Plasticity of gastro-intestinal vagal afferent endings.

PHB-10342; No of Pages 9 Physiology & Behavior xxx (2014) xxx–xxx

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Plasticity of gastro-intestinal vagal afferent endings Stephen J. Kentish a, Amanda J. Page a,b,⁎ a b

Discipline of Medicine, University of Adelaide, Frome Road, Adelaide, SA, 5005, Australia 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.

a r t i c l e

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Article history: Received 30 November 2013 Received in revised form 6 February 2014 Accepted 10 March 2014 Available online xxxx Keywords: Vagal afferents Obesity Plasticity Peptides Nutrients Microbiota

a b s t r a c t Vagal afferents are a vital link between the peripheral tissue and central nervous system (CNS). There is an abundance of vagal afferents present within the proximal gastrointestinal tract which are responsible for monitoring and controlling gastrointestinal function. Whilst essential for maintaining homeostasis there is a vast amount of literature emerging which describes remarkable plasticity of vagal afferents in response to endogenous as well as exogenous stimuli. This plasticity for the most part is vital in maintaining healthy processes; however, there are increased reports of vagal plasticity being disrupted in pathological states, such as obesity. Many of the disruptions, observed in obesity, have the potential to reduce vagal afferent satiety signalling which could ultimately perpetuate the obese state. Understanding how plasticity occurs within vagal afferents will open a whole new understanding 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 periphery and central nervous system (CNS). It conveys a vast array of sensory information and participates in the regulation of numerous functions. It has been well studied and, in the gastrointestinal (GI) tract alone, it presents itself as a target for treatment of a number of common conditions including functional dyspepsia, gastroesophageal reflux disease and obesity [1–6]. Vagal afferent plasticity ranges from the basic changes in vagal afferent signalling in response to direct mechanical and chemical stimuli to modulation of these direct effects induced by a number of factors, including nutrients, hormones, circadian signals and the gut microbiota. The very fact that vagal afferent nerves convey information from the periphery to the CNS implies that these afferents need to display a high degree of plasticity responding directly to both mechanical and/or ⁎ Corresponding author at: Discipline of Medicine, Level 6 Eleanor Harrald Building, University of Adelaide, Frome Road, Adelaide, SA 5005 Australia. Tel.: +61 8 8222 5644. E-mail addresses: [email protected] (S.J. Kentish), [email protected] (A.J. Page).

chemical stimuli. As a consequence a full understanding of the interactions between vagal afferent endings and the local environment is necessary to fully appreciate the full range of plasticity these afferents exhibit. This review will provide an overview of the basic functionality of gastrointestinal vagal afferent function, and describe the remarkable plasticity the vagus demonstrates through being modulated by nutrients, peptides and the microbiota with a focus on how the plasticity is altered in an obese state. This is important as vagal afferent nerves are a major pathway by which food related signals, from the stomach and small intestine, access the brain to modulate food intake and associated behaviour. Our cognitive perception of fullness following food intake depends on activation of these afferents via two principal routes: 1) mechanical distension of the stomach and 2) the presence of luminal nutrients which trigger endocrine and paracrine secretions from both the stomach and small intestine (Fig. 1). 2. Anatomy and function of gastrointestinal vagal afferents The vagal nerves are responsible for transmitting information to and from the GI tract as well as much of the viscera. Whilst the

http://dx.doi.org/10.1016/j.physbeh.2014.03.012 0031-9384/© 2014 Published by Elsevier Inc.

Please cite this article as: Kentish SJ, Page AJ, Plasticity of gastro-intestinal vagal afferent endings, Physiol Behav (2014), http://dx.doi.org/ 10.1016/j.physbeh.2014.03.012

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S.J. Kentish, A.J. Page / Physiology & Behavior xxx (2014) xxx–xxx

Fig. 1. Vagal feedback mechanisms from the proximal gastrointestinal tract. (A) Gastric vagal afferents are sensitive to mechanical stimuli such as gastric distension and can be modulated by 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).

vagus does have efferent fibers, it has been suggested that as much as 90% of the fibers within the vagus are afferent fibers, comprised almost entirely of unmyelinated C fibers and myelinated Aδ fibers [7]. The cell bodies of vagal afferent nerves lie within the nodose and jugular ganglia which then terminate centrally within the nucleus tractus solitarius (NTS). From here multiple synapses can be made locally within other regions of the brainstem such as to the dorsal motor nucleus of the vagus (DMV) and also into the area postrema (AP). The connections between the NTS and DMV are particularly important in initiating reflex loops such as the vago-vagal reflex control of gastric function. Modulation of vagal afferent synapses within the NTS has also been well studied and shown to profoundly alter GI functions [8,9]. However, this review will largely concentrate on the plasticity and modulation that occurs in the afferent endings within the GI tract. The afferent limb of the vagus has been well studied in terms of anatomy. It has been revealed that there are afferent fibers within all layers of the gut wall, including of interest to this review, the stomach and small intestine. The anatomy and morphology of gastrointestinal afferents strongly influences the modality of these afferents in terms of direct responses to mechanical or chemical stimuli. Below is a brief summary of the properties of the different classes of vagal afferents.

