypothalamus and forebrain regions associated with integration of visceral sensory
information as well as coordination of autonomic function and behavioural responses.23,24
Peripheral administration of bacterial lipopolysaccharide (also known as endotoxin) or IL-1

causes afferent vagus nerve activation, as determined by increased c-Fos expression and
electrical activity.24,25 IL-1 receptors expressed on vagus nerve afferents and
chemosensory (glomus) cells in paraganglia surrounding afferent vagus nerve endings have
been implicated in the recognition of immune activation (Figure 1).24,26,27 Prostaglandindependent mechanisms have also been implicated in activating vagus nerve afferents by
increasing levels of circulating IL-1.26 Intraportal administration of IL-1 to rats increases
afferent and, subsequently, efferent vagus nerve and splenic nerveactivity.25 Peripheral
immune stimulation causes sickness behaviour, which is attenuated in rodents who have
undergone surgical transection of the vagus nerve to prevent immune signalling at peripheral
nerve endings.24 This attenuation is dependent on the magnitude of immune activation,
because fairly large quantities of circulating IL-1 produce fever and sickness behaviour by
bypassing the neural circuits, acting through brain circumventricular organs (including the
area postrema) and via other humoral mechanisms (Figure 1).28,29 Accordingly, afferent
vagus nerve endings appear to be important for relaying information about immune status to
the brain when proinflamma tory cytokines are present at fairly low levels.24,28 However,
TLR4 (which can be activated by lipopolysaccharide) is expressed in the nodose
ganglion,30,31 which suggests a mechanism by which lipopolysaccharide and other
inflammatory molecules can activate vagus nerve afferents above their visceral endings
(Figure 1).
Efferent arm
A little more than a decade ago, an important role of efferent vagus nerve cholinergic
signalling in brain-to-immune communication was revealed by observations that vagus
nerve stimulation suppresses local and serum proinflammatory cytokine levels in rodents
with endo-toxaemia, and that acetylcholine inhibits the release of TNF, IL-1 and IL-18
from lipopolysaccharide-stimulated macrophages.21 These findings led to the definition of
the cholinergic anti-inflammatory pathway as the efferent vagus nerve-based arm of the
inflammatory reflex (Figure 1).21 This efferent arm can be centrally regulated, and
muscarinic acetylcholine receptors in the brain have been implicated in this regulation
(Figure 1).3235 Galantamine is a centrally acting acetylcholinesterase inhibitor and activates
the efferent cholinergic arm of the inflammatory reflex by through a muscarinic receptordependent mechanism in the brain.34 Defining a brain network that can be used to explore
central mechanisms of inflammatory reflex control is the aim of ongoing studies.
In peripheral tissues, the 7 nicotinic acetylcholine receptor (7nAChR) is important for
mediating anti-inflammatory signalling within the efferent arm of the inflammatory reflex
(Figure 2).22 Accordingly, several 7nAChR agonists have been identified as experimental
anti-inflammatory therapeutics with potential for clinical development.2,3638 The 7
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subunit of the receptor is expressed in macrophages, monocytes, dendritic cells, T cells,

endothelial and other non-neuronal cells, and the structural and functional characterization
of non-neuronal 7nAChRs is an area of ongoing study.2,38 The presence of 7nAChRs on
bone marrow-derived cells is required for the functional integrity of the inflammatory reflex,
but their presence on T cells and neuronal cells is not essential.39 The anti-inflammatory
action of 7nAChR agonists or vagus nerve stimulation is associated with downregulation
of CD14 and TLR4 expression in immune cells.40 Cholinergic inhibition of
proinflammatory cytokine production is mediated through intracellular signal pathways
downstream of 7nAChR that culminate in suppression of NF-B nuclear translocation
(Figure 2).3638,4042 The tyrosine protein kinase JAK2 might also be recruited and
activated by 7nAChR upon cholinergic stimulation.43 Subsequent phosphorylation of the
transcription factor STAT3 results in suppression of proinflammatory cytokine production in
intestinal macrophages (Figure 2).43
The anti-inflammatory effects of vagus nerve stimulation in animals with endotoxaemia

require neural signals along the adrenergic splenic nerve,44 which originates in the celiac
ganglion that is innervated by the efferent vagus nerve (Figure 1, Figure 2). Somewhat
unexpectedly, a specific subset of T cells (memory CD4+ T cells, which express
adrenoreceptors), instead of neurons, provide an endogenous source of acetylcholine in the
spleen (Figure 2).45 T cell production of acetylcholine in the spleen is critical for the
inflammatory reflex. In nude mice, which lack T cells, vagus nerve stimulation fails to
suppress TNF levels during endotoxaemia. However, transfer of acetylcholine-producing T
cells, which repopulate the spleen in nude mice, restores the integrity of the neural circuit.45
In addition to this spleen-mediated mechanism in endotoxaemia, efferent vagus nerve
endings might directly regulate the immune function by releasing acetylcholine, without the
requirement for either signalling along the splenic nerve or T cells (Figure 1, Figure 2). Such
a direct mechanism has been implicated in the suppression of inflammation in experimental
settings of haemorrhagic shock, ileus, inflammatory bowel disease, autoimmune myocarditis
and other inflammatory and autoimmune conditions.2,10,41,43,4649 Importantly, many of
these disorders are associated with autonomic dysfunction and decreased vagus nerve tone.
Enhancement of vagus nerve output could, therefore, have therapeutic potential in these
settings.50,51
Vagus nerve in metabolic regulation

