Reviews

The metabolic role of vagal afferent

innervation
T. M. Zaved Waise1, Helen J. Dranse1 and Tony K. T. Lam1,2,3,4*
Abstract | The regulation of energy and glucose balance contributes to whole-​body metabolic
homeostasis, and such metabolic regulation is disrupted in obesity and diabetes. Metabolic
homeostasis is orchestrated partly in response to nutrient and vagal-​dependent gut-​initiated
functions. Specifically, the sensory and motor fibres of the vagus nerve transmit intestinal signals
to the central nervous system and exert biological and physiological responses. In the past
decade, the understanding of the regulation of vagal afferent signals and of the associated
metabolic effect on whole-​body energy and glucose balance has progressed. This Review
highlights the contributions made to the understanding of the vagal afferent system and
examines the integrative role of the vagal afferent in gastrointestinal regulation of appetite and
glucose homeostasis. Investigating the integrative and metabolic role of vagal afferent signalling
represents a potential strategy to discover novel therapeutic targets to restore energy and
glucose balance in diabetes and obesity.

The gastrointestinal tract, a highly specialized chemo­ on the integrative metabolic role of the vagal afferent sys­
sensory organ and the largest barrier tissue of the human tem. This Review highlights the current understanding
body, detects ingested nutrients and maintains homeo­ of the dynamic anatomical structure and neurochemi­
stasis. The intestinal sensing system regulates gut motil­ cal signalling properties of the vagal afferent system and
ity, appetite and glucose homeostasis1,2. The complex but the associated gut–brain-​dependent influence on food
delicate regulation of food intake and glucose homeosta­ intake and glucose regulation.
sis involves the integration of the central nervous system
(CNS) with nutrient, humoral and neural signals partly Dynamic properties of the vagus nerve
derived directly from vagal afferent intestinal innerva­ The vagal nervous system comprises sensory pathways
tion, as well as indirectly from the enteric nervous sys­ that transmit afferent signals to the CNS, and motor
tem. The lumen of the gastrointestinal tract responds to pathways that transmit efferent signals to the periph­
a large array of signals through which the quantity and ery13,14. Sensory neurons are equipped with molecular
quality of nutrients is monitored and contains subtypes sensors that detect diverse chemical stimuli (for exam­
of enteroendocrine cells that are in direct contact with ple, cholecystokinin (CCK), glucagon-​like peptide 1
ingested and digested nutrients, secreting a wide range (GLP1) and ghrelin; discussed further in a later section)
of peptide hormones3,4. These hormones transmit sig­ and mechanical stimuli (stretch or tension), whereas
nals to the CNS either via the circulation or by activating the motor neurons integrate vagal sensory and CNS
1
Toronto General Hospital
Research Institute, UHN,
paracrine pathways on the nerve terminals of both the inputs to affect motor outputs that control physiological
Toronto, Canada. intrinsic and the extrinsic neurons5. functions15,16.
2
Departments of Physiology,
Nutrients and hormones activate the tenth cranial
University of Toronto, nerve, known as the vagus nerve, whose sensory affer­ Gross structure of the vagal afferent system. The
Toronto, Canada. ent terminals lie in the lamina propria and in different rapid processing and transmission of gut signals relies
3
Departments of Medicine, layers of the gastrointestinal tract6. The vagus is the on the structure and activities of the vagal afferent sys­
University of Toronto, most widely innervating nervous system in the gastro­ tem, and so the branching pattern of the vagal afferent
Toronto, Canada.
intestinal tract7–9, and it detects the amount and nutri­ nerve is essential for selective biological functions. The
4
Banting and Best Diabetes ent content of ingested foods and signals to the brain neurons of the vagal afferent system are pseudo bipolar
Centre, University of Toronto,
Toronto, Canada.
to modulate different physiological responses that are and detect multiple events in the periphery (Fig. 1a,b) that
essential to maintain appropriate metabolic functions. transmit to the nucleus tractus solitarius (NTS) of the
*e-​mail: tony.lam@
uhnres.utoronto.ca Given that the molecular signals within the gut epithelial brainstem to exert autonomic, endocrine and behav­
https://doi.org/10.1038/ cells, the enteric nervous system and splanchnic afferents ioural responses17. These neuronal cell bodies are located
s41575-018-0062-1 have been reviewed elsewhere3,10–12, we will instead focus in two separate spindle-​shaped structures known as the