2.1. Intraganglionic laminar endings (IGLEs) IGLEs were first identified in 1946 in the striated esophageal muscle in canines [10] with subsequent identification throughout the GI tract in a variety of species including rats, mice and cats [11–13]. IGLEs have been observed to be positioned between the longitudinal and circular smooth muscle [14]. Anterograde tracing from the nodose ganglia confirmed that IGLEs were of vagal origin [15]. More than four decades earlier these vagal afferents were characterised as low-threshold tension sensitive mechanoreceptors [16], and subsequently reported to respond to both distension and contraction [17]. It is hypothesised that IGLEs detect distortion of the tissue surrounding their endings through a mechanism involving an unidentified ion channel(s) [18]. This responsiveness suggests that they may be a prime candidate for signalling gastric distension after consumption of a meal. There is a dense population of IGLEs within the proximal GI tract including the stomach and small intestine. However, the properties of IGLEs appears to differ regionally even within a single organ. For example, stomach tension receptors within the body and fundus respond largely to distension of the gastric wall whereas antral receptive fields are more sensitive to contraction [19]. This is consistent with the primary roles of the different regions of the stomach i.e. distension of the fore



stomach to accommodate consumed food and contraction of the distal stomach to control motility. 2.2. Intramuscular arrays Morphological tracing studies from the nodose ganglia have revealed a second type of ending within the muscular layers of the GI tract. Dubbed intramuscular arrays (IMAs) they consist of fibers which exist in parallel bundles to the muscularis externa [14]. Whilst located throughout the GI tract the highest density of these endings appears to be around the sphincter regions of the stomach [20]. They have been shown to be closely associated with intramuscular interstitial cells of Cajal (ICC) [21] which led to speculation that they may act in conjunction with the ICC to form a functional complex [22]. Given their morphology it has been argued that IMAs would function as tension receptors, specifically monitoring the length of the stomach [23]. However, to date there is no electrophysiological data that can be attributed directly to IMAs, thus it is not possible to conclude with any degree of certainty whether IMAs 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 to light stroking [24,25]. Their endings can extend through the submucosal layers and form networks within the lamina propria of the crypts and villi of the gut. The location of their endings, within the parenchyma of mucosal villi in close contact with the basal lamina, but not with the epithelial surface [26], suggests that they are positioned to respond to mediators released from enteroendocrine cells (Fig. 1) as well as nutrients absorbed across the basal lamina. Whilst initially it was suggested that mucosal vagal afferents were a single population that could innervate both villi and crypts [26], more recent studies have revealed the possible existence of 3 potentially independent populations of mucosal vagal afferent within the proximal GI tract [27]. Whilst discussing the finer details of “independent” populations is outside the scope of this review there is nevertheless mucosal afferents that lie strategically close to the basal pores of intestinal enterocytes and other specialised epithelial cells putting them in a prime position to respond to mediators released from chemosensory cells [27,28]. There have been suggestions for the role of mechanosensory mucosal afferents within the GI tract; however, there is a distinct lack of direct evidence for these proposed functions. To date most of the suggestions are based on mucosal afferent responsiveness and location. Within the gastric antrum there are a population of mucosal afferents that are sensitive to chemical stimuli such as changes in pH as well as light mechanical probing [29]. It was hypothesised that such afferents would detect the presence and passage of luminal material with the chemosensory ability able to detect the acidity of chime and potentially the osmolarity [27]. Furthermore, there is some evidence to suggest that the mucosal afferents detect particle size within the stomach to control the rate of gastric emptying [30]. However, these findings involved a physical removal of the mucosa rather than direct and specific stimulation of mucosal afferent endings. A study, in ferrets, found that probing of the gastric antral mucosa resulted in a reduction in corpus pressure and an inhibition of contraction [31]. Taken together these studies do support the theory of gastric mucosal afferents being involved in the regulation of gastric motility and emptying. However, this still needs to be confirmed by more refined and well directed experiments. All of the different types of vagal afferent nerves mentioned above are not in a rigid state with direct responses to mechanical and chemical stimulation modulated by an array of nutrients, peptides and hormones known to affect appetite. Thus the plasticity of this system under normal physiological conditions is considerable. In addition, metabolic conditions, such as obesity, can alter the effect of nutrients and appetite regulating hormones on vagal afferent satiety signals, which in many cases may

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promote the consumption of food perpetuating the obese state. Below we review the role of nutrients, GI hormones, circadian signals and the gut microbiota in the control of GI vagal afferent function in normal physiological states and how this changes in conditions such as obesity.