Vagus nerve afferent and efferent signalling has an important role in the regulation of
feeding behaviour and metabolic homeostasis. This finely tuned regulation is aimed at
preserving energy balance and preventing fluctuations in body weight and metabolism that
can be detrimental to the individual.
Dietary intake and metabolism
Vagus nerve afferents innervating the gastrointestinal tract and liver are major constituents
of a sensory system that detects changes in micronutrient and metabolic molecules. These
nerve fibres transmit information detected by associated mechanoreceptors, chemoreceptors
and specific metabolite receptors in the gut and hepatic portal system concerning levels of
lipids, cholecystokinin, leptin, peptide YY, insulin and glucose to the brain (Figure 3).52,53
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Vagus nerve efferents, on the other hand, provide brain-derived output to the gastrointestinal
tract, liver and pancreas (Figure 3).52 Vagus nerve innerva-tion of white adipose tissue has
also been demonstrated using retrograde neuronal tracing.54 Other researchers, however,
found limited retrograde labelling in the dorsal motor nucleus following injection of the
tracer into white adipose tissue and a lack of some parasympathetic markers in adipose
tissue.55 Therefore, the anatomy and a functional role of the vagus nerve in relation to
adipose tissue is an area of active study.
Hepatic and gastrointestinal vagus nerve afferents are involved in the regulation of shortterm feeding behaviour.52,53 Afferent vagus nerve signalling mediates gastric
cholecystokinin-induced satiety and meal termination.52 Synergistic activation of vagus
nerve afferents by both cholecystokinin and leptin mediates their short-term inhibitory
effects on food intake.53 Lipid accumulation in the upper intestine, and consequent intestinal
cholecystokinin release, also triggers vagus nerve-mediated and brain-integrated suppression
of hepatic glucose production.56,57 Additionally, the efferent arm of this reflex mechanism
can be stimulated by direct activation of neurons in the dorsal vagal complex.58
Glucose-induced pancreatic insulin secretion can be stimulated by treatment with a truncated

form of glucagon-like peptide-1, which activates hepatic vagus nerve afferents and,
subsequently, vagus nerve efferents innervating the pancreas.59,60 In addition to its intrinsic
effects on the enteric nervous system, glucose in the lumen of the gastrointestinal tract
causes neuronal activation in vagus nerve afferents, the nucleus tractus solitarius, the arcuate
hypothalamic nucleus and the dorsal motor nucleus, thus highlighting the role of brain
circuitry in vagus nerve regulation of gastrointestinal function and pancreatic secretion.61
Additionally, metabolic molecules can act directly in the brain to trigger efferent output that
regulates metabolic homeostasis (Figure 3). Insulin signalling in the mediobasal
hypothalamus is mediated through modulation of ATP-sensitive potassium channels and has
been implicated in the suppression of hepatic glucose production.62,63 Efferent vagus nerve
signalling to the liver is essential for this regulation.63 Hypothalamic sensing of fluctuations
in circulatory lipid levels triggers efferent vagus nerve-mediated output that regulates
hepatic glucose production and glucose homeostasis.64 In the hypothalamus, cholinergic
activation dependent on muscarinic receptors increases hepatic glycogen synthesis through a
mechanism mediated by the vagus nerve.65,66 Vagus nerve-derived cholinergic signalling
through a mechanism mediated by M3 muscarinic receptors has also been implicated in
stimulating insulin release in the pancreas.67
The dorsal vagal complex and different hypothalamic regions are important constituents of a
brain network associated with vagus nerve-mediated regulation of peripheral metabolic
functions (Figure 3). Interconnections between these and other forebrain regions also have a
role in the integration of afferent and efferent signalling in terms of the control of metabolic
homeostasis and the regulation of hedonic and motivational aspects of feeding behaviour
(Figure 3).6870
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Postprandial inflammation
Serum lipopolysaccharide levels in healthy individuals are increased after consuming highfat, or high-fat and high-carbohydrate meals.71,72 Endotoxaemia following high-fat diet
ingestion or lipid intake has been implicated in postprandial inflammation as plasma levels
of IL-6 and the expression of TLR4, TLR2 and SOCS3 in mononuclear cells increases.7274
Postprandial endotoxaemia and inflammation are transient, however, and data from several
studies suggest that the vagus nerve and the inflammatory reflex might have a role in
suppressing postprandial inflammation. Afferent vagus nerve signalling has a primary role
in informing the brain about the presence of peripheral inflammation during exposure to low
levels of proinflammatory stimuli.28 TLR4, which is expressed by vagus nerve
afferents,30,31 provides a molecular sensory component for neural detection of
lipopolysaccharide in postprandial inflammation.
Dietary lipid infusion causes the release of chole-cystokinin, which acts both via vagus
nerve afferents and directly in the brain to trigger activation of efferent vagus nerve
signalling, which in turn suppresses the release of proinflammatory cytokines.75 Activation
of vagus nerve afferents by cholecystokinin or leptin is potentiated by IL-1.76,77
Furthermore, in rats, truncal vagotomy is associated with increased bacterial trans location
across the intestinal mucosa,78 which suggests a tonic vagus nerve control of intestinal
permeability and postprandial endotoxaemia.
The inflammatory reflex and obesity

