Plasticity of gastro-intestinal vagal afferent endings

Physiology & Behavior xxx (2014) xxx–xxx

PHB-10342; No of Pages 9

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Physiology & Behavior

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Plasticity of gastro-intestinal vagal afferent endings

Stephen J. Kentish a, Amanda J. Page a,b,⁎a Discipline of Medicine, University of Adelaide, Frome Road, Adelaide, SA, 5005, Australiab Royal Adelaide Hospital, North Terrace, Adelaide, SA, 5000, Australia

H I G H L I G H T S

• Vagal afferent plasticity occurs in a normal day to day manner as well as in response to metabolic perturbations.• Vagal afferent function is modulated by factors including nutrients, hormones, circadian signals and the gut microbiota.• Diet induced obesity reduces vagal afferent satiety signals induced by mechanical and peptide signals.• The highly plastic nature of vagal afferents makes them a desirable peripheral target for the treatment of obesity.

⁎ Corresponding author at: Discipline of Medicine, LeUniversity of Adelaide, Frome Road, Adelaide, SA 5005 Au

E-mail addresses: [email protected] ([email protected] (A.J. Page).

http://dx.doi.org/10.1016/j.physbeh.2014.03.0120031-9384/© 2014 Published by Elsevier Inc.

Please cite this article as: Kentish SJ, Page A10.1016/j.physbeh.2014.03.012

a b s t r a c t
a r t i c l e i n f o
Article history:Received 30 November 2013Received in revised form 6 February 2014Accepted 10 March 2014Available online xxxx

Keywords:Vagal afferentsObesityPlasticityPeptidesNutrientsMicrobiota

Vagal afferents are a vital link between the peripheral tissue and central nervous system (CNS). There is an abun-dance of vagal afferents present within the proximal gastrointestinal tract which are responsible for monitoringand controlling gastrointestinal function. Whilst essential for maintaining homeostasis there is a vast amount ofliterature emergingwhich describes remarkable plasticity of vagal afferents in response to endogenous aswell asexogenous stimuli. This plasticity for the most part is vital in maintaining healthy processes; however, there areincreased reports of vagal plasticity being disrupted in pathological states, such as obesity. Many of the disrup-tions, observed in obesity, have the potential to reduce vagal afferent satiety signalling which could ultimatelyperpetuate the obese state. Understanding how plasticity occurs within vagal afferents will open a whole newunderstanding of gut function as well as identify new treatment options for obesity.

© 2014 Published by Elsevier Inc.

1. Introduction

The vagus, cranial nerve X, is an important link between the peripheryand central nervous system (CNS). It conveys a vast array of sensoryinformation and participates in the regulation of numerous functions. Ithas been well studied and, in the gastrointestinal (GI) tract alone, itpresents itself as a target for treatment of a number of common condi-tions including functional dyspepsia, gastroesophageal reflux diseaseand obesity [1–6]. Vagal afferent plasticity ranges from the basic changesin vagal afferent signalling in response to directmechanical and chemicalstimuli to modulation of these direct effects induced by a number offactors, including nutrients, hormones, circadian signals and the gutmicrobiota. The very fact that vagal afferent nerves convey informationfrom the periphery to the CNS implies that these afferents need to displaya high degree of plasticity responding directly to bothmechanical and/or

vel 6 Eleanor Harrald Building,stralia. Tel.: +61 8 8222 5644..J. Kentish),

J, Plasticity of gastro-intesti

chemical stimuli. As a consequence a full understanding of the interac-tions between vagal afferent endings and the local environment is neces-sary to fully appreciate the full range of plasticity these afferents exhibit.This review will provide an overview of the basic functionality of gastro-intestinal vagal afferent function, and describe the remarkable plasticitythe vagus demonstrates through being modulated by nutrients, peptidesand the microbiota with a focus on how the plasticity is altered in anobese state. This is important as vagal afferent nerves are a major path-way by which food related signals, from the stomach and small intestine,access the brain to modulate food intake and associated behaviour. Ourcognitive perception of fullness following food intake depends onactivation of these afferents via two principal routes: 1) mechanicaldistension of the stomach and 2) the presence of luminal nutrientswhich trigger endocrine and paracrine secretions from both the stomachand small intestine (Fig. 1).