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Reviews

Key points (endoneurial, perineurial and epineurial) cells and

immune (microglia) cells44–48, although the function of
• Vagal afferent nerve terminals innervate layers of the gastrointestinal wall to sense these cells remains unclear. Considered as a whole, the
nutrient-​related hormonal and/or mechanical signals and trigger neuronal vagal afferent system is well structured and appropriately
transmission to the central nervous system to affect metabolic homeostasis.
positioned to sense gastrointestinal status and convey
• Nutrient-​dependent hormonal and mechanical stimulation in the stomach and the signals to the brain for gut–brain communication.
intestine regulate feeding through the vagal afferent network.
• Nutrient-​dependent hormonal stimulation in the intestine regulates glucose Vagal afferent signal transmission in the gut–brain
homeostasis through the vagal afferent network. axis. Vagal afferent nerves innervate the gastrointestinal
• Manipulating gut nutrient-​dependent and vagal-​dependent afferent firing represents tract and contain dense axonal projections and complex
a potential novel therapeutic strategy for obesity and diabetes. terminal structures that detect sensory stimuli and trans­
mit signals towards the CNS. The transmission begins at
left and right nodose ganglia (cranial sensory ganglia) the nerve terminals of the vagal afferent chemosensitive
and reside under the jugular foramen (between the tem­ and mechanosensitive neurons, which exhibit discrete
poral and the occipital bones) near the carotid sinus18,19. structural characteristics and distribution properties.
The branching pattern of these neurons is similar in most For example, the three structural distinct nerve ter­
species studied, including humans20,21, in which the left minals of the vagal afferent system are intraganglionic
and right vagus nerve enter the abdomen as two trunks laminar endings (IGLEs), intramuscular arrays (IMAs)
(ventral and dorsal) and divide into distinct primary and mucosal afferent endings22,49,50 (Fig. 2). The IGLEs are
branches at the subdiaphragmatic oesophageal level22. distributed throughout the upper and lower gastrointes­
The left nodose ganglion innervates the liver via the tinal tract, and they contain tension receptors and form
hepatic branches, the dorsal surface of the stomach via a flattened plate-​like structure by wrapping enteric neu­
the gastric branches and the pancreas via the accessory rons of the myenteric ganglia within the external muscle
coeliac and hepatic branches. The right nodose ganglion layers of the gut wall51,52. IMAs are concentrated in the
receives signals from the ventral surface of the stomach upper gastrointestinal tract and are found in parallel to
via the gastric branches and from the pancreas via the the circular or longitudinal smooth muscle fibres and in
coeliac branches9,22,23. Although both the left and the right close contact with the interstitial cells of Cajal49,53,54. Vagal
nodose ganglia innervate the small intestine (that is, from tension receptors detect nutrient volume or amount by
the lower duodenum to ileum9), the lower duodenum is responding to not only changes in length of the gut wall
primarily innervated by the left nodose ganglion neu­ but also increases in gut wall tension55. Mucosal afferents
rons8. Central terminals of primary vagal afferents project extend towards the gut epithelium and terminate within
to different regions of the NTS24 and transmit signals to the lamina propria of the intestinal mucosa56. Mucosal
the vagal dorsal motor nucleus, the nucleus ambiguous mechanoreceptors are insensitive to distension and con­
and the motor V nucleus in the brainstem, as well as to traction of the gut wall but can respond to light mucosal
the higher regions of the brain including the hypothal­ stroking (for example, by passing a probe over the area
amus and amygdala via second-​order and third-​order of interest)50,57,58 as well as nutrient influx59.
neurons, to control and coordinate gut function25,26. Of note, the intestinal epithelium, which is essential
for nutrient-​sensing and absorption, comprises absorp­
Cellular composition of nodose ganglia. Although the tive enterocytes, mucus-​producing goblet cells, hormone-​
number of sensory neurons in each nodose ganglion producing enteroendocrine cells and antimicrobial
varies between species27–29, the neuroanatomical struc­ peptide-​producing Paneth cells60. Most of these cells are
ture and cellular compositions are similar (Fig. 1c). The structurally similar and contain microvilli on the apical
nodose ganglia contain a heterogeneous population of surface that faces the intestinal lumen to sense ingested
neuronal cells that can be distinguished by their elec­ nutrients, whereas the basolateral surface faces the under­
trophysiological membrane properties30,31, in which lying basement membranes. Although enteroendocrine
~80% are C-​type neurons and the remaining ~20% are cells represent only ~1% of the total epithelial popula­
A-​type neurons. C-​type neurons contain axons without tion, these cells contain the majority of nutrient-​sensing
myelination, whereas A-​type neurons contain myelin­ receptors and secrete >20 hormones that are known to
ated axons. Specifically, C-​type neurons are connected date5. Among these enteroendocrine hormones, the most
to small-​diameter (unmyelinated) axons that conduct studied and the ones with the greatest effect on metabolic
a slow rise but sustained electrical potential, while regulation are GLP1, CCK and ghrelin (Table 1), which
A-type neurons are connected to large-​diameter (mye­ are secreted from L cells, I cells and X/A-​like cells, respec­
linated) axons that conduct a sharp rise but short-​lived tively61. In fact, changes in nutritional status trigger the
electrical potential32–35. At the subdiaphragmatic level, release of CCK, GLP1 and ghrelin, which interact with
nearly all vagal sensory nerve fibres are C-​type36–38. The their receptors on mucosal afferent endings62,63, whereas
neuronal cell bodies of the nodose ganglia synthesize CCK also activates tension-​receptor-containing vagal
CCK receptors, GLP1 receptor (GLP1R) and ghrelin afferent nerves64,65 (Fig. 2).
receptor (GHSR)39–41 and the CCK receptors and GHSR Various nerve terminals of the vagal afferent sys­
are actively transported along axons to the nerve ter­ tem innervate different layers of the gastrointestinal
minal to determine hormonal sensitivity and regulate wall to sense multiple nutrient-​related chemical and/or
synaptic transmission42,43. The nodose ganglia also mechanical signals and initiate signal transmission to
contain satellite glial cells, Schwann cells, endothelial the CNS (Fig. 3). Although the integrative signalling

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a b
Cell
AP Brain body Periphery

Brain
Nodose DMV Pseudobipolar
stem
ganglion NTS
c Nodose ganglion

Vagal afferent
nerves
Stomach

Liver C-type neuron (unmyelinated)

Intestine A-type neuron (myelinated)

Schwann and/or satellite glial cell
Pancreas IBA1+ microglial cell
Vagal afferent and/or efferent fibre