Disruption in metabolic and immune homeostasis in obesity is associated with
hyperglycaemia, insulin resistance, dyslipidaemia and hypertension. This cluster of
conditions characterizes the metabolic syndrome.79 Moreover, levels of proinflammatory
cytokines and acute-phase proteins such as CRP are increased in individuals with obesity,
indicating chronic inflammation.11,80 This inflammatory state is considered to be an
essential pathophysiological constituent in obesity, underlying its adverse consequences and
linking it to the other components of the metabolic syndrome.80,81 Several lines of evidence
indicate that vagus nerve activity could be impaired in obesity, and enhancing cholinergic
signalling within the inflammatory reflex can suppress obesity-associated inflammation and
its adverse implications.
Inflammation and obesity pathogenesis

The characteristic inflammatory state in obesity has been extensively discussed
elsewhere.11,13,80,82,83 White adipose tissue in individuals with obesity is expanded and
infiltrated with T cells, bone-marrow-derived macrophages, mast cells and B cells.83 As
such, this tissue becomes a major source of proinflammatory factors.80,8386 Adipocyte
enlargement as a result of increased lipid deposition leads to metabolic alterations associated
with dysregulated secretion of adipokines, including leptin, resistin, adiponectin and
visfatin.80,84 Additionally, cell death and hypoxia occur in adipose tissue, leading to
increased macrophage recruitment and generation of reactive oxygen species, which
promote inflammation.85,87 Increased production and release of TNF, IL-6, CCL2 and other
proinflammatory mediators from adipocytes, as well as from activated M1 macrophages and
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other immune cells, also drives inflammation.80,82,84,85 In addition to adipose tissue,

activation of inflammatory pathways also occurs in the liver, skeletal muscle and brain.12,82
Adipocyte and macrophage expression of TLR4 and TLR2 provides a mechanism for
transforming metabolic overload (high levels of saturated free fatty acids and glucose) into
proinflammatory responses, as free fatty acids and glucose can be ligands for TLRs.
Subsequent intracellular signalling mediated through JNK, IKK and PKR leads to
stimulation of the transcription factors NF-B and AP-1, and increased production of proinflammatory mediators.82,84,85,88 Metabolic overload also results in endoplasmic reticulum
stress, which is associated with JNK and IKK signalling and generation of reactive oxygen
species, triggering inflammation.13,82 In addition, activation of macrophages and T cells in
the adipose tissue of patients with obesity can be mediated by inflammasomes.89 Pancreatic
islet inflammation, as occurs in patients with type 2 diabetes mellitus, can also be mediated
by these protein complexes.90
The intestinal microflora also contribute to the development of inflammation in individuals

with obesity.91,92 Chronic ingestion of a high-fat diet increases the proportion of
lipopolysaccharide-containing microbiota in the gut and this increase is associated with lowgrade metabolic endotoxaemia in both mice and humans.92,93 In mice, mimicking metabolic
endotoxaemia by chronic administration of a low dose of lipopoly-saccharide results in
inflammation, increased adiposity, weight gain and metabolic complications.93 These
changes result from activation of CD14TLR4 signalling, which triggers increased
production of proinflammatory cytokines by adipocytes and macrophages.85,93
The role of specific cytokines and adipokines in mediating obesity-associated complications

(Table 1) has been the subject of several reviews.83,84,88,9496 Inflammation is causally
linked with impaired insulin signalling in peripheral target tissues and insulin resistance, a
major complication in obesity and type 2 diabetes mellitus.12,84,85,95 Activation of
inflammatory pathways in the brain interferes with insulin and leptin signalling in the brain
and also contributes to insulin resistance.82,97 Increased lipolysis in insulin-resistant adipose
tissue leads to enhanced release of free fatty acids, which stimulate inflammatory responses
and reinforce insulin resistance. Proinflammatory cytokines and adipokines can inhibit
insulin signalling by targeting IRS proteins or the insulin receptor. Specifically, TNF
induces inhibition of insulin-activated tyrosine phosphorylation of the insulin receptor and
serine phosphorylation of IRS-1, which leads to inactivation of insulin signalling.85,95 TNF
and other proinflammatory cytokines act in a paracrine manner to stimulate JNK, IKK and
possibly other kinases, which mediate serine phosphorylation of IRS proteins.82
Additionally, proinflammatory cytokines such as TNF, IL-6 and the adipokine resistin
induce the expression of SOCS proteins, which block insulin signalling through inhibition of
insulin receptor tyrosine kinase activity or IRS-1 ubiquitination and degradation.95,98 The
net result is a negative influence of proinflammatory cytokines on insulin signalling.
Vagus nerve signalling in obesity
Obesity and obesity-related type 2 diabetes mellitus are associated with attenuation of the
afferent and efferent vagus nerve signalling that is implicated in metabolic regulation.
Obesity in rodents fed a high-fat diet results in leptin resistance (indicated by decreased
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leptin-mediated STAT3 phosphorylation) in afferent vagus neurons.31 This decrease occurs