2. Anatomy and function of gastrointestinal vagal afferents

The vagal nerves are responsible for transmitting information toand from the GI tract as well as much of the viscera. Whilst the

nal vagal afferent endings, Physiol Behav (2014), http://dx.doi.org/

http://dx.doi.org/10.1016/j.physbeh.2014.03.012

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Fig. 1.Vagal feedbackmechanisms from the proximal gastrointestinal tract. (A) Gastric vagal afferents are sensitive to mechanical stimuli such as gastric distension and can bemodulatedby locally released peptides such as leptin and ghrelin. Together these peripheral afferents transmit sensory signals to the brainstem, which can then trigger a variety of efferent responses.(B) Intestinal vagal afferents respond to an enteroendocrine effect elicited by the presence of luminal nutrients which triggers the release of mediators such as cholecystokinin (CCK),serotonin (5-HT), peptide YY (PYY) and glucagon-like peptide 1 (GLP-1).

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vagus does have efferent fibers, it has been suggested that as muchas 90% of the fibers within the vagus are afferent fibers, comprisedalmost entirely of unmyelinated C fibers and myelinated Aδ fibers[7]. The cell bodies of vagal afferent nerves lie within the nodoseand jugular ganglia which then terminate centrally within the nucle-us tractus solitarius (NTS). From here multiple synapses can bemadelocally within other regions of the brainstem such as to the dorsalmotor nucleus of the vagus (DMV) and also into the area postrema(AP). The connections between the NTS and DMV are particularlyimportant in initiating reflex loops such as the vago-vagal reflexcontrol of gastric function. Modulation of vagal afferent synapseswithin the NTS has also been well studied and shown to profoundlyalter GI functions [8,9]. However, this reviewwill largely concentrateon the plasticity and modulation that occurs in the afferent endingswithin the GI tract.

The afferent limb of the vagus has been well studied in terms ofanatomy. It has been revealed that there are afferent fibers withinall layers of the gut wall, including of interest to this review, thestomach and small intestine. The anatomy and morphology ofgastrointestinal afferents strongly influences the modality of theseafferents in terms of direct responses to mechanical or chemicalstimuli. Below is a brief summary of the properties of the differentclasses of vagal afferents.

Please cite this article as: Kentish SJ, Page AJ, Plasticity of gastro-intesti10.1016/j.physbeh.2014.03.012

2.1. Intraganglionic laminar endings (IGLEs)

IGLEs were first identified in 1946 in the striated esophageal mus-cle in canines [10] with subsequent identification throughout the GItract in a variety of species including rats, mice and cats [11–13].IGLEs have been observed to be positioned between the longitudinaland circular smooth muscle [14]. Anterograde tracing from the no-dose ganglia confirmed that IGLEs were of vagal origin [15]. Morethan four decades earlier these vagal afferents were characterisedas low-threshold tension sensitive mechanoreceptors [16], and sub-sequently reported to respond to both distension and contraction[17]. It is hypothesised that IGLEs detect distortion of the tissuesurrounding their endings through a mechanism involving an un-identified ion channel(s) [18]. This responsiveness suggests thatthey may be a prime candidate for signalling gastric distensionafter consumption of a meal.

There is a dense population of IGLEs within the proximal GI tractincluding the stomach and small intestine. However, the propertiesof IGLEs appears to differ regionally evenwithin a single organ. For exam-ple, stomach tension receptors within the body and fundus respondlargely to distension of the gastric wall whereas antral receptive fieldsaremore sensitive to contraction [19]. This is consistent with the primaryroles of the different regions of the stomach i.e. distension of the fore




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stomach to accommodate consumed food and contraction of the distalstomach to control motility.

2.2. Intramuscular arrays

Morphological tracing studies from the nodose ganglia have revealeda second type of endingwithin themuscular layers of theGI tract. Dubbedintramuscular arrays (IMAs) they consist of fibers which exist in parallelbundles to themuscularis externa [14]. Whilst located throughout the GItract the highest density of these endings appears to be around thesphincter regions of the stomach [20]. They have been shown to beclosely associated with intramuscular interstitial cells of Cajal (ICC)[21] which led to speculation that they may act in conjunction withthe ICC to form a functional complex [22]. Given their morphology ithas been argued that IMAs would function as tension receptors, specif-icallymonitoring the length of the stomach [23]. However, to date thereis no electrophysiological data that can be attributed directly to IMAs,thus it is not possible to conclude with any degree of certainty whetherIMAs do in fact form a second class of tension sensitive ending.