Fig. 1 | Subdiaphragmatic vagal afferent innervation and gross anatomical organization of the nodose ganglia.
a | At the subdiaphragmatic level, vagal afferent neurons innervate the stomach, intestines, liver and pancreas and relay
signals to the brainstem to regulate whole-​body functions. b | Vagal afferent neurons are pseudobipolar. The parent axon
bifurcates with one end terminating at the brainstem and another at a periphery site. c | An illustration of a coronal slice of
a typical nodose ganglion is shown. The nodose ganglia consist primarily of unmyelinated C-​type neurons that mediate vagal
afferent transmission. Other cell types that are found in the nodose ganglia are A-​type neurons, ionized calcium-binding
adapter molecule 1 (IBA1; also known as AIF1)+ microglia and Schwann or satellite glial cells. AP, area postrema; DMV, dorsal
motor nucleus of the vagus; NTS, nucleus tractus solitaries.

pathways of these hormone-​related or volume-​related central terminal through a series of sodium or potas­
signals in the visceral afferent terminals remain elusive, sium channels (Fig. 3). Alternatively, signal transmission
the tension receptors in IGLEs as well as the orexi­ occurs via calcium wave propagation, whereby intra­
genic (hunger generating) and anorexigenic (satiety cellular calcium activates inositol 1,4,5-trisphosphate
generating) metabotropic G protein-​coupled receptors receptor (ITPR) and the ryanodine receptor (RYR) on
(GPCRs) expressed in the vagal afferent system (Table 1) the endoplasmic reticulum surface, creating a regener­
are likely involved. For example, stretching in either ative calcium wave that propagates towards the central
the longitudinal or circumferential axes of the gut wall terminal75,76. Overall, both pathways enable robust
activates tension receptors to evoke electrical firing of and precise information transmission along the long
the vagal afferent nerves17,66,67. Similarly, the anorectic axons of the vagal afferent system, which alters central
hormone CCK and GLP1, which predominantly act terminal calcium conductance and thereby transfers an
through CCK1 receptors (CCK1Rs) and GLP1 receptors appropriate response to the target neurons.
(GLP1Rs), respectively, increase vagal afferent neuronal The action potentials and calcium conductance
activity by inhibiting potassium channels, resulting in within the central nerve terminal located in the brain­
an increase in action potential firing frequency68,69. The stem determine the rate of synaptic vesicle fusion and
orexigenic hormone ghrelin70 decreases the excitability facilitate the release of neurotransmitters such as glu­
of vagal afferent neurons by inducing potassium currents tamate into the synaptic cleft77–79 (Fig. 3). Thus, the out­
through a GHSR–phosphoinositide 3-kinase (PI3K)– put from the central end of the vagal afferent nerves is
extracellular signal-​regulated protein kinase 1 (ERK1; relayed to the NTS neurons via glutamate13,80. As such,
also known as MAPK3) and/or ERK2 (also known as evidence from animal models suggests that CCK exerts
MAPK1) signalling cascade71. Future investigations its feeding regulatory actions by modulating glutamate
are warranted to examine whether any of these vagal release from the vagal afferent central terminals81,82.
afferent signalling pathways mediate other gut-​derived Cocaine-​regulated and amphetamine-​regulated tran­
anorexigenic or orexigenic peptides (Table 1). script protein (CART) is utilized by the vagal afferent
To transmit signals from the peripheral terminals to neurons to transmit peripheral CCK or leptin-​mediated
the NTS, the vagal afferent system utilizes an electro­ satiation signals to activate NTS neurons in rats 83
chemical signalling mechanism, whereby different (Table 1). Melanin-​concentrating hormone, calcitonin-​
stimuli such as nutrient volume and hormones (CCK gene-related peptide and substance P are alternative
and/or GLP1) can induce membrane depolarization transmitters that are involved with this synaptic integra­
at the nerve end, which in turn increases intracellular tion and, thereby, also contribute in vagal afferent signal
calcium levels72–74 and propagates action potentials to the transmission84,85. Upon receiving vagal afferent signals,

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Nutrients
Enteroendocrine cell

CCK
GLP1
Ghrelin
Mucosa

Gut
epithelium Mucosal
afferent
Lamina propria
Muscularis mucosa
Submucosa

Circular muscle IMA

Gut wall tension

Myenteric plexus IGLE

Longitudinal muscle IMA

Mesothelium (serosa)

Stretch Stretch

Fig. 2 | Distribution of the vagal afferent nerve terminals that respond to hormonal and mechanically dependent
signals. This figure is a simplified diagram showing three basic types of nerve terminal known as intramuscular arrays
(IMAs), intraganglionic laminar endings (IGLEs) and mucosal afferent endings. The IMAs are located within either the
circular or the longitudinal muscle layers and can detect gut stretch-​related signals. The IGLEs have a plate-​like structure,
wrapping around enteric neurons within the myenteric plexus, which resides between the longitudinal and the circular
layers of the external musculature of the gut. IGLEs can receive both longitudinal and circumferential stretching signals
and are, therefore, sensitive to any distension and contraction of the gut wall. The mucosal afferent nerve terminal
innervates the gut mucosa, remains in close position to different cells of the gut epithelium and can sense diverse stimuli
within the lamina propria. Changes in nutritional status affect the levels of cholecystokinin (CCK), glucagon-​like peptide 1
(GLP1) and ghrelin secreted by enteroendocrine cells, and changes in these hormones affect their respective receptors
expressed on mucosal afferent endings and IGLEs.