in parallel with an increase in expression of SOCS3 (an inhibitor of STAT3
phosphorylation) in nodose ganglia.31 SOCS3 expression is also induced by
lipopolysaccharide. Consequently, endotoxaemia, resulting from impaired gut
permeability,99 could also contribute to leptin resistance in vagus nerve afferents through
activation of TLR4.31 In rodents, the progression of obesity-related type 2 diabetes mellitus
is associated with attenuation of glucose-induced afferent vagus nerve signalling.100
Experimental evidence indicates that vagus nerve signalling regulating hepatic glucose
production, a major determinant of blood glucose levels, is decreased in obesity. For
instance, a high-fat diet causes impairment of a cholecystokinin-triggered vagus nerve reflex
circuit that suppresses hepatic glucose production.57 Additionally, the fatty acid-triggered
hypothalamic suppression of hepaticglucose production, which is vagus nerve-mediated,101
is attenuated by voluntary overeating.102 This attenuation has been suggested to contribute
to the rapid onset of weight gain and hepatic insulin resistance,102 and has been postulated
as a feature of obesity-related type 2 diabetes mellitus.101
Insulin resistance in sucrose-fed rats is associated with impaired muscarinic receptormediated hepatic vagus nerve signalling,103 as well as impaired baroreflex sensitivity
resulting from decreased vagus nerve activity104 Vagus nerve cholinergic and muscarinic
receptor-dependent signalling controls glucose-stimulated insulin secretion by pancreatic
cells, and mice with selective deficiency of the M3 muscarinic acetylcholine receptor in
pancreatic cells have suppressed insulin secretion and impaired glucose tolerance.105
Furthermore, a high-fat diet fails to induce glucose intolerance and hyperglycaemia in
transgenic mice with selective overexpression of the M3 muscarinic receptor on pancreatic
cells.105
Autonomic dysfunction and diminished vagus nerve activity occur frequently in individuals
with obesity and type 2 diabetes mellitus. 1416 A 15-year follow-up study has revealed a
strong relationship between autonomic dysfunction and insufficient vagus nerve activity
(revealed by impaired heart rate recovery following exercise cessation), impaired glucose
homeostasis and development of type 2 diabetes mellitus.17 Together, these preclinical and
clinical findings support the hypothesis that diminished vagus nerve signalling in obesity
could lead to enhanced inflammation and metabolic complications.
Cholinergic alleviation of obesity
Targeting cholinergic mechanisms in the inflammatory reflex using 7nAChR agonists or a
centrally-acting acetylcholinesterase inhibitor could alleviate in flammation and metabolic
complications in obesity.
Attenuation of inflammationMurine adipocytes express 7nAChR, and treatment
with the receptor agonist nicotine suppresses adipocyte TNF levels.19,106 This receptor is
also expressed in human adipocytes and has a role in suppressing proinflammatory gene
expression.107 Oral administration of the selective 7nAChR agonist TC-7020 to genetically
obese Leprdb/db mice (which lack functional leptin receptors) significantly suppresses serum
TNF levels. This effect is abolished by co-administration of the selective 7nAChR
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antagonist methyllycaconitine.18 Administration of a selective 4/2nAChR agonist failed

to suppress serum TNF levels in Leprdb/dbmice, which indicates the 7nAChR-specific
nature of this effect18 Administration of nicotine to Leprdb/db mice and mice with high-fatdiet-induced obesityin doses that did not affect food intake and body weight
significantly ameliorated inflammation in adipose tissue and the systemic proinflammatory
state that is characteristic of both groups of mice.19 Nicotine administration significantly
reduced levels of TNF in serum and abdominal adipose tissue, and decreased adipose tissue
levels of TNF, IL-6 and IL-1 mRNAs. Nicotine also inhibited adipose tissue expression of
CCL2 and the macrophage marker F4/80, indicating that macrophage infiltration and
inflammation were both suppressed.19
Mice lacking 7nAChR that were fed a high-fat diet had greater M1 macrophage infiltration
and higher expression of TNF and CCL2 in adipose tissue than was observed in wild-type
mice.19 Additionally, expression of proinflammatory genes following exposure to free fatty
acids or TNF was higher in macrophages from mice lacking 7nAChR than in macrophages
from wild-type mice.19 Nicotine treatment failed to suppress this increased expression of
proinflammatory genes in macro-phages from mice lacking the receptor.19 These results
provide a mechanistic link between the inflammatory reflex and signalling through
7nAChR in the inhibition of obesity-associated inflammation.
One pharmacological strategy to activate the efferent cholinergic arm of the inflammatory
reflex is administration of the centrally-acting acetylcholinesterase inhibitor galantamine.34
This compound enhances cholinergic muscarinic receptor-mediated signalling in the brain
and stimulates efferent vagus nerve activity.34,108 Galantamine treatment of mice with highfat-diet-induced obesity and hyperglycaemia suppressed plasma IL-6, CCL2, leptin and
resistin levels.20 Importantly, galantamine treatment of obese mice lowered plasma IL-6 and
CCL2 expression to levels detected in lean control mice.20 Collectively, these findings
highlight that activation of components of the inflammatory reflex results in inhibition of
obesity-associated inflammation.
Alleviation of metabolic complicationsNicotine administration to mice fed a highfat diet significantly improves glucose homeostasis and insulin signalling by restoring
tyrosine phosphorylation of the insulin receptor and IRS-1 in skeletal muscle, adipose tissue
and liver. 19 Administration of the 7nAChR agonist TC-7020 to Leprdb/dbmice reduces
weight gain, food intake and levels of blood glucose, HbA1c and triglycerides.18 When this
treatment is combined with administration of the selective 7nAChR antagonist
methyllycaconitine, these effects are abolished.18 In contrast to the effects of TC-7020
administration, treatment with a selective agonist targeting 4/2nAChR, which is
predominantly expressed on brain neurons, suppresses only weight gain and food intake.18
Administration of an inhibitor of JAK2 counters the effects of TC-7020 treatment on body
weight, food intake and blood glucose levels, thus indicating a mechanistic link between
7nAChR and JAK2-mediated signalling. Mice lacking 7nAChR that are fed a high-fat
diet have greater impairment in glucose homeostasis, insulin sensitivity, and insulin
signalling in muscle and liver than do wild-type mice fed the same diet.19 In addition, the
expression of human adipocyte 7nAChR (which suppresses proinflammatory responses) is
significantly decreased in individuals with obesity; however, weight loss partially restores
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expression of 7nAChR.107 These findings further suggest a critical role for 7nAChR in
maintaining metabolic homeostasis.
Galantamine treatment of mice with high-fat-diet-induced obesity reduces body weight and
food intake, and selectively suppresses abdominal adiposity.20 Galantamine also lowers
fasting blood glucose, plasma insulin and cholesterol levels, improves glucose homeostasis
and insulin resistance, and decreases serum alanine transaminase levels, liver weight and
hepatosteatosis in these mice.20 The role of brain and peripheral cholinergic activation by
galantamine (acting as an acetylcholinesterase inhibitor and a positive allosteric modulator
of nicotinic receptors, including 7nAChRs)109 in mediating these beneficial metabolic
alterations remains to be further elucidated.
Cholinergic signalling, including via 7nAChR-mediated mechanisms in brain regions such