2.3. Mucosal afferents

Mucosal afferents are both mechanosensitive and chemosensitive.They are insensitive to stretch or tension, however they do respond tolight stroking [24,25]. Their endings can extend through the submucosallayers and form networks within the lamina propria of the crypts andvilli of the gut. The location of their endings, within the parenchymaof mucosal villi in close contact with the basal lamina, but not withthe epithelial surface [26], suggests that they are positioned to respondto mediators released from enteroendocrine cells (Fig. 1) as well asnutrients absorbed across the basal lamina. Whilst initially it was sug-gested that mucosal vagal afferents were a single population thatcould innervate both villi and crypts [26], more recent studies have re-vealed the possible existence of 3 potentially independent populationsof mucosal vagal afferent within the proximal GI tract [27]. Whilstdiscussing the finer details of “independent” populations is outside thescope of this review there is neverthelessmucosal afferents that lie stra-tegically close to the basal pores of intestinal enterocytes and otherspecialised epithelial cells putting them in a prime position to respondto mediators released from chemosensory cells [27,28].

There have been suggestions for the role of mechanosensorymucosalafferents within the GI tract; however, there is a distinct lack of directevidence for these proposed functions. To date most of the suggestionsare based on mucosal afferent responsiveness and location. Within thegastric antrum there are a population of mucosal afferents that are sensi-tive to chemical stimuli such as changes in pH aswell as lightmechanicalprobing [29]. It was hypothesised that such afferents would detect thepresence and passage of luminal material with the chemosensory abilityable to detect the acidity of chime and potentially the osmolarity [27].Furthermore, there is some evidence to suggest that the mucosal affer-ents detect particle size within the stomach to control the rate of gastricemptying [30]. However, these findings involved a physical removal ofthemucosa rather thandirect and specific stimulation ofmucosal afferentendings. A study, in ferrets, found that probing of the gastric antralmucosa resulted in a reduction in corpus pressure and an inhibition ofcontraction [31]. Taken together these studies do support the theoryof gastric mucosal afferents being involved in the regulation of gastricmotility and emptying. However, this still needs to be confirmed bymore refined and well directed experiments.

All of the different types of vagal afferent nerves mentioned aboveare not in a rigid statewith direct responses tomechanical and chemicalstimulationmodulated by an array of nutrients, peptides and hormonesknown to affect appetite. Thus the plasticity of this systemunder normalphysiological conditions is considerable. In addition,metabolic conditions,such as obesity, can alter the effect of nutrients and appetite regulatinghormones on vagal afferent satiety signals, which in many cases may


promote the consumption of food perpetuating the obese state. Belowwe review the role of nutrients, GI hormones, circadian signals and thegutmicrobiota in the control of GI vagal afferent function in normal phys-iological states and how this changes in conditions such as obesity.

3. Nutrient sensing

GI vagal afferents act as important nutrient sensors. It is currentlybelieved that nutrient sensing within the GI tract occurs through therelease of mediators from specialised enteroendocrine cells within thewall of the gut. However, the exact signalling mechanisms involved inenteroendocrine transduction are not yet completely understood.Nevertheless, it is becoming increasingly evident that vagal afferentsare involved in the satiation induced by GI tract exposure to differentnutrients.

The long chain fatty acids oleate and linoleate have been shown toactivate mouse vagal afferents innervating the small intestine [32,33].This effect is virtually abolished by application of the cholecystokininreceptor 1 (CCK1R) antagonist lorglumide, suggesting that activationof vagal afferents by fatty acids is dependent on cholecystokinin (CCK)signalling [32,34]. This suggests that vagal afferents are not respondingdirectly to the presence of nutrients, but are responding to endocrinemediators released from cells in response to luminal fatty acids actingon nutrient receptors, such as GPR40, on the luminal surface of thecell [35]. However, a report by Ogawa et al. found jejunal infusion oflinoleate still reduced 3 hour food intake after a vagotomy as well asin OLTEF rats, which lack CCK1R [36]. Therefore the satiating effect offatty acid in the jejunum is not mediated through CCK acting on jejunalvagal afferents. This is perhaps not surprising as CCK secreting I-cells arepredominantly located in the duodenum [37,38]. Recent findings of in-creased meal-related CCK secretion, in patients with Roux-en-Y gastricbypass, indicate that indirect mechanisms can contribute to CCK secre-tion [39,40]. This may indicate that the effect of fatty acids on vagalafferents is distinct from their role in modulating food intake. Giventhe involvement of vagal afferents in regulating gastric emptying,which both fatty acids and CCK can modulate [41,42], perhaps activa-tion of vagal afferents in response to luminal fatty acids is mediatingmotor events whereas the satiation effects are mediated elsewhere.