3. Nutrient sensing GI vagal afferents act as important nutrient sensors. It is currently believed that nutrient sensing within the GI tract occurs through the release of mediators from specialised enteroendocrine cells within the wall of the gut. However, the exact signalling mechanisms involved in enteroendocrine transduction are not yet completely understood. Nevertheless, it is becoming increasingly evident that vagal afferents are involved in the satiation induced by GI tract exposure to different nutrients. The long chain fatty acids oleate and linoleate have been shown to activate mouse vagal afferents innervating the small intestine [32,33]. This effect is virtually abolished by application of the cholecystokinin receptor 1 (CCK1R) antagonist lorglumide, suggesting that activation of vagal afferents by fatty acids is dependent on cholecystokinin (CCK) signalling [32,34]. This suggests that vagal afferents are not responding directly to the presence of nutrients, but are responding to endocrine mediators released from cells in response to luminal fatty acids acting on nutrient receptors, such as GPR40, on the luminal surface of the cell [35]. However, a report by Ogawa et al. found jejunal infusion of linoleate still reduced 3 hour food intake after a vagotomy as well as in OLTEF rats, which lack CCK1R [36]. Therefore the satiating effect of fatty acid in the jejunum is not mediated through CCK acting on jejunal vagal afferents. This is perhaps not surprising as CCK secreting I-cells are predominantly located in the duodenum [37,38]. Recent findings of increased meal-related CCK secretion, in patients with Roux-en-Y gastric bypass, indicate that indirect mechanisms can contribute to CCK secretion [39,40]. This may indicate that the effect of fatty acids on vagal afferents is distinct from their role in modulating food intake. Given the involvement of vagal afferents in regulating gastric emptying, which both fatty acids and CCK can modulate [41,42], perhaps activation of vagal afferents in response to luminal fatty acids is mediating motor events whereas the satiation effects are mediated elsewhere. Protein has long been shown to have satiating abilities. More recent work suggests that protein in general is not sufficient for satiation, but instead specific amino acids are able to induce satiety and can do so via vagal pathways. For example, intragastric administration of L -lysine reduces food intake in rats [43]. This effect is abolished by local vagal capsaicin treatment in an attempt to selectively destroy vagal afferents [43], however, capsaicin treatment has also been shown to destroy vagal efferents [44]. In addition, it has been demonstrated that some vagal afferents are resistant to capsaicin treatment [45], although the majority of these afferents are located in the stomach and esophagus. Within the stomach there is less evidence of nutrient sensing and even less for the involvement of the vagus. However, there is the presence of known nutrient signalling molecules including α-gustducin [46] and T1R3 [47,48] within the gastric epithelium. Furthermore there is evidence to suggest that gastric glutamate can activate gastric vagal endings through a 5-HT and nitric oxide dependent pathway [49]. However, this study did not determine the physiological response in regards to gastric function or satiety, and therefore the physiological effect of glutamate on gastric vagal afferents remains to be conclusively determined. Results from other studies certainly support the notion that nutrient detection within the stomach is important for creating specific sensations. For example, an increase in intragastric pressure only results in increased satiety after intragastric infusion of nutrients [50]. So whilst a definite link between nutrient sensing in the stomach, activation of vagal afferents and changes in satiety remains to be established, it is likely that vagal function within the stomach is able to be modulated by nutrients.