as the lateral hypothalamus, is implicated in the complex regulation of appetite and feeding
behaviour.110 Suppression of food intake following nicotine administration is thought to
involve activation of 3/4nAChR in pro-opiomelanocortin neurons of the hypothalamic
arcuate nucleus, which induces activation of melanocortin 4 receptors in the hypothalamic
paraventricular nucleus.111 Thus, several cholinergic receptors, including 7nAChR, 4/
2nAChR and 3/4nAChR, have been implicated in suppressing food intake and weight
gain. However, 7nAChR is unique in having been specifically linked to controlling
obesity-associated metabolic complications through suppression of inflammation.
Therapeutic implications
Obesity is directly linked with the epidemic of type 2 diabetes mellitus and cardiovascular
disease.112,113 Although weight loss through increased physical activity and dietary
alterations can be beneficial in counteracting obesity and its adverse consequences,81 these
lifestyle modifications are difficult to implement and can be problematic to sustain.
Permanent weight loss and attenuation of dyslipidaemia and type 2 diabetes mellitus can be
achieved through bariatric surgery, but these operations are associated with considerable
risks and are currently recommended only for individuals with morbid obesity. Current
pharmacological options for treatment of the metabolic syndrome are limited to targeting its
individual components separately and, therefore, multiple medications are required.81,114
Accordingly, an unmet need remains for new treatments for the metabolic syndrome and
type 2 diabetes mellitus, especially for drugs that target common steps in their pathogenesis.
The chronic inflammatory state associated with obesity is one such common step that could
be targeted. Some anti-inflammatory approaches have already been explored in the
treatment of obesity-linked disorders in preclinical and clinical scenarios.82,95 For example,
patients with type 2 diabetes mellitus who were treated with a recombinant human IL-1
receptor antagonist (anakinra) experienced reductions in levels of IL-6 and CRP.
Additionally, HbA1c levels in these patients were reduced and their pancreatic -cell
secretory function improved.115 Administration of salicylatea known IKK inhibitor in
rodents, which propagates proinflammatory signalssignificantly improved glucose
homeostasis, reduced free fatty acid levels and increased adiponectin levels in patients with
type 2 diabetes mellitus.116
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The importance of the vagus nerve in the regulation of metabolic and immune homeostasis
and the efficacy of selective cholinergic modalities in alleviation of inflammation and
metabolic complications indicate that specific drugs or devices that stimulate neural circuits
directly to activate the inflammatory reflex could be used in the treatment of obesity-related
complications (Figure 4).
Pharmacological approaches
The efficacy of galantamine in suppressing inflammation, insulin resistance and