Protein has long been shown to have satiating abilities. More recentwork suggests that protein in general is not sufficient for satiation, butinstead specific amino acids are able to induce satiety and can doso via vagal pathways. For example, intragastric administration ofL-lysine reduces food intake in rats [43]. This effect is abolished bylocal vagal capsaicin treatment in an attempt to selectively destroyvagal afferents [43], however, capsaicin treatment has also beenshown to destroy vagal efferents [44]. In addition, it has been demon-strated that some vagal afferents are resistant to capsaicin treatment[45], although themajority of these afferents are located in the stomachand esophagus. Within the stomach there is less evidence of nutrientsensing and even less for the involvement of the vagus. However,there is the presence of known nutrient signalling molecules includingα-gustducin [46] and T1R3 [47,48] within the gastric epithelium.Furthermore there is evidence to suggest that gastric glutamate can ac-tivate gastric vagal endings through a 5-HT and nitric oxide dependentpathway [49]. However, this study did not determine the physiologicalresponse in regards to gastric function or satiety, and therefore thephysiological effect of glutamate on gastric vagal afferents remains tobe conclusively determined. Results from other studies certainly sup-port the notion that nutrient detection within the stomach is importantfor creating specific sensations. For example, an increase in intragastricpressure only results in increased satiety after intragastric infusion of nu-trients [50]. So whilst a definite link between nutrient sensing in thestomach, activation of vagal afferents and changes in satiety remains tobe established, it is likely that vagal function within the stomach is ableto be modulated by nutrients.





In terms of carbohydrates there is very little evidence available for adirect effect on GI vagal afferents. It has been demonstrated thatincreasing arterial glucose increases gastric vagal afferent dischargevia inhibition of ATP sensitive potassium (KATP) channels [51]. In thisstudy elements essential for glucosensing including glucose transporter3 (GLUT3) and glucokinase (hexokinase IV) were identified in thenodose ganglia which when silenced resulted in an inability for glucoseto excite isolated gastric nodose neurons [51]. However, whether glucoseis acting directly on the nodose ganglia, as demonstrated previously [52],or on the afferent ending to produce the excitation remains to be deter-mined conclusively. It should be noted that like protein and fat, carbo-hydrate has been shown to stimulate release of mediators such asglucagon-like peptide 1 (GLP-1) [53] and 5-HT [54] from cells withinthe intestinal epithelium. Therefore, luminal carbohydrate may beable to cause an indirect modulation of vagal afferents through releaseof such mediators.

On top of inducing satiation, nutrients in the small intestine haverecently been shown to induce an increase in thermogenesis in brownadipose tissue (BAT) via CCK mediated activation of local vagal afferentendings [55]. A single point mutation in uncoupling protein 1 (UCP1),which mediates the generation of heat in BAT causes a reduction inenergy expenditure following a high fat, but not high carbohydratemeal [56]. Given that CCK is released preferentially by exposure tolipid rather than carbohydrate [38] it is likely that vagal afferents are in-volved in the increase in energy expenditure following ameal. This sug-gests that as well as being involved in controlling food intake, vagalnutrient sensing within the small intestine is also a regulator of energyexpenditure. However, intestinal infusion of hypertonic NaCl also in-duces thermogenesis and increased energy expenditure through amechanism that involves vagal afferents [57]. This suggests that bothnutrient responsive and osmotic responsive fibers participate in vagalinduced energy expenditure [58].

It has been demonstrated that the suppression of food intake bynutrient infusion into the stomach with an open pyloric cuff is greaterthan the suppression in food intake caused by gastric distension or in-testinal nutrient exposure alone [59]. This indicates that both locationswork together to cause a larger net reduction in food intake than eithercould on their own. An example of such a mechanism is CCK, which isreleased from the small intestine and has been shown to activate thesame vagal afferents activated by gastric distension [60].

4. GI peptides as modulators of vagal activity

Whilst capable of spontaneous activity the signalling of vagalafferents within the GI tract are modulated or activated by an arrayof substances released from specialised cells within the GI tract whichallows for rapid communication in response to GI tract activity. Belowis an overview of a selection of mediators, located in specialised cellswithin the stomach and small intestine that alter the activity of vagalafferents. It cannot be stressed enough that this is in no way a compre-hensive list or discussion of all modulators.