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In terms of carbohydrates there is very little evidence available for a direct effect on GI vagal afferents. It has been demonstrated that increasing arterial glucose increases gastric vagal afferent discharge via inhibition of ATP sensitive potassium (KATP) channels [51]. In this study elements essential for glucosensing including glucose transporter 3 (GLUT3) and glucokinase (hexokinase IV) were identified in the nodose ganglia which when silenced resulted in an inability for glucose to excite isolated gastric nodose neurons [51]. However, whether glucose is acting directly on the nodose ganglia, as demonstrated previously [52], or on the afferent ending to produce the excitation remains to be determined conclusively. It should be noted that like protein and fat, carbohydrate has been shown to stimulate release of mediators such as glucagon-like peptide 1 (GLP-1) [53] and 5-HT [54] from cells within the intestinal epithelium. Therefore, luminal carbohydrate may be able to cause an indirect modulation of vagal afferents through release of such mediators. On top of inducing satiation, nutrients in the small intestine have recently been shown to induce an increase in thermogenesis in brown adipose tissue (BAT) via CCK mediated activation of local vagal afferent endings [55]. A single point mutation in uncoupling protein 1 (UCP1), which mediates the generation of heat in BAT causes a reduction in energy expenditure following a high fat, but not high carbohydrate meal [56]. Given that CCK is released preferentially by exposure to lipid rather than carbohydrate [38] it is likely that vagal afferents are involved in the increase in energy expenditure following a meal. This suggests that as well as being involved in controlling food intake, vagal nutrient sensing within the small intestine is also a regulator of energy expenditure. However, intestinal infusion of hypertonic NaCl also induces thermogenesis and increased energy expenditure through a mechanism that involves vagal afferents [57]. This suggests that both nutrient responsive and osmotic responsive fibers participate in vagal induced energy expenditure [58]. It has been demonstrated that the suppression of food intake by nutrient infusion into the stomach with an open pyloric cuff is greater than the suppression in food intake caused by gastric distension or intestinal nutrient exposure alone [59]. This indicates that both locations work together to cause a larger net reduction in food intake than either could on their own. An example of such a mechanism is CCK, which is released from the small intestine and has been shown to activate the same vagal afferents activated by gastric distension [60].

Leptin has been shown to reduce acute food intake in a manner that is not dependent on CCK action, but which requires intact vagal nerves [67]. However, the vagal pathway of leptin appears to be largely involved in short term regulation of food intake with disruption of vagal afferent signalling not disturbing food intake over a period of 4 h or greater [67,68]. Obesity has been shown to induce leptin resistance within the hypothalamus which abolishes the satiation inducing effect of leptin [69]. Shortly after this observation, leptin resistance was also reported to occur within vagal afferents at a point which precedes hypothalamic leptin resistance [70]. Furthermore, vagal afferent leptin resistance reduced the satiation inducing effect of CCK [71]. Within the stomach leptin has been shown to potentiate the mechanosensitivity of mucosal afferents in lean mice via a phospholipase C (PLC) mediated activation of TRPC1 channels [12]. However, in diet induced obese mice, leptin no longer potentiates mucosal receptors, but instead causes an inhibition of tension receptor mechanosensitivity via activation of large conductance calcium sensitive potassium (BKCa) channels [12]. Upon removal of the high fat diet and feeding with a standard chow diet for 12 weeks, obese mice enter a state where both the potentiation of mucosal and inhibition of tension receptors by leptin occurs concurrently, but both occur to a smaller magnitude than they did in the lean and obese mice respectively [72]. 4.2. Ghrelin

Whilst capable of spontaneous activity the signalling of vagal afferents within the GI tract are modulated or activated by an array of substances released from specialised cells within the GI tract which allows for rapid communication in response to GI tract activity. Below is an overview of a selection of mediators, located in specialised cells within the stomach and small intestine that alter the activity of vagal afferents. It cannot be stressed enough that this is in no way a comprehensive list or discussion of all modulators.

Ghrelin is a 28 amino acid peptide secreted from X/A cells within the gastric fundus [73]. It acts as an endogenous mediator of growth hormone release [74]. Ghrelin has also been shown to be expressed along the length of the GI tract; however the level of expression diminishes distally from the stomach [75]. The endogenous ghrelin receptor (GHS-R) has been detected centrally and also within the nodose ganglia and gastric vagal afferents [76]. It has been demonstrated that ghrelin causes an inhibition of vagal afferent firing [77,78], but within the jejunum, ghrelin has been shown to augment the vagal response to distension [78]. This suggests specific vagal afferent populations respond differently to ghrelin. However, the consequence of this inhibition is still being debated with some studies showing the orexigenic effect of ghrelin is mediated by vagal pathways [79], whereas others show the opposite [80]. Currently, there is some evidence suggesting that within the arcuate nucleus (ARC) ghrelin resistance occurs in obesity [81]. The fact that ghrelin still increases energy intake in obese humans [82] and that ghrelin blockade reduces food intake in diet induced obese mice [83] suggests that ghrelin must still be able to activate an orexigenic mechanism in the obese state. The inhibitory effect of ghrelin of gastric vagal afferents has been shown to be maintained and in fact broadened as in lean mice ghrelin only inhibits gastric tension receptors, whereas in obese mice ghrelin inhibits both tension and mucosal receptors [84]. The physiological relevance, in terms of food intake and gastrointestinal motility, of the observed increase in effect of ghrelin on gastric vagal afferents remains to be determined.