NTS neurons release transmitters such as glutamate, glucose load88, and observations that lactisole, a sweet
GABA and noradrenaline to different hindbrain and taste receptor inhibitor, diminished glucose-​mediated
GLP1 secretion in humans89, it has been suggested
mid-​brain regions and, ultimately, orchestrate a coherent
pattern of CNS responses to maintain metabolic homeo­ that, in the gastrointestinal lumen, glucose activates
stasis13,86. In the next section, we focus on the underlying
TAS1R2–TAS1R3-expressing cells to trigger hormone
mechanisms that link intestinal and vagal sensing to the secretion. However, this sensing pathway has been
control of whole-​body metabolism. challenged, as artificial sweeteners fail to induce GLP1
secretion from intestinal L cells in both rodents and
Vagal signalling and metabolism humans90–93. Alternatively, both in vitro and in vivo
Dietary intake, nutrient-​s ensing and hormone animal studies suggest that SGLT1-dependent glucose
secretion. Mammals utilize carbohydrate, protein uptake triggers membrane depolarization of L cells
and fat as their main sources of energy, which are pri­ through concomitant uptake of sodium ions, which in
marily broken down inside the intestinal lumen and turn release GLP1 by activating voltage-​gated calcium
sensed by intestinal epithelial cells through nutrient-​ channels94–98. Glucose has also been shown to stimulate
specific receptors (for example, the sweet receptors CCK release in humans89,99; however, the precise sensing
taste receptor type 1 member 2 (TAS1R2) and TAS1R3) mechanisms have not yet been elucidated.
and transporters (for example, high-​affinity sodium– Proteins are digested by acid hydrolysis and pro­
glucose cotransporter (SGLT1; also known as SLC5A1), teases to produce protein hydrolysates (a mixture of
peptide transporter 1 (PEPT1; also known as SLC15A1) peptones, peptides and amino acids), and protein stimu­
and CD36)3,87. On the basis of previous observations lates enteroendocrine hormone release in rodents
in which α-​gustducin (a component of the sweet taste and humans100–105. For example, both protein and its
receptor signalling cascade)-knockout mice showed an digested products (protein hydrolysates) increase
impairment in secreting GLP1 in response to an oral CCK release from isolated, vascularly perfused rat

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duodenojejunum106, and protein hydrolysate activates proteins110–113. Although the specific intracellular mech­
the GPCR lysophosphatidic acid receptor 5 (LPA5) to anisms underlying digested protein-​stimulated GLP1
stimulate CCK release from intestinal STC-1 cells107. secretion are poorly understood, they are likely associ­
This GPCR-​specific, protein hydrolysate-​sensing mech­ ated with specific receptor activation and the subsequent
anism of I cells triggers membrane depolarization, which increased intracellular cAMP and calcium response of
is necessary for CCK release107,108. By contrast, whereas L cells114. In parallel, intestinal PEPT1, expressed on the
undigested proteins are weak stimulators of GLP1 apical membrane of enteroendocrine cells, is consid­
secretion109, GLP1 is released in response to digested ered the primary oligopeptide transporter in the small
intestine115,116, and PEPT1 activation results in GLP1
Table 1 | Metabotropic G protein-coupled receptors expressed in vagal afferents secretion from enteroendocrine L cells117.
Receptor Natural Effect on Species Detection Refs Fat is the most energy-​dense and satiating energy
ligand appetite method source and has been shown to act as a potent stimulus
for the secretion of a number of enteroendocrine hor­
CCK1R CCK Decrease Rat RT-​PCR 39,231,232
mones, such as GLP1 and CCK99,109,118–120. During the
IHC 175,176,233–237
postprandial state, hydrolysis of triglyceride into free fatty
IH 39,232,235 acids appears necessary for the stimulation of hormone
RA 39,42,238 secretion, as secretion of both CCK and GLP1 in response
to intestinal triglyceride infusion is substantially attenu­
Human RT-​PCR 39
ated in humans in the presence of a lipase inhibitor121.
IHC 176,237
Additionally, the length of fatty acids and the degree of
Mouse RT-​PCR 239 saturation are important for hormone secretion122,123.
For example, evidence from human studies suggests that
Rabbit RA 240,241
fats rich in monounsaturated fatty acids (for example,
GLP1R GLP1 Decrease Rat RT-​PCR 40,140,141,167
olive oil) induce higher GLP1 responses than fats rich in
IHC 141 saturated fatty acids (for example, butter)124. Moreover,
CCK and GLP1 are the major hormones released from
IH 40
I cells and L cells in response to luminal medium-​chain
NB 40
and long-​chain fatty acids, respectively118,125,126. In paral­
WB 167 lel, short-​chain fatty acids have also been shown to trig­
Mouse GLP1R 242 ger GLP1 secretion from L cells127,128. The most studied
(transgenic) fluorescence GPCRs for fatty acids (medium-​chain and long-​chain),
free fatty acid receptor 1 (FFAR1) and FFAR4, play a major
GHSR Ghrelin Increase Rat RT-​PCR 41,43,231,243
part in luminal lipid sensation118,129–131; however, it remains
IHC 41,175,237,244
to be established which receptor plays a more important
IH 43,243 role in enteroendocrine hormone secretion. Additionally,
RA 43 studies have highlighted the role of GPCR 119 (GPR119)
(a GPCR responsive to oleoylethanolamide 132 and
Human RT-​PCR 41
N-​oleoyldopamine133; in the gut, GPR119 expression is
IHC 41
restricted to enteroendocrine cells93,134) in fat-​induced
Mouse RT-​PCR 149,162 GLP1 and CCK secretion in humans135. Alternatively,
fatty acid transportation into enteroendocrine cells by
NPY2R PYY Decrease Rat RT-​PCR 231,237
CD36136,137 or long-​chain fatty acid transport protein 4
IHC 245,246
(FATP4)138 and subsequent fatty acid metabolism can
IH 237 trigger CCK secretion139 (reviewed elsewhere1).
RA 245
Vagal afferent signalling in feeding control. Feeding
Human IHC 237
control is a highly regulated process at the level of
Rabbit RA 240 the brain, requiring accurate information regard­
OX1R Orexin A Increase? Rat RT-​PCR 176,232 ing the amount and nutrient content of food ingested
into the gastrointestinal tract. Gut nutrient-​sensing,
IHC 176,237
hormone-​derived satiety or hunger signals communi­
Human RT-​PCR 176 cate with the CNS via the vagal afferent system, which
IHC 176 expresses multiple receptors for orexigenic and anorexi­
genic peptides39–43,140,141 (Fig. 4; Table 1). The support for a
Mouse RT-​PCR 239
vagal afferent-​mediated feeding control is derived from
GPR7 NPW Increase? Mouse RT-​PCR 161,247
chemical or surgical vagal lesion studies in animals and
SCTR Secretin Decrease? Mouse RT-​PCR 248 humans, whereby the absence of vagal afferent trans­
CCK, cholecystokinin; CCK1R, cholecystokinin 1 receptor; GHSR, growth hormone secretagogue
mission attenuates the inhibitory or stimulatory effect
receptor type 1; GLP1, glucagon-​like peptide 1; GLP1R, glucagon-​like peptide 1 receptor; GPR7, of peripherally administered anorexigenic or orexigenic
G protein-​coupled receptor 7 (also known as NPBWR1); IH, in situ hybridization; IHC, immuno­ peptides, respectively142–148. The vagal mucosal afferent
histochemistry; NB, northern blot; NPW, neuropeptide W; NPY2R, neuropeptide Y receptor
type 2; OX1R, orexin receptor type 1; PYY, peptide YY; RA, receptor autoradiography; RT-​PCR, nerve endings are present in a close position to the basal
reverse transcription PCR; SCTR, secretin receptor; WB, western blot. membranes of enteroendocrine cells to transmit rapid