4.1. Leptin

Whilst the traditional source of leptinwas thewhite adipocytes [61],it is now accepted that the stomach is also a source of leptin [62]. Thelong form of the leptin receptor (LepRb) has been identified on vagalafferent endings innervating the GI tract [12,63] suggesting that leptinmay have a vagal modulatory role. This was confirmed in a series ofstudies which identified that leptin alone was able to activate culturednodose neurons [64] and, more specifically, gastric and duodenal [65]nodose neurons but also had a profound synergistic effect with CCK.Leptin infused directly into the gastric blood supply had the ability tocause a substantial reduction in food intake, an effect that was lost invagotomised animals [66]. This suggested that the effect of leptin onacute food intake is mediated through a vagal pathway.


Leptin has been shown to reduce acute food intake in a manner thatis not dependent on CCK action, but which requires intact vagal nerves[67]. However, the vagal pathway of leptin appears to be largelyinvolved in short term regulation of food intake with disruption ofvagal afferent signalling not disturbing food intake over a period of 4 hor greater [67,68].

Obesity has been shown to induce leptin resistance within thehypothalamus which abolishes the satiation inducing effect of leptin[69]. Shortly after this observation, leptin resistance was also reportedto occur within vagal afferents at a point which precedes hypothalamicleptin resistance [70]. Furthermore, vagal afferent leptin resistancereduced the satiation inducing effect of CCK [71]. Within the stomachleptin has been shown to potentiate themechanosensitivity of mucosalafferents in lean mice via a phospholipase C (PLC) mediated activationof TRPC1 channels [12]. However, in diet induced obese mice, leptinno longer potentiates mucosal receptors, but instead causes an inhibi-tion of tension receptor mechanosensitivity via activation of large con-ductance calcium sensitive potassium (BKCa) channels [12]. Uponremoval of the high fat diet and feeding with a standard chow diet for12 weeks, obese mice enter a state where both the potentiation of mu-cosal and inhibition of tension receptors by leptin occurs concurrently,but both occur to a smaller magnitude than they did in the lean andobese mice respectively [72].

4.2. Ghrelin

Ghrelin is a 28 amino acid peptide secreted fromX/A cells within thegastric fundus [73]. It acts as an endogenous mediator of growthhormone release [74]. Ghrelin has also been shown to be expressedalong the length of the GI tract; however the level of expression dimin-ishes distally from the stomach [75]. The endogenous ghrelin receptor(GHS-R) has been detected centrally and alsowithin the nodose gangliaand gastric vagal afferents [76]. It has been demonstrated that ghrelincauses an inhibition of vagal afferent firing [77,78], but within thejejunum, ghrelin has been shown to augment the vagal response to dis-tension [78]. This suggests specific vagal afferent populations responddifferently to ghrelin. However, the consequence of this inhibition isstill being debated with some studies showing the orexigenic effect ofghrelin is mediated by vagal pathways [79], whereas others show theopposite [80]. Currently, there is some evidence suggesting that withinthe arcuate nucleus (ARC) ghrelin resistance occurs in obesity [81]. Thefact that ghrelin still increases energy intake in obese humans [82] andthat ghrelin blockade reduces food intake in diet induced obese mice[83] suggests that ghrelin must still be able to activate an orexigenicmechanism in the obese state. The inhibitory effect of ghrelin of gastricvagal afferents has been shown to bemaintained and in fact broadenedas in lean mice ghrelin only inhibits gastric tension receptors, whereasin obese mice ghrelin inhibits both tension and mucosal receptors[84]. The physiological relevance, in terms of food intake and gastroin-testinal motility, of the observed increase in effect of ghrelin on gastricvagal afferents remains to be determined.