4.1. Leptin

4.3. CCK

Whilst the traditional source of leptin was the white adipocytes [61], it is now accepted that the stomach is also a source of leptin [62]. The long form of the leptin receptor (LepRb) has been identified on vagal afferent endings innervating the GI tract [12,63] suggesting that leptin may have a vagal modulatory role. This was confirmed in a series of studies which identified that leptin alone was able to activate cultured nodose 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 to cause a substantial reduction in food intake, an effect that was lost in vagotomised animals [66]. This suggested that the effect of leptin on acute food intake is mediated through a vagal pathway.

CCK is released from I-cells located largely within the proximal small intestine. The release of CCK is mediated by the presence of luminal nutrients, with a preference for the digestion products of amino acids and fatty acids rather than those of carbohydrates [38,85,86]. There is an abundance of evidence for CCK having a food intake modulatory effect, with its exogenous administration causing a reduction in food intake as well as a slowing of gastric emptying, both of which are lost after vagotomy [87,88]. The expression of CCK1R does not appear to be effected by acute nutritional changes (i.e. fasting) [89], but there are examples of upregulation in response to high fat diet feeding [90] although this is not consistently reported [91]. The ability for CCK to activate CCK1 receptors on vagal afferents is inhibited by the orexigenic

4. GI peptides as modulators of vagal activity



peptides ghrelin, orexin A and anandamide [76,92–94]. The ability for CCK to reduce food intake appears to be compromised in response to changes in nutrient composition [95]. This may be due to a reduced ability of CCK to activate intestinal vagal afferents as previously described in diet-induced obese mice [96]. A study by de Lartigue et al. demonstrated that only rats that became obese whilst on a high fat diet and not those that remained lean lost sensitivity to CCK [71]. This would suggest that obesity rather than the high fat diet reduced sensitivity to CCK in vagal afferent 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 digestion products of carbohydrates, fats and proteins [98,99]. Its release causes a decrease in food intake [100], stimulation of insulin release [101], reduction of glucagon secretion [102] and a reduction in gastric emptying [103]. GLP-1 can activate vagal afferents [104] and this is believed to be the mechanism responsible for its effects on insulin release and food intake [105]. However, there is some debate over whether the vagal pathway is the main effector pathway by which GLP-1 signals to the CNS. Subdiaphragmatic vagotomy has been shown to have no effect on the ability of GLP-1 to reduce food intake when administered into the hepatic portal vein, but when administered intraperitoneally (IP), subdiaphragmatic vagotomy abolishes the ability for GLP-1 to reduce food intake [106]. This has led to the suggestion that local and circulating GLP-1 may have different effector locations. GLP-1 receptor has been localised on the endings of vagal afferents [107], within the nodose ganglia [108] and on neurons within the dorsal vagal complex within the brainstem [109]. GLP-1 has been shown to cause an increase in gastric and jejunal vagal afferent activity [104,107]. The relevance of the action on gastric afferents is debatable as the half-life of bioactive GLP-1 in plasma has been reported to be as short as two minutes [110]. With no strong evidence suggesting that GLP-1 is produced in the stomach GLP-1 may not reach the stomach in sufficient concentration to activate the afferents. In terms of obesity there is no electrophysiological data showing whether there is a change in the ability for GLP-1 to activate vagal afferents. However, there is evidence that GLP-1 activates vagal afferents in lean rats [107,111]. GLP-1 receptor mRNA expression in the vagal nodose ganglia is decreased in response to chronic ingestion of a high fat diet in obesity prone rats [112] and this is accompanied by a reduction in the satiating effect of the GLP-1 receptor agonist exendin-4 [112]. Therefore, it could be hypothesised that GLP1 signalling in 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 levels in the proximal small intestine, increasing substantially in the ileum and even more into the colon [113]. The mechanism regulating the release of PYY from the proximal gut appears to involve both direct contact with luminal nutrients and also through CCK release in response to more proximal exposure to fat [114]. PYY release is also related to caloric load and is triggered by carbohydrate, fatty acid and to a lesser extent amino acid presence in the lumen [115]. Just like GLP-1, PYY is released from intestinal L-cells [116]. It acts to slow gastric emptying as well as promote satiation [117,118]. There are two endogenous forms of PYY [119]. Initially PYY is released as PYY1-36, however once in the circulation the first two amino acids are cleaved to form PYY3-36 , the major circulating type [120]. IP administration of PYY3-36 has been shown to have an anorectic effect in rodents [121], which is completely abolished by sub-diaphragmatic vagotomy [122,123]. The PYY receptor (Y2) has been identified on both intestinal vagal afferents [124] as well as neurons within the arcuate nucleus [125], indicating that PYY3–36 may elicit its anorectic effects through either a central, peripheral or a combination of pathways.