development of fatty liver in preclinical settings provides a rationale for further clinical
studies.20 Galantamine is approved by the FDA as a treatment for Alzheimer disease, and
this drug has also been used in Europe for decades in the clinical management of myasthenia
gravis as well as other diseases. The availability of data related to the previous clinical use
of galantamine might facilitate its utilization in obesity-driven disorders, particularly in
subgroups of individuals who have limited capacity to benefit from lifestyle interventions,
such as elderly people. The efficacy of galantamine in alleviating liver damage and
inhibiting hepatosteatosis in rodents with obesity is a rationale for clinical studies to
investigate the utility of this drug in the treatment of fatty liver diseases (Figure 4), such as
nonalcoholic steato-hepatitis, which is considered to be the hepatic manifestation of the
metabolic syndrome. Current treatments for nonalcoholic steatohepatitis are not efficient and
the disease can progress to cirrhosis and liver cancernew therapies are clearly needed.117
The preclinical efficacy of nAChR agonists in obesity models identify nAChRs, including
7nAChR, as molecular targets for drug development for the treatment of the metabolic
syndrome and type 2 diabetes mellitus (Figure 4). Several 7nAChR agonists, including
TC-7020 and GTS-21, have proven anti-inflammatory properties and the latter had good
tolerability in human volunteers.118 Currently, a phase II clinical trial of the selective
7nAChR agonist TC-6987 is ongoing in patients with type 2 diabetes mellitus.119
Obesity and the metabolic syndrome are closely associated with atherosclerosis and
impaired cardiovascular regulation. Donepezil, another centrally acting and FDA-approved
acetylcholinesterase inhibitor, suppresses CCL2 and TNF expression, attenuates atherosclerosis and improves long-term survival following chronic heart failure in rodents.120,121
These findings suggest that centrally acting acetylcholinesterase inhibitors could potentially
be developed for the treatment of atherosclerosis.
Efferent vagus nerve-derived cholinergic activation of pancreatic insulin secretion is well
documented. In addition, human pancreatic cells secrete acetylcholine, which might act
through a M3 muscarinic receptor-mediated mechanism as a paracrine stimulator of glucoseinduced -cell insulin release.122 An interesting consideration is the hypothesis that this
local acetyl-choline release in the pancreas could also exert a regulatory influence on
immune cells. Future studies might test the capacity of M3 muscarinic receptor agonists to
promote pancreatic insulin secretion and of 7nAChR agonists to suppress pancreatic
inflammation in patients with type 2 diabetes mellitus (Figure 4).
Patients taking antipsychotic medication, particularly clozapine or olanzapine, frequently
develop obesity, insulin resistance and other metabolic complications. These adverse effects
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represent a challenging clinical problem.123 Adipose tissue inflammation could contribute to

the metabolic derangements associated with antipsychotic treatment, as chronic
administration of olanzapine to rodents even at a dose that does not induce significant body
weight gain results in enhanced adiposity and increased adipose tissue macrophage
infiltration and TNF expression.124 Furthermore, the adverse metabolic effects of
antipsychotic treatments are postulated to be related to their antagonism of peripheral and
central M3 muscarinic receptors and their consequent suppression of positive cholinergic
effects on insulin signalling and glucose homeostasis.125,126 Using galantamine treatment to
alleviate the metabolic syndrome in patients taking antipsychotics is an interesting
possibility to explore. Galantamine and other centrally-acting acetylcholinesterase inhibitors
have already been tested in the context of schizophrenia and shown to ameliorate selective
cognitive deficits in patients with the disease.127 Intriguingly, progression of type 2 diabetes
mellitus often correlates with cognitive deterioration, and new therapeutic agents for type 2
diabetes mellitus that prevent or reduce this decline in cognitive function would be
advantageous.128 Treatment of patients with type 2 diabetes mellitus with galantamine,
which has proven efficacy in ameliorating cognitive deficiency, could represent a promising
intervention targeting this pathophysiological relationship.127
Devices for vagus nerve stimulation

Vagus nerve activity is decreased in chronic inflammatory conditions, including obesity.
Weight loss resulting from increased physical activity, dieting or bariatric surgery is
accompanied by reductions in levels of inflammatory markers, amelioration of metabolic
complications and an increase in the vagus nerve-activity component of heart rate
variability.15,129 A role for vagus nerve signalling in achieving and maintaining weight loss
after bariatric surgery has also been reported.130 In view of these findings and the
importance of the vagus nerve in immune and metabolic regulation, restoring or augmenting
vagus nerve activity could attenuate inflammation and other conditions associated with
obesity (Figure 4).
Stimulation of the vagus nerve using surgically implanted devices is in clinical use for
epilepsy and depression and, as a result, the safety profile for this approach is well
described.131 In patients with obesity and treatment-resistant depression, vagus nerve
stimulation is associated with significant weight loss, which was positively correlated with
the degree of obesity.132 These clinical findings are in agreement with those of several
studies in obese rodents and minipigs, in which vagus nerve stimulation suppressed food
intake and weight gain.133,134 The devices used in these studies predominantly stimulated
afferent vagus nerve fibres; however, afferent and efferent vagus nerve signals converge
within the dorsal vagal complex and higher brain regions, which also provide
neurophysiological circuitry to activate efferent vagus nerve activity that regulates metabolic
homeostasis and immune function. Thus, stimulation of afferent and efferent vagus nerve
signalling has the potential for controlling the inflammatory state in obesity and re storing
metabolic regulation and insulin signalling (Figure 4).
Unpublished data from our group indicate that vagus nerve stimulation suppresses insulin
resistance in rodents. Vagus nerve activities regulating hepatic glucose metabolism and
Pavlov and Tracey
Page 13
cardiac function are both impaired in obesity, which suggests that augmentation of efferent
vagus nerve activity could be beneficial in patients with hyper glycaemia, insulin resistance
and cardiovascular diseases (Figure 4). Vagus nerve stimulation is also being studied as a
method to suppress cardiac inflammation in patients with heart failure.135 Additionally, this
approach could be studied in patients with obesity-associated disorders, such as the
metabolic syndrome and type 2 diabetes mellitus. Carefully designed clinical studies are
needed to assess the potential for treatment with selective cholinergic agonists or
neurostimulating devices in such patients.
Conclusions
The inflammatory reflex mediated by the vagus nerve has been successfully exploited
therapeutically in preclinical models of diseases with aetiologies characterized by excessive
inflammatory responses. Insufficient efferent vagus nerve cholinergic output might have a
causative role in the dysfunctional immune and metabolic regulation observed in obesity, as
selective activation of the efferent cholinergic arm of the inflammatory reflex attenuates
both inflammation and metabolic derangements. Although cholinergic suppression of
inflammation can contribute specifically to alleviating metabolic complications, direct
cholinergic effects on metabolic pathways could also have a role in alleviating symptoms
associated with the metabolic syndrome and type 2 diabetes mellitus. These complex
interactions and the contribution of central and peripheral mechanisms in this regulation are
topics of ongoing study. Additionally, intracellular mechanisms by which cholinergic
signals control obesity-associated inflammation and modulate insulin signalling are under
investigation. 7nAChR agonists, centrally acting acetylcholinesterase inhibitors and direct
electrical stimulation of the vagus nerve offer potential therapeutic strategies for treating
obesity, the metabolic syndrome, type 2 diabetes mellitus and other disorders associated
with obesity. The use of cholinergic modalities in combination with existing or new
therapeutic approaches to target neural, endocrine and immune functions for therapeutic
benefit in patients with obesity-related disorders should also be considered.
Acknowledgments
The authors research work is supported in part by grants from the National Institute of General Medical Sciences,
NIH. The authors thank Peder S. for critical reading of the manuscript.
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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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Review criteria
Original research papers and reviews (in English) were considered for inclusion in this
manuscript on the basis of the authors knowledge of the field and the results of PubMed
and Google Scholar searches using the following keywords: vagus, feeding
behaviour, metabolism, obesity, inflammation, metabolic syndrome, type 2
diabetes mellitus, and cholinergic, alone and in combination. The authors have also
reviewed the reference lists of key manuscripts to identify additional relevant papers.
Paper selection was limited to the past 35 years (19672012).