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hormonal messages from the gut to the brain (Fig. 2). Hormones also modulate mechanosensitive neu­
For example, the anatomical relationship between CCK-​ rons that could potentially affect feeding55 (Fig. 4). For
containing, GLP1-containing and ghrelin-​containing example, both CCK and leptin increase the firing of
enteroendocrine cells and vagal afferents has been vagal afferent fibres (which affect feeding) that are also
examined149–151, revealing close apposition between the responsive to mechanical distension in rodents64,65,157,158.
cells and mucosal afferents. These findings are consist­ Moreover, 5-HT is secreted from gastric enterochro­
ent, in principle, with a paracrine mode of hormonal maffin cells in response to gastric distension to provide
action on vagal afferent nerve terminals at the level of intake inhibitory signals by activating vagal mechano­
the mucosal lamina propria23 to alter feeding (Table 1). sensitive neurons59,159,160, whereas neuropeptide W and
On the other hand, enteroendocrine cells have also ghrelin inhibit gastric tension receptors to lower the
been shown to be directly contacted by afferent neu­ mechanosensitivity of the vagal afferent neurons161,162.
rons via synapse-​like structures152–154. By using high-​ Of note, vagal mechanosensitive afferent activity is also
resolution imaging and transgenic methods in mice, modulated directly by volumetric gastrointestinal dis­
CCK-​producing, peptide YY (PYY)-producing and tention163, which is critical in controlling food intake
serotonin (5-HT)-producing enteric cells were shown behaviour by generating satiety or fullness sensations164.
to be trans-​synaptically connected with afferent nerve In 2016, an in vivo genetic molecular profiling study in
fibres and to develop a neuroepithelial circuit, which mice74 characterized subsets of gastrointestinal inner­
was accompanied by enteric glial cells that secrete vating vagal afferent neurons that encode different
neuro­tropic factors to nourish circuit development and gastrointestinal signals. A combined Cre-​recombinant
postsynaptic density protein 95 (PSD95; also known as and optogenetic method was used to provide a selective,
DLG4) and synapsin 1, which are involved in postsyn­ genetically guided approach for visualization and func­
aptic and presynaptic transmission, respectively152,155,156. tional characterization of the molecular diversity of vagal
However, the in vivo functional relevance of direct con­ afferent neurons in response to sensory signals during
tact of enteroendocrine cells by neurons as stated above digestion. They demonstrated that GPR65-expressing
remains elusive. nodose neurons innervate the upper duodenum villi

Gastrointestinal NTS
Vagal tract
afferent Intracellular Glutamate
Orexigenic nerve Ca2+ stores
stimulus βγ Neuron
terminal
(e.g. ghrelin) α0/i Nodose
ganglion
ER (vagal
Membrane afferent Na+
neuron) +
hyperpolarization + Secondary
Ca2+ messenger
Anorexigenic + Ca2+ wave? + cascades
stimulus βγ Ca2+
(e.g. CCK αs Ca2+
and GLP1)
Action potential +
CICR propagation
Membrane +
depolarization K+ Ca2+
Na+
Nucleus
Ca2+
Mechanical
stimulus
(e.g. nutrient
volume)

Metabotropic
Ca2+ channel ITPR and/or RYR Na+ channel K+ channel NMDAR Non-NMDAR
receptor