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A decrease in Y2 receptor expression in nodose ganglia of fasted rats and an increase in re-fed rats or fasted rats that have received an infusion of CCK has been reported [124]. This upregulation of the Y2 receptor is believed to be due to increased cocaine- and amphetamine-regulated transcript (CART) expression in response to CCK, with CART acting in an autocrine fashion to upregulate Y2 expression [92]. A blockade of the Y2 receptor has been shown to abolish the anorectic effects of PYY3–36 [126] and Y2 knockout mice exhibit hyperphagia and obesity highlighting the 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]. There is also reduced expression of Y2 receptors in vagal afferent neurons [71], which together suggests that in obesity there may be blunted intestinal satiety signals conveyed via PYY3–36. However, exogenous PYY3–36 still reduced food intake in obese mice [128]. It still remains to be determined whether obesity affects the ability for endogenous PYY to modulate food intake and whether the effect of PYY on vagal pathways is altered.

5. Circadian variation Like most physiological processes, food intake is highly regulated and shows strong circadian patterns with mice consuming the majority of their daily food within the active dark phase [130]. Most circadian functions are entrained by a central clock located in the suprachiasmatic nucleus (SCN) which in turn is entrained by exposure to light. Whilst the SCN can influence and drive eating behaviour [131] it is likely that there is another source of circadian drive as SCN lesioned rats are still entrainable to a feeding schedule [132]. A recent study has identified circadian expression of the molecular clock genes Per1, Per2, Bmal1 and Nr1d1 within the nodose ganglia of mice suggesting the existence of a peripheral neural clock [133]. Given the involvement of vagal afferents in controlling food intake it is not surprising that gastric vagal afferents exhibit profound oscillations in their mechanosensitivity which are inversely related to the amount of food present in the stomach [133]. Meal size in rodents varies dramatically between the light and dark phase with increased meal frequency and size during the dark phase [134]. The finding that gastric vagal afferent mechanosensitivity is reduced during the dark phase, when food intake is high in mice, provides a potential mechanism to allow this to occur. Activation of tension receptors by gastric distension has been shown to induce satiety [135], therefore, reduced responses to distension during the dark phase would allow for more food to be consumed before satiation is reached. Given that these oscillations were only seen in gastric afferents, independent of food intake or exposure to light, raises the possibility that the vagus can operate as an autonomous circadian food intake regulator. Whilst to our knowledge this is the first instance demonstrating a diurnal variation in the mechanosensitivity of vagal afferents it has previously been concluded that colonic sensory afferents also exhibit circadian variation in mechanosensitivity [136]. This study found that the pain response to colonic distension, mediated through a spinal afferent pathway, was greater during the dark phase than the light [136]. However, this study did not actually measure the afferent response to the colorectal distension, thus the variation observed may actually be caused by CNS mediated effects. Within the small intestine there is circadian variation in absorptive function [137]. However, information behind mechanisms is relatively scarce. It has been demonstrated that a number of key proteins oscillate in their levels of expression throughout the light dark cycle [138,139]. Furthermore, it has previously been reported that diurnal variation of mucosal transporter Peptide Transporter 1 (PEPT1) protein is abolished after a vagotomy, but there is still variation at the mRNA level [140]. This suggests that vagal signalling has a subtle yet profound modulatory effect on small intestine absorptive function.