4.3. CCK

CCK is released from I-cells located largelywithin the proximal smallintestine. The release of CCK is mediated by the presence of luminalnutrients, with a preference for the digestion products of amino acidsand fatty acids rather than those of carbohydrates [38,85,86]. There isan abundance of evidence for CCK having a food intake modulatoryeffect, with its exogenous administration causing a reduction in food in-take aswell as a slowing of gastric emptying, both of which are lost aftervagotomy [87,88]. The expression of CCK1R does not appear to beeffected by acute nutritional changes (i.e. fasting) [89], but there areexamples of upregulation in response to high fat diet feeding [90]although this is not consistently reported [91]. The ability for CCK to ac-tivate CCK1 receptors on vagal afferents is inhibited by the orexigenic





peptides ghrelin, orexin A and anandamide [76,92–94]. The ability forCCK to reduce food intake appears to be compromised in response tochanges in nutrient composition [95]. Thismay be due to a reduced abil-ity of CCK to activate intestinal vagal afferents as previously described indiet-induced obesemice [96]. A studybyde Lartigue et al. demonstratedthat only rats that became obese whilst on a high fat diet and not thosethat remained lean lost sensitivity to CCK [71]. This would suggest thatobesity rather than the high fat diet reduced sensitivity to CCK in vagalafferent neurons.

4.4. Glucagon-like peptide-1 (GLP-1)

GLP-1 is an incretin hormone released from intestinal L-cells [97],which have the ability to respond and broadly detect the digestionproducts of carbohydrates, fats and proteins [98,99]. Its release causesa decrease in food intake [100], stimulation of insulin release [101], re-duction of glucagon secretion [102] and a reduction in gastric emptying[103]. GLP-1 can activate vagal afferents [104] and this is believed to bethe mechanism responsible for its effects on insulin release and foodintake [105]. However, there is some debate over whether the vagalpathway is the main effector pathway by which GLP-1 signals to theCNS. Subdiaphragmatic vagotomy has been shown to have no effecton the ability of GLP-1 to reduce food intake when administered intothe hepatic portal vein, but when administered intraperitoneally (IP),subdiaphragmatic vagotomy abolishes the ability for GLP-1 to reducefood intake [106]. This has led to the suggestion that local and circulatingGLP-1 may have different effector locations. GLP-1 receptor has beenlocalised on the endings of vagal afferents [107], within the nodoseganglia [108] and on neurons within the dorsal vagal complex withinthe brainstem [109]. GLP-1 has been shown to cause an increase in gastricand jejunal vagal afferent activity [104,107]. The relevance of the actionon gastric afferents is debatable as the half-life of bioactive GLP-1 inplasma has been reported to be as short as two minutes [110]. With nostrong evidence suggesting that GLP-1 is produced in the stomachGLP-1may not reach the stomach in sufficient concentration to activatethe afferents. In terms of obesity there is no electrophysiological datashowing whether there is a change in the ability for GLP-1 to activatevagal afferents. However, there is evidence that GLP-1 activates vagalafferents in lean rats [107,111]. GLP-1 receptor mRNA expression inthe vagal nodose ganglia is decreased in response to chronic ingestionof a high fat diet in obesity prone rats [112] and this is accompaniedby a reduction in the satiating effect of the GLP-1 receptor agonistexendin-4 [112]. Therefore, it could be hypothesised that GLP1 signallingin vagal afferents is reduced in high fat diet induced obesity.

4.5. Peptide YY (PYY)

There is PYY present throughout the intestines, with very low levelsin the proximal small intestine, increasing substantially in the ileumandeven more into the colon [113]. The mechanism regulating the releaseof PYY from the proximal gut appears to involve both direct contactwith luminal nutrients and also through CCK release in response tomore proximal exposure to fat [114]. PYY release is also related to caloricload and is triggered by carbohydrate, fatty acid and to a lesser extentamino acid presence in the lumen [115]. Just like GLP-1, PYY is releasedfrom intestinal L-cells [116]. It acts to slow gastric emptying as well aspromote satiation [117,118]. There are two endogenous forms of PYY[119]. Initially PYY is released as PYY1-36, however once in the circulationthe first two amino acids are cleaved to form PYY3-36, the majorcirculating type [120]. IP administration of PYY3-36 has been shownto have an anorectic effect in rodents [121], which is completelyabolished by sub-diaphragmatic vagotomy [122,123]. The PYY receptor(Y2) has been identified on both intestinal vagal afferents [124] as wellas neurons within the arcuate nucleus [125], indicating that PYY3–36

may elicit its anorectic effects through either a central, peripheral or acombination of pathways.


A decrease in Y2 receptor expression in nodose ganglia of fasted ratsand an increase in re-fed rats or fasted rats that have received an infusionof CCK has been reported [124]. This upregulation of the Y2 receptor isbelieved to be due to increased cocaine- and amphetamine-regulatedtranscript (CART) expression in response to CCK, with CART acting inan autocrine fashion to upregulate Y2 expression [92]. A blockade of theY2 receptor has been shown to abolish the anorectic effects of PYY3–36

[126] andY2knockoutmice exhibit hyperphagia andobesity highlightingthe importance of this pathway in the long term control of body weight[127].