Fig. 3 | Schematic diagram for the proposed signal transmission pathways hormones, can induce membrane depolarization at the nerve end, which, in
for the vagal afferent system. Various nerve terminals of the vagal afferent turn, increases intracellular calcium levels and propagates action potentials
system innervate different layers of the gastrointestinal wall to sense multiple to the central terminal through a series of sodium or potassium channels.
nutrient-​related chemical and/or mechanical signals and, thereby, initiate Alternatively , signal transmission occurs via calcium wave propagation,
the process of signal transmission to the central nervous system. Although the whereby intracellular calcium activates the inositol 1,4,5-trisphosphate
integration of nutrient-​dependent, hormone-​related or volume-​related receptor (ITPR) and/or the ryanodine receptor (RYR) on the endoplasmic
chemical and mechanical signals in the visceral afferent terminals remains reticulum (ER) surface via calcium-​induced calcium release (CICR), creating a
elusive, the tension receptors in intraganglionic laminar endings sensing regenerative calcium wave that propagates towards the central terminal.
mechanical stimuli and the orexigenic and anorexigenic receptors are At the brainstem, both action potentials and calcium conductance facilitate
probably directly involved in facilitating the integration processes that affect the release of neurotransmitters (glutamate) into the synaptic cleft that act on
feeding. To transmit signals from the peripheral terminals to the nucleus either N-​methyl-d-aspartate receptors (NMDARs) or non-​NMDARs (glutamate
tractus solitarius (NTS), the vagal afferent system utilizes an electrochemical receptor channel) to activate target NTS neurons and relay the signal to higher
signalling mechanism in which different stimuli, such as nutrient volume and brain areas. CCK, cholecystokinin; GLP1, glucagon-like peptide 1.

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Ghrelin induces hunger, at least in part, via the ascend­

• Food intake Metabolic ing neural network through the vagal afferent nerve and
• Glucose homeostasis NTS signalling pathway, which ultimately modulates the
homeostasis
reward system in the forebrain169 (Table 1). In addition,
Nodose ghrelin inhibits the resting mechanosensitive vagal affer­
ganglion Vagal efferent signals
ent activity in rodents162, and vagotomy abolishes the
hunger-​inducing actions of ghrelin in rats43,170 (Table 1).
Although one study suggests that vagal afferent signal­
ling is not required for intraperitoneal injection of ghrelin
Signals received from stomach to increase food intake in rats171, the peripheral action of
Signals received from intestine ghrelin on food intake was also found to be absent in
Vagal Signals received from stomach and intestine? humans that have had truncal vagotomy144. Interestingly,
afferent
nerves one study in 2018 indicated that a 60% restoration of
GHSR expression in the vagal afferent system of GHSR-​
Orexigenic Stomach null mice enhances the ability of ghrelin injection to alter
mediators glucose homeostasis172, further suggesting that vagal
Lack of
nutrients afferent signalling is necessary for the metabolic effect
Branch of ghrelin. Taken together, it is reasonable to speculate
point
Volumetric
(although such speculation requires future investigation)
stretches that ghrelin binds to its receptor on the vagal afferent
Nutrients nerve terminals and alters the firing rate of nerve fibres
to initiate a hunger drive for food and alter metabolism.
Intestine Glucose
production
Anorexigenic
Interaction of hormones. The orexigenic and anorexi­
mediators Liver genic hormones previously mentioned could function
independently to regulate food intake via the vagal affer­
ent system, but the hormones might also interact with
each other to regulate metabolic homeostasis. For
Fig. 4 | Role of the gut vagal afferent system in feeding and glucose regulation. example, although ghrelin, CCK and GLP1 alter the firing
Before a meal, gastrointestinal-​derived orexigenic mediators (ghrelin) initiate a hunger rate of the vagal afferent neurons indepen­dently43,140,162,173,
drive through the vagal afferent system. In response to a meal, nutrient-​sensing and
studies have reported that ghrelin opposes CCK to stim­
volumetric-​stretch-sensing mechanisms in the stomach and the intestine trigger various
signalling pathways within the vagal afferent nerves to regulate appetite and glucose
ulate vagal afferent fibres174–176. Further, ghrelin inhibits
homeostasis via the central nervous system. Ganglionic neurons lead to various branches GLP1R translocation in the vagal afferent neuron177,
that innervate the gastrointestinal tract. As the total number of axons of all downstream attenuates GLP1-induced vagal afferent activation178
vagal branches is higher than the number of axons of the upstream vagus, it is likely that and reduces the anorexigenic effect of peripherally
one nodose ganglion neuron can potentially receive signals from various branches that administered GLP1 in rats179. Thus, it appears that the
innervate the stomach and the intestine. Branch points, where the parent vagal nerves orexigenic and anorexigenic hormones can poten­
intersect with the downstream neuronal branches, might facilitate the interaction of tially interact at the level of the vagal afferent nerve to
orexigenic and anorexigenic signals, potentially via the A-​type potassium channels, modulate feeding behaviour (Fig. 4), but the underly­
thereby affecting feeding and glucose homeostatic control. ing mechanisms remain unclear. However, ganglionic
neurons form branches that innervate the gastrointes­
and respond to luminal nutrients to control gut motility, tinal tract180,181 and, as the total number of axons of all
whereas GLP1R-​expressing neurons innervating the downstream vagal branches is higher than the number
stomach were mostly stretch sensors that detect mechan­ of axons of the upstream vagus182, it is likely that one
ical stimuli74. Although these findings highlight nutrient-​ nodose ganglion neuron can potentially receive sig­
sensing, discrete chemosensitive and mechanosensitive nals from various branches that innervate the stomach
neurons in the vagal afferent system that innervate the and the intestine (Fig. 4). At the point where the parent
duodenum and the stomach74, the metabolic effects of vagal nerves intersect with the downstream neuronal
these neurons remain to be investigated. branches (branch point), we speculate that the branch
With respect to feeding regulation, the necessity of point might facilitate potential interactive gastrointes­
vagal afferent neurons in GLP1 action has been docu­ tinal CCK-​derived, GLP1-derived and ghrelin-​derived
mented, as vagotomy blocks the satiating effect of exo­ signals to regulate feeding (Fig. 4). This working hypoth­
genous GLP1 administration in healthy rats148 as well as esis is based on the fact that CCK receptors, GLP1R and
in patients receiving pyroplasty165 (Table 1). In addition, GHSR are co-​expressed within the same nodose gan­
inhibiting peripheral GLP1R increased light-​phase food glion neuron41,174,175,183 and that branch points within the
intake in rats166, whereas selective GLP1R knockdown in CNS (it remains to be determined whether this is true
vagal afferent neurons in rats diminished the ability of in the nodose ganglia) can regulate parental axon action
both peripheral GLP1 injection to lower feeding167 and potential via the A-​type potassium channels184–186.
d-allulose (a non-​calorie sweetener) to lower feeding in In summary, both gut hormonally derived and
obese rodents168. These findings collectively indicate that mechanically derived signals might regulate feeding
vagal afferent innervation is necessary for GLP1 action via the vagal afferent system. However, it is impor­
to lower feeding. tant to note that high-​fat diet (HFD) feeding can alter