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Figure 1.
The functional anatomy of the inflammatory reflex. Inflammatory mediators, such as

cytokines, are released by activated macrophages and other immune cells when TLRs and
NLRs are activated upon immune challenge. These mediators are detected by sensory
components of the afferent arm of the inflammatory reflex (red). Neuronal interconnections
between the NTS, A P, DMN, NA, and higher forebrain regions (not shown) integrate
afferent signalling and efferent vagus nerve-mediated immunoregulatory output. Efferent
vagus nerve cholinergic output to the spleen, liver and gastrointestinal tract (blue) regulates
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immune activation and suppresses proinflammatory cytokine release (dotted red lines). This
efferent cholinergic arm of the inflammatory reflex can be activated in the brain through
mAChR-mediated mechanisms triggered by mAChR ligands and AChE inhibitors, such as
galantamine. Abbreviations: AChE, acetylcholinesterase; A P, area postrema; DMN, dorsal
motor nucleus of the vagus nerve; LPS, lipopolysaccharide (endotoxin); mAChR,
muscarinic acetylcholine receptor; NA, nucleus ambiguus; NLRs, nucleotide-binding
oligomerization domain-like receptors; NTS, nucleus tractus solitarius; TLR4, toll-like
receptor 4.

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Figure 2.
Molecular mechanisms of cholinergic control of inflammation. Efferent vagus nerve activity

is translated into catecholamine-mediated activation of T-cell-derived acetylcholine release
in the spleen and into direct acetylcholine release from efferent vagus nerve endings in other
organs. Inhibition of NF-B nuclear translocation and activation of a JAK2-STAT3mediated signalling cascade in macrophages and other immune cells are implicated in
cholinergic 7nAChR-mediated control of proinflammatory cytokine production.
Abbreviations: ACh, acetylcholine; 2AR, 2 adrenergic receptor; JAK2, Janus kinase 2;
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7nAChR, 7 nicotinic acetylcholine receptor; NA, noradrenaline; NF-B, nuclear factor

B; STAT3, signal transducer and activator of transcription 3.

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Figure 3.
The role of the vagus nerve in metabolic regulation. Gastrointestinal and hepatic vagus
nerve afferents (red) communicate alterations in peripheral levels of micronutrients and
metabolic molecules to the brain. Neural interaction between the interconnected NTS, DMN
and A P, within the dorsal vagal complex, and reciprocal projections between this brainstem
region and several hypothalamic areas (arcuate and paraventricular nuclei and mediobasal
and lateral areas), underlie brain integration of visceral information and the modulation of
efferent motor vagus nerve output, leading to regulation of metabolic homeostasis. Efferent
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vagus nerve signalling (blue) can be triggered by sensing metabolic alterations in the
brainstem and the hypothalamus. Complex communication between hypothalamic nuclei
and other forebrain structures (such as the insula and premotor cortex, amygdala, nucleus
accumbens, parabrachial nucleus and thalamus) mediate hedonic, motivational and
rewarding aspects of feeding behaviour and their interaction with vagus nerve-mediated
homeostatic mechanisms. Abbreviations: A P, area postrema; CCK, cholecystokinin; DMN,
dorsal motor nucleus of the vagus nerve; GLP-1, glucagon-like peptide-1; NA, nucleus
ambiguus; NTS, nucleus tractus solitarius; PYY, peptide YY.