In human obesity the postprandial release of PYY is impaired [128]and diet-induced obese rats exhibit reduced plasma PYY [129]. Thereis also reduced expression of Y2 receptors in vagal afferent neurons[71], which together suggests that in obesity there may be blunted in-testinal satiety signals conveyed via PYY3–36. However, exogenousPYY3–36 still reduced food intake in obese mice [128]. It still remainsto be determined whether obesity affects the ability for endogenousPYY to modulate food intake and whether the effect of PYY on vagalpathways is altered.

5. Circadian variation

Like most physiological processes, food intake is highly regulatedand shows strong circadian patterns with mice consuming themajorityof their daily food within the active dark phase [130]. Most circadianfunctions are entrained by a central clock located in the suprachiasmaticnucleus (SCN) which in turn is entrained by exposure to light. Whilstthe SCN can influence and drive eating behaviour [131] it is likely thatthere is another source of circadian drive as SCN lesioned rats are stillentrainable to a feeding schedule [132]. A recent study has identifiedcircadian expression of the molecular clock genes Per1, Per2, Bmal1and Nr1d1 within the nodose ganglia of mice suggesting the existenceof a peripheral neural clock [133]. Given the involvement of vagal affer-ents in controlling food intake it is not surprising that gastric vagal affer-ents exhibit profound oscillations in their mechanosensitivity which areinversely related to the amount of food present in the stomach [133].Meal size in rodents varies dramatically between the light and darkphase with increased meal frequency and size during the dark phase[134]. The finding that gastric vagal afferent mechanosensitivity is re-duced during the dark phase, when food intake is high inmice, providesa potential mechanism to allow this to occur. Activation of tension re-ceptors by gastric distension has been shown to induce satiety [135],therefore, reduced responses to distension during the dark phasewould allow for more food to be consumed before satiation is reached.Given that these oscillations were only seen in gastric afferents, inde-pendent of food intake or exposure to light, raises the possibility thatthe vagus can operate as an autonomous circadian food intake regulator.Whilst to our knowledge this is the first instance demonstrating a diurnalvariation in the mechanosensitivity of vagal afferents it has previouslybeen concluded that colonic sensory afferents also exhibit circadianvariation in mechanosensitivity [136]. This study found that the pain re-sponse to colonic distension,mediated through a spinal afferent pathway,was greater during the dark phase than the light [136]. However, thisstudy did not actually measure the afferent response to the colorectaldistension, thus the variation observed may actually be caused by CNSmediated effects.

Within the small intestine there is circadian variation in absorptivefunction [137]. However, information behind mechanisms is relativelyscarce. It has been demonstrated that a number of key proteins oscillatein their levels of expression throughout the light dark cycle [138,139].Furthermore, it has previously been reported that diurnal variation ofmucosal transporter Peptide Transporter 1 (PEPT1) protein is abolishedafter a vagotomy, but there is still variation at the mRNA level [140].This suggests that vagal signalling has a subtle yet profoundmodulatoryeffect on small intestine absorptive function.





Given the involvement of the vagus in controlling gastric function andthe now described phenomenon of circadian variation in their respon-siveness it is likely that circadian variations in mechanisms includinggastric emptying [141,142] and slow wave activity [143] are being atleast in part controlled by the variation in activity of local vagal neurons.

6. Microbiota

It is well established that the collection of bacteria that colonise theGI tract are able to influencemultiple processes both locally and system-ically [144]. The type of bacteria within the GI tract is highly dynamicand can be influenced by factors including diet and stress.