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responsiveness of vagal afferent nerves to hormonal that GLP1R knockdown in vagal afferents via nodose
and mechanical signals in rodents149,187,188. As such, ganglion lentiviral injection disrupts glucose homeostasis
manipulation of vagal afferent activity might carry ther­ during refeeding in rats167. Although the sequential role of
apeutic potential for the treatment of obesity. Indeed, the PKCδ-​dependent pathway mediating the CCK and
alteration of vagal activation by direct electrical vagal GLP1 pathways remains to be resolved, these findings
blockade and stimulation189–194 or by bariatric surgery1,195 collectively highlight the important role of both CCK
prevents weight gain in obesity. However, it remains to and GLP1 action in the gut in mediating mechanisms
be investigated whether modifying vagal afferent branch dependent on nutrient-​sensing to regulate hepatic glucose
points and/or the stimulation of a specific group of vagal production and glucose homeostasis (Fig. 4).
afferent nerves can similarly reverse obesity. The most widely prescribed anti-​diabetic medica­
tion, metformin, also stimulates GLP1 secretion205–207.
Vagal afferent signalling in glucose homeostasis. In This finding raises the question of whether the identi­
parallel to changes in food intake, glucose homeostasis is fied GLP1-dependent gut–brain axis mediates the anti-​
largely influenced by the availability of the luminal nutri­ diabetic action of metformin. Although metformin
ents (carbohydrates, fats or proteins) in the small intestine. action was initially postulated to result from activation
Importantly, various vagal lesion model studies highlight of the energy sensor 5′-AMP-​activated protein kinase
the role of the vagus nerve in glucose control. For example, (AMPK) in the liver208, other studies in rodents indi­
vagal deafferentation in rats leads to early hyperglycaemia cate that only high doses of metformin activate hepatic
in response to nutrient-​related signals139,196,197, indicating AMPK209 and that the glucose-​lowering effect of oral
that vagal afferents have a role in the control of post-​meal metformin is intact in rodents lacking hepatic AMPK210.
blood glucose. Consistent with this understanding, trun­ Metformin has instead been suggested to improve glu­
cal vagotomy in a patient receiving pyloroplasty resulted cose homeostasis through direct action in the gut. For
in reduced gastrointestinal-​mediated glucose disposal198, example, oral metformin intake lowers glucose levels
suggesting that the vagus nerve is also involved in the more effectively than intravenous administration211,212,
control of post-​meal blood glucose in humans. whereas upper small intestinal metformin infusion in
The CNS is necessary for the modulation of glu­ diabetic rats activates upper small intestinal AMPK (like
cose homeostasis by vagal afferent signalling, whereby resveratrol213), triggering a GLP1R–PKA-​dependent
the activation of the vagal efferent system at the level pathway to lower glucose production via the gut–brain
of the dorsal vagal complex relays nutrient-​dependent axis214. The clinical relevance of gut metformin action
signals generated from the upper small intestine to the was highlighted in a 2016 study that reported that a
liver to regulate hepatic glucose production1,199 (Fig. 4). gut-​restricted formulation of metformin lowers plasma
Specifically, upper intestinal lipid infusion lowers hepatic glucose levels in humans with T2DM independently of
glucose production and plasma glucose levels through a rise in metformin in the blood circulation215. Together
activation of a gut–brain axis139, whereby lipid influx into with the fact that administration of a low dose of sita­
the upper small intestine activates a protein kinase C gliptin (an inhibitor of dipeptidyl peptidase 4 (DDP4),
δ-​type (PKCδ)-dependent pathway200 to stimulate CCK which is responsible for the degradation of GLP1 and
release201. This pathway is dependent on the prior forma­ glucose-​dependent insulinotropic polypeptide (GIP))
tion of long-​chain fatty acyl-​CoA via long-​chain acyl-​CoA increases vagal afferent firing and improves glucose tol­
synthetase139 and subsequent activation of vagal afferent erance216, these findings implicate the therapeutic poten­
firing through a CCK1R–protein kinase A (PKA) signal­ tial of targeting the GLP1-dependent gut–brain axis to
ling axis202. This lipid-​induced vagal afferent signal is first lower glucose levels in patients with T2DM.
transmitted to the brain by the activation of glutamatergic The vagal afferent nerve that innervates the hepatic
receptors in the dorsal vagal complex, which in turn signal portal vein also responds rapidly to changes in glucose
through the vagal efferent system to the liver to regulate and GLP1 levels and controls metabolism217,218. This
glucose production139,203. The physiological role of CCK finding was initially reported by early studies in which
action in the gut was demonstrated in a refeeding pro­ portal nutrient or GLP1 infusion altered the firing rate
tocol in which glucose homeostasis was disrupted in rats of the hepatic vagus nerve219,220. Follow-​up studies pro­
with selective inhibition of CCK1R in the gut or global posed that portal vein glucose-​sensing (achieved via
CCK1R deficiency203. Importantly, the glucoregulatory portal glucose infusion221 or gastric bypass-​induced
effect of upper small intestinal lipid infusion is abolished increase in intestinal gluconeogenesis217) and GLP1-
in HFD-​fed rodents139,203, and this impairment is due to sensing141 modulate glucose homeostasis through a
CCK resistance at the level of CCK1R signalling that leads vagal-​dependent pathway. In light of the fact that GLP1
to impairments in PKA activation202, highlighting the is rapidly degraded by DPP4, resulting in a diminished
pathophysiological relevance of this pathway in obesity concentration of GLP1 in the hepatoportal vein222, future
and type 2 diabetes mellitus (T2DM). investigation is warranted to assess the relative gluco­
Interestingly, one study in 2017 reported that direct regulatory role of GLP1 signalling in the vagal afferent
GLP1 infusion into the upper intestine activates intesti­ nerves that innervate the intestine versus the portal vein.
nal GLP1–PKCδ signalling to lower glucose production Intestinal inflammation has been linked to metabolic
through a gut–brain–liver neuronal axis, whereas block­ homeostatic control223. HFD feeding in rodents induces
ing intestinal GLP1R signalling abolished the improve­ immunological changes that trigger an inflammatory
ments in glucose homeostasis of healthy rodents during response in the gut223 and in the nodose ganglia and is
refeeding204. This finding confirms the previous report implicated in the disruption of vagal afferent signalling in