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Given the involvement of the vagus in controlling gastric function and the now described phenomenon of circadian variation in their responsiveness it is likely that circadian variations in mechanisms including gastric emptying [141,142] and slow wave activity [143] are being at least 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 the GI tract are able to influence multiple processes both locally and systemically [144]. The type of bacteria within the GI tract is highly dynamic and can be influenced by factors including diet and stress. The gut microbiota have a vital role in breaking down substances which the human GI tract cannot [145]. Through this breakdown there is a well-documented formation of short chain fatty acids (SCFAs) [145]. These SCFAs can be absorbed by the host, however there is evidence that they can also interact with L-cells within the GI tract through the receptors GPR41 and GPR43 [146]. This could lead to an increase in the release of GLP-1 and PYY which can act on vagal afferents to increase satiety, as described earlier in Sections 4.4 and 4.5. One SCFA of interest is butyrate. Whilst the vast majority of bacterial fermentation production of SCFA occurs within the cecum and proximal colon there is evidence that butyrate is able to activate jejunal vagal afferents in a pathway that is distinct from that used by long chain fatty acids. Whilst long chain fatty acids such as oleate tend to activate vagal afferents via a CCK mediated mechanism, butyrate caused activation of extrinsic afferents despite blockade of L, N, P and Q-type calcium channels suggesting no involvement of neurotransmitter release from intrinsic neurons, smooth muscle action or enterochromaffin cells [147]. Thus it is possible that SCFAs such as butyrate may directly activate specific populations of vagal afferents after crossing the epithelium. However, if this is occurring, the actual mechanisms still needs further examination as no report has localised SCFA receptors such as GPR43 on vagal afferent endings within the jejunum. The actual physiological relevance of SCFA production via microbiota still needs to be determined, as for the most part the predominant site of SCFA production is the colon where it is used as fuel for the colonic epithelium and after metabolism within the liver there is very little systemic circulating butyrate [148,149]. This suggests a local site of action. There is vagal innervation of the colon, albeit to a lesser extent than the upper GI tract [15]. In addition, L-cells have been located in the colon [15,150]. Therefore SCFAs could act on vagal afferents in this region either directly or via action on L-cells. On top of producing nutrients, the gut microbiota also releases bioactive molecules some of which can cross the epithelium and act on a variety of tissues. One such molecule is the endotoxin lipopolysaccharide (LPS). The vagal afferent neurons within the GI tract express the receptor for LPS, toll-like receptor 4 (TLR4) [151]. Within cultured vagal neurons LPS treatment causes an increase in suppressor of cytokine signalling 3 (SOCS3) and a subsequent inhibition of leptin signalling through signal transducer and activator of transcription-3 (STAT3) [70], suggesting that microbiota can modulate the action of endogenous peptides. There is strong evidence demonstrating bacterial products including LPS have food modulatory effects with LPS administration causing substantial reductions in food intake [152]. However, the actual mechanism behind this modulation is yet to be conclusively determined. Intrajejunal lumenal LPS has been shown to increase Fos-positive cell number within the NTS without an accompanying increase in systemic LPS [153] suggesting that vagal afferents are the mechanism which conveys LPS signals from the gut to the brain. Similarly oral gavages of Campylobacter jejuni and Salmonella typhimurium in mice results in an increase in c-Fos immunoreactivity within the NTS, with complete ablation of this increase after capsaicin treatment, which disrupts vagal signalling [154]. However, what this activation actually means physiologically is uncertain as rats that have had a subdiaphragmatic vagotomy still show a reduction in food intake in response to IP LPS [155]. Electrophysiological studies have revealed that