The gut microbiota have a vital role in breaking down substanceswhich the human GI tract cannot [145]. Through this breakdown thereis a well-documented formation of short chain fatty acids (SCFAs)[145]. These SCFAs can be absorbed by the host, however there is evi-dence that they can also interact with L-cells within the GI tract throughthe receptors GPR41 and GPR43 [146]. This could lead to an increase inthe release of GLP-1 and PYYwhich can act on vagal afferents to increasesatiety, as described earlier in Sections 4.4 and 4.5. One SCFA of interest isbutyrate. Whilst the vast majority of bacterial fermentation productionof SCFA occurs within the cecum and proximal colon there is evidencethat butyrate is able to activate jejunal vagal afferents in a pathwaythat is distinct from that used by long chain fatty acids. Whilst longchain fatty acids such as oleate tend to activate vagal afferents via aCCK mediated mechanism, butyrate caused activation of extrinsic affer-ents despite blockade of L, N, P and Q-type calcium channels suggestingno involvement of neurotransmitter release from intrinsic neurons,smoothmuscle action or enterochromaffin cells [147]. Thus it is possiblethat SCFAs such as butyrate may directly activate specific populations ofvagal afferents after crossing the epithelium. However, if this is occur-ring, the actual mechanisms still needs further examination as no reporthas localised SCFA receptors such as GPR43 on vagal afferent endingswithin the jejunum. The actual physiological relevance of SCFA produc-tion via microbiota still needs to be determined, as for the most partthe predominant site of SCFA production is the colon where it is usedas fuel for the colonic epithelium and after metabolism within the liverthere is very little systemic circulating butyrate [148,149]. This suggestsa local site of action. There is vagal innervation of the colon, albeit to alesser extent than the upper GI tract [15]. In addition, L-cells have beenlocated in the colon [15,150]. Therefore SCFAs could act on vagal affer-ents in this region either directly or via action on L-cells.

On top of producing nutrients, the gut microbiota also releasesbioactive molecules some of which can cross the epithelium and acton a variety of tissues. One such molecule is the endotoxin lipopolysac-charide (LPS). The vagal afferent neurons within the GI tract express thereceptor for LPS, toll-like receptor 4 (TLR4) [151]. Within cultured vagalneurons LPS treatment causes an increase in suppressor of cytokinesignalling 3 (SOCS3) and a subsequent inhibition of leptin signallingthrough signal transducer and activator of transcription-3 (STAT3) [70],suggesting that microbiota can modulate the action of endogenouspeptides. There is strong evidence demonstrating bacterial productsincluding LPS have food modulatory effects with LPS administrationcausing substantial reductions in food intake [152]. However, the actualmechanism behind this modulation is yet to be conclusively determined.

Intrajejunal lumenal LPS has been shown to increase Fos-positivecell number within the NTS without an accompanying increase insystemic LPS [153] suggesting that vagal afferents are the mechanismwhich conveys LPS signals from the gut to the brain. Similarly oralgavages of Campylobacter jejuni and Salmonella typhimurium inmice results in an increase in c-Fos immunoreactivity within theNTS, with complete ablation of this increase after capsaicin treatment,which disrupts vagal signalling [154]. However, what this activationactually means physiologically is uncertain as rats that have had asubdiaphragmatic vagotomy still show a reduction in food intake in re-sponse to IP LPS [155]. Electrophysiological studies have revealed that


LPS has the ability to cause a transient increase in jejunal vagal afferentmechanosensitivity as well as an increase in mesenteric afferentactivity [156], supporting the theory of vagal afferents being involvedin the transmission of microbiota induced signals.

Consumption of a high fat diet has been demonstrated to elevateplasma LPS levels [157]. Furthermore, a high fat diet causes the develop-ment of an obese microbiota independent of weight gain as seen in dietinduced obese prone and resistant rats [157]. Given that obesity is asso-ciated with a chronic low grade inflammation it is not surprising thatthere is an accompanying increase in systemic LPS. However, this in-crease, like the inflammation level, is relatively low when compared toan acute severe infection induced inflammation. This suggests thatboth obesity and a high fat diet are capable of leading to vagal plasticitythrough increased production of LPS as well as switching the residentmicrobiota which have different secretion and metabolic profiles[158–160].

7. Conclusion

Vagal afferents represent a highly plastic connection between the GItract and the CNS. Much of the plasticity it exhibits is well suited toensuring appropriate functionality especially in controlling the intakeof food. However, it also appears to be a system which is exceptionallysusceptible to disruption by conditions such as obesity and the plasticityobserved with obesity appears to largely support the maintenance ofadiposity through inhibition of peripheral satiety signals. Future studieswithin this area will no doubt determine the molecular mechanismswhich drive these changes and will reveal ways of overcoming theadaptationswhich ultimately could establish awhole new set of periph-eral targets for pharmacological treatment of obesity.

Acknowledgements

This manuscript is based onwork presented during the 2013 AnnualMeeting of the Society for the Study of Ingestive Behavior, July 30–August 3, 2013.

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Plasticity of gastro-intestinal vagal afferent endings