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 Reviews

diet-​induced obese rodents188. HFD-​induced inflamma­ information and consequently relay signals to periph­
tion plays a critical role in the progression of obesity and eral organs to regulate metabolic homeostasis. The
insulin resistance224–226, and treating gut inflammation by modification of any one signal in isolation by target­
administration of gut-​specific anti-​inflammatory agents ing a different branch of the vagal system could pro­
in obese mice improves glucose tolerance226. Bile acids duce selective metabolic outcomes. Consequently,
and farnesoid X-​activated receptor (FXR; also known as our understanding of the vagal afferent intrinsic and
NR1H4) action in the gut have been demonstrated to reg­ extrinsic mechanisms that underlie meta­bolic control is
ulate glucose homeostasis in rodents227–229, and treatment quickly evolving. The available evidence indicates that
with the bile acid sequestrant colesevelam improves glu­ targeting vagal afferent signalling to influence feeding
cose homeostasis in individuals with impaired fasting and glucose homeostasis might have therapeutic poten­
glucose through a mechanism potentially dependent on tial to restore metabolic homeostasis in patients with
CCK action230. Whether a gut–brain–vagal afferent axis T2DM and obesity. This Review summarizes the cur­
is necessary for the glucoregulatory effects of intestinal rent knowledge concerning the basic properties of the
anti-​inflammatory agents, bile acids and FXR action vagal afferent system and its function on metabolism
remains an active area of research. and provides a foundation for future molecular studies.
We propose that future challenges lie in performing
Conclusions vagal afferent branch point signal gating studies to pro­
The vagus nerve has been extensively studied for centuries, vide a comprehensive understanding of how different
whereby a wide variety of vagal afferent properties, nutrient-​dependent gut-​derived hormonal signals are
features and functions have been elucidated in detail. integrated and how they contribute to the regulation of
The integration of multiple gut signals in the nodose metabolic homeostasis.
ganglion neurons enables the vagal afferent nerve to
respond rapidly to a large volume of nutrient-​dependent Published online 5 September 2018

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Nauck, M. A. Effects of sitagliptin and metformin adipose tissue browning and reduces obesity and Acknowledgements
treatment on incretin hormone and insulin secretory insulin resistance. Nat. Med. 21, 159–165 (2015). T.M.Z.W. is supported by a postdoctoral fellowship from the
responses to oral and “isoglycemic” intravenous 229. Trabelsi, M. S. et al. Farnesoid X receptor Banting and Best Diabetes Centre. H.J.D. is supported by
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206. Maida, A., Lamont, B. J., Cao, X. & Drucker, D. J. enteroendocrine L cells. Nat. Commun. 6, 7629 Canada postdoctoral fellowships. Part of the work discussed
Metformin regulates the incretin receptor axis via a (2015). in this Review conducted by the Lam laboratory was sup-
pathway dependent on peroxisome proliferator-​ 230. Marina, A. L. et al. Colesevelam improves oral ported by a CIHR Foundation Grant to T.K.T.L. (FDN-
activated receptor-​alpha in mice. Diabetologia 54, but not intravenous glucose tolerance by a 143204). T.K.T.L. holds the John Kitson McIvor (1915–1942)
339–349 (2011). mechanism independent of insulin sensitivity and Endowed Chair in Diabetes Research and the Canada
207. Bahne, E. et al. Involvement of glucagon-​like peptide-1 beta-​cell function. Diabetes Care 35, 1119–1125 Research Chair in Obesity at the Toronto General Hospital
in the glucose-​lowering effect of metformin. Diabetes (2012). Research Institute and the University of Toronto.
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209. Madiraju, A. K. et al. Metformin suppresses 232. Burdyga, G. et al. Expression of cannabinoid CB1
gluconeogenesis by inhibiting mitochondrial receptors by vagal afferent neurons is inhibited Publisher’s note
glycerophosphate dehydrogenase. Nature 510, by cholecystokinin. J. Neurosci. 24, 2708–2715 Springer Nature remains neutral with regard to jurisdictional
542–546 (2014). (2004). claims in published maps and institutional affiliations.

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