LPS has the ability to cause a transient increase in jejunal vagal afferent mechanosensitivity as well as an increase in mesenteric afferent activity [156], supporting the theory of vagal afferents being involved in the transmission of microbiota induced signals. Consumption of a high fat diet has been demonstrated to elevate plasma LPS levels [157]. Furthermore, a high fat diet causes the development of an obese microbiota independent of weight gain as seen in diet induced obese prone and resistant rats [157]. Given that obesity is associated with a chronic low grade inflammation it is not surprising that there is an accompanying increase in systemic LPS. However, this increase, like the inflammation level, is relatively low when compared to an acute severe infection induced inflammation. This suggests that both obesity and a high fat diet are capable of leading to vagal plasticity through increased production of LPS as well as switching the resident microbiota which have different secretion and metabolic profiles [158–160]. 7. Conclusion Vagal afferents represent a highly plastic connection between the GI tract and the CNS. Much of the plasticity it exhibits is well suited to ensuring appropriate functionality especially in controlling the intake of food. However, it also appears to be a system which is exceptionally susceptible to disruption by conditions such as obesity and the plasticity observed with obesity appears to largely support the maintenance of adiposity through inhibition of peripheral satiety signals. Future studies within this area will no doubt determine the molecular mechanisms which drive these changes and will reveal ways of overcoming the adaptations which ultimately could establish a whole new set of peripheral targets for pharmacological treatment of obesity. Acknowledgements This manuscript is based on work presented during the 2013 Annual Meeting of the Society for the Study of Ingestive Behavior, July 30– August 3, 2013. References [1] Toouli J, Collins J, Wray N, Billington C, Knudson M, Pulling C, et al. Vagal blocking for obesity control. Obes Surg 2007;17:1043. [2] Andrews PLR, Sanger GJ. Abdominal vagal afferent neurones: an important target for the treatment of gastrointestinal dysfunction. Curr Opin Pharmacol 2002;2:650–6. [3] Hausken T, Svebak S, Wilhelmsen I, Haug TT, Olafsen K, Pettersson E, et al. Low vagal tone and antral dysmotility in patients with functional dyspepsia. Psychosom Med 1993;55:12–22. [4] Holtmann G, Goebell H, Jockenhoevel F, Talley NJ. Altered vagal and intestinal mechanosensory function in chronic unexplained dyspepsia. Gut 1998;42:501–6. [5] Hong D, Kamath M, Wang S, Tabet J, Tougas G, Anvari M. Assessment of the afferent vagal nerve in patients with gastroesophageal reflux. Surg Endosc 2002;16:1042–5. [6] Mizrahi M, Ben Ya'acov A, Ilan Y. Gastric stimulation for weight loss. World J Gastroenterol 2012;18:2309–19. [7] Agostoni E, Chinnock JE, Daly MDB, Murray J. Functional and histological studies of the vagus nerve and its branches to the heart, lung and abdominal viscera in the cat. J Physiol 1957;135:182–205. [8] Babic T, Browning KN. The role of vagal neurocircuits in the regulation of nausea and vomiting. Eur J Pharmacol 2014;722:38–47. [9] Browning KN, Travagli RA. Plasticity of vagal brainstem circuits in the control of gastrointestinal function. Auton Neurosci 2011;161:6–13. [10] Nonidez JF. Afferent nerve endings in the ganglia of the intermuscular plexus of the dog's oesophagus. J Comp Neurol 1946;85:177–89. [11] Berthoud HR, Blackshaw LA, Brookes SJH, Grundy D. Neuroanatomy of extrinsic afferents supplying the gastrointestinal tract. Neurogastroenterol Motil 2004;16:28–33. [12] Kentish SJ, O'Donnell TA, Isaacs NJ, Young RL, Li H, Harrington AM, et al. Gastric vagal afferent modulation by leptin is influenced by food intake status. J Physiol 2013;591:1921–34. [13] Rodrigo J, de Felipe J, Robles-Chillida EM, Perez Anton JA, Mayo I, Gomez A. Sensory vagal nature and anatomical access paths to esophagus laminar nerve endings in myenteric ganglia. Determination by surgical degeneration methods. Acta Anat 1982;112:47–57. [14] Berthoud HR, Powley TL. Vagal afferent innervation of the rat fundic stomach: morphological characterization of the gastric tension receptor. J Comp Neurol 1992;319:261–76.


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4 receptor agonist.

Stimulation of afferent vagal endings in the intrapulmonary airways by prostaglandin endoperoxide analogues.

Vagal afferent modulation of nociception.

Afferent sympathetic nerve fibres with aortic endings.

Circadian variation in gastric vagal afferent mechanosensitivity.

In vitro functional characterization of mouse colorectal afferent endings.

Ultrastructure of afferent axon endings in a neuroma.

Afferent sympathetic unmyelinated fibres with left ventricular endings in cats.

Excitotoxin-induced degeneration of rat vagal afferent neurons.

Vagal plasticity the key to obesity.

[Measurement method of vagal afferent and efferent activity].

Putative roles of neuropeptides in vagal afferent signaling.

Vagal afferent dysfunction in obesity: cause or effect.

Cytosolic calcium regulation in rat afferent vagal neurons during anoxia.

Structure of cells and nerve endings in abdominal vagal paraganglia of the rat.

Activation of intestinal spinal afferent endings by changes in intra-mesenteric arterial pressure.

Diabetes induces GABA receptor plasticity in murine vagal motor neurons.

Topography of efferent vagal innervation of the rat gastrointestinal tract.

Lack of effect of vagal afferent input on central neural respiratory afterdischarge.

Vagal afferent control of abdominal expiratory activity in response to hypoxia and hypercapnia in rats.

Presence of functional vasopressin V1 receptors in rat vagal afferent neurones.

Vagal afferent and reflex responses to changes in surface osmolarity in lower airways of dogs.

Central and peripheral vagal transport of cholecystokinin binding sites occurs in afferent fibers.

Conduction velocity along the afferent vagal dendrites: a new type of fibre.