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Figure 4.
Possible therapies based on cholinergic-based approaches for the treatment of obesity-driven

disorders. Obesity progression and the metabolic syndrome are closely associated with
debilitating diseases, including T2DM, CVD and NASH. Dysregulated immune and
metabolic homeostasis is associated with inflammation underlying obesity-related disease
pathogenesis, which mediates insulin resistance and other complications. Efficacy of
cholinergic agents in activating regulatory mechanisms in the inflammatory reflex in
animals indicates a rationale for developing novel treatments for humans. Cholinergic
therapeutics and devices for vagus nerve stimulation could selectively control the complex
interplay between immune and metabolic pathways. Abbreviations: CVD, cardiovascular
disease; M3 mAChR, M3 muscarinic acetylcholine receptor; 7nAChR, 7 nicotinic
acetylcholine receptor; 4/2nAChR, 4/2 nicotinic acetylcholine receptor; 3/4nAChR,
3/4 nicotinic acetylcholine receptor; NASH, nonalcoholic steatohepatitis; T2DM, type 2
diabetes mellitus; VNS, vagus nerve stimulation.

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Table 1
Contributions of key adipokines and cytokines to obesity-related disease
Cytokines and adipokines
Cell source
Role in obesity pathogenesis
Leptin (adipokine)
Adipocytes
Gastric mucosa cells
Regulates food intake and energy balance136*

Increased release in parallel with weight gain*
Activates anorexigenic pathways in the hypothalamic arcuate nucleus and other
brain regions69,136*
Acts through leptin receptors on vagus nerve afferents and on brain neurons and
via intracellular JAK2STAT3-mediated signalling31,69,136*
Positive regulator of glucose homeostasis and insulin sensitivity in muscle and
liver136*
Leptin resistance in obesity associated with intracellular SOCS3-mediated
suppression of STAT3 phosphorylation98,136
Hyperleptinaemia has proinfammatory effects in obesity84,137,138
TNF (proinfammatory cytokine)
Macrophages
Other immune cells
Adipocytes
Major contributor to local and systemic insulin resistance80,82,85,139

Increased expression in adipose tissue139
Stimulates resistin expression in human macrophages and suppresses adiponectin
expression in human adipocytes83,88
Implicated in pathogenesis of fatty liver disease94
IL-6 (proinfammatory cytokine)
Macrophages
Other immune cells
Adipocytes
Mediates local and systemic insulin resistance80,82,85

Suppresses adiponectin expression in human adipocytes
Implicated in pathogenesis of fatty liver disease94
Inducer of acute-phase proteins, including C-reactive protein in liver, which is
linked to an increased risk of cardiovascular disease80,96,140
Increased expression in adipose tissue and increased circulating levels in
obesity13,80
CCL2 (chemokine)
Adipocytes
Endothelial cells
Macrophages
Mediates macrophage and other immune cell infltration into adipose tissue141
Linked to insulin resistance and hepatosteatosis in rodents141
Increased levels in obesity85
Resistin (adipokine)
Adipocytes (mice)
Macrophages (humans)
Induces insulin resistance in mice, and might have a similar role in humans85,142
Stimulates TNF and IL-6 production84
Increased circulating and adipose tissue levels in rodent models of obesity11
Adiponectin (adipokine)
Adipocytes
Anti-infammatory and insulin-sensitizing functions95

Suppresses macrophage activation and proinfammatory cytokine release84
Inversely correlated with insulin resistance, type 2 diabetes mellitus, fatty liver
disease and atherosclerosis84,94
Decreased circulating levels in obesity84
Physiological functions under normal conditions.
Abbreviations: CCL2, CC-motif chemokine 2 (also known as monocyte chemotactic protein 1 or MCP-1); TNF, tumour necrosis factor.


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What is the vagus nerve and what are its functions?

What is the vagus nerve and what are its functions?

What is the inflammatory reflex and how does it control immune responses?

What is the inflammatory reflex and how does it control immune responses?

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Published in final edited form as:

The vagus nerve and the inflammatory reflexlinking immunity

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Innate immune responses are activated by pathogen-associated and danger-associated

2012 Macmillan Publishers Limited. All rights reserved

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proinflammatory cytokines.1,7 In addition, activation of NLRs is associated with the

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Chronic inflammation as a result of immune and metabolic dysregulation is a characteristic

The inflammatory reflex

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Peripheral administration of bacterial lipopolysaccharide (also known as endotoxin) or IL-1

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subunit of the receptor is expressed in macrophages, monocytes, dendritic cells, T cells,

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The anti-inflammatory effects of vagus nerve stimulation in animals with endotoxaemia

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Vagus nerve in metabolic regulation

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Glucose-induced pancreatic insulin secretion can be stimulated by treatment with a truncated

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The inflammatory reflex and obesity

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Inflammation and obesity pathogenesis

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other immune cells, also drives inflammation.80,82,84,85 In addition to adipose tissue,

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The intestinal microflora also contribute to the development of inflammation in individuals

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The role of specific cytokines and adipokines in mediating obesity-associated complications

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leptin-mediated STAT3 phosphorylation) in afferent vagus neurons.31 This decrease occurs

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antagonist methyllycaconitine.18 Administration of a selective 4/2nAChR agonist failed

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