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. 2014 Dec 23;593(Pt 4):775–786. doi: 10.1113/jphysiol.2014.278226

The role of gastrointestinal vagal afferent fibres in obesity

Stephen J Kentish 1,2, Amanda J Page 1,2,3,✉
PMCID: PMC4398521  PMID: 25433079

Abstract

Gastrointestinal (GI) vagal afferents are a key mediatory of food intake. Through a balance of responses to chemical and mechanical stimuli food intake can be tightly controlled via the ascending satiety signals initiated in the GI tract. However, vagal responses to both mechanical and chemical stimuli are modified in diet-induced obesity (DIO). Much of the research to date whilst in relatively isolated/controlled circumstances indicates a shift between a balance of orexigenic and anorexigenic vagal signals to blunted anorexigenic and potentiated orexigenic capacity. Although the mechanism responsible for the DIO shift in GI vagal afferent signalling is unknown, one possible contributing factor is the gut microbiota. Nevertheless, whatever the mechanism, the observed changes in gastrointestinal vagal afferent signalling may underlie the pathophysiological changes in food consumption that are pivotal for the development and maintenance of obesity.

Introduction

Food intake is a highly regulated process that is normally effectively controlled to enable maintenance of a stable weight over relatively long periods of time. However, despite the usual effective control of food consumption there is an obvious predisposition to weight gain as demonstrated by the prevalence of obesity. Obesity at the most basic level is caused by an energy imbalance with energy consumption being greater than expenditure. However, whilst obesity is a very common condition, with the exception of known congenital conditions, our understanding of the mechanisms responsible for allowing the overconsumption of food and the subsequent development of obesity are largely unknown or in dispute. Gastrointestinal (GI) vagal afferents are a vital link between the GI tract and central nervous system (CNS). There is an abundance of vagal afferents present within the proximal GI tract which are responsible for monitoring and controlling GI function. The vagus constitutes an important pathway for the transmission of meal-related signals and is involved in the regulation of satiety and food intake. Emerging studies are increasingly showing dysfunction of vagal pathways and this is probably involved in the development and maintenance of obesity. This review will briefly outline changes that occur in food intake in obesity, and then focus on the vagal mechanisms that are disrupted in obesity and provide evidence suggesting that the vagus is an important pathway in the development of obesity. It should be pointed out that GI vagal afferents are involved in many different processes, not just regulation of food intake and satiety. However, this review will largely focus on possible contributions vagal afferents make in relation to food intake. Beyond the scope of the current review, but equally important in food intake regulation, are reward and emotional factors associated with external stimuli, such as palatable food, which influence regions in the CNS involved in the control of ‘hedonic’ feeding (Berthoud, 2011).

Changes in feeding behaviour in obesity

It has long been observed that obesity is accompanied by changes in food intake behaviour. Human studies have suggested that the primary changes are increased levels of snacking (Bertéus Forslund et al. 2002, 2005), increased portion sizes (Bertéus Forslund et al. 2002; Berg et al. 2009) and meal number (Bertéus Forslund et al. 2002). However, there are a number of inherent issues with the majority of human-based food intake studies. Firstly, with the exception of studies involving remote isolated populations or monozygotic twins it is almost impossible to control for genetic factors. Secondly, it would not normally be possible to observe the changes in food intake that occurred as the obesity developed. Finally, well-controlled long term food intake studies are very rare and as such most of the evidence comes from self-reported means including food diaries and surveys, which are prone to errors (Cook et al. 2000). In contrast, there are some very elegant data that have come from rodent studies that support the human data. Firstly, rats fed a cafeteria diet (suggested to be representative of the obesogenic foods humans consume) display long term increases in meal size, eating rate, total caloric increase and a transient increase in meal number (Rogers & Blundell, 1984). High fat diet-induced obese (DIO) rats are hyperphagic displaying an increase in meal size and eating rate, but no changes in meal number (Furnes et al. 2009), which suggests that there may be intricate differences between the impact in excess of specific macronutrients with regard to food intake patterns; however, an in depth discussion of this falls outside the scope of this review.

From both the human and rodent data available it becomes evident that, at least with respect to the change in meal size, there is a likely dampening in the response to food intake through a reduction in the ability to initiate satiety signals which helps to perpetuate and protect the obese state (Fig.1). This is supported by findings that obese humans can tolerate an increased level of intragastric volume before discomfort is felt (Geliebter, 1988). The major neural pathway by which gastric and small intestinal meal-related signals are transmitted to the CNS is through vagal afferents. The following is a description of the vagal connection between the GI tract and a selection of vagal afferent signals that are disrupted in obesity and how they may contribute to altered eating behaviour.

Figure 1. Maintenance of diet-induced obesity through a cycle of obesity, weight gain and impaired vagal signalling.

Figure 1

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Feeding of a palatable high fat diet induces excessive caloric intake (hyperphagia), which in turn causes an increase in weight and suppresses anorexigenic vagal satiety signals induced by mechanical stimuli or chemicals. This impaired vagal satiety signalling leads to continued hyperphagia and weight gain even in the absence of a palatable high fat diet, protecting and perpetuating the obese state.

The vagal gut–brain axis in food intake

The vagus has dense afferent innervation through the layers of the stomach and small intestine. The endings respond to mechanical and chemical (hormonal/nutrient/peptide) stimuli to initiate satiety signals as well as other modulatory effects (Fig.2). They project from the GI tract to activate neurons within the nucleus of the solitary tract (NTS; Gil et al. 2011). Activation of regions of the brain involved in the regulation of food intake, including the arcuate nucleus (Faipoux et al. 2008) and the paraventricular nucleus (Mönnikes et al. 1997), then occurs subsequent to NTS neuronal activation. Initial studies investigating the role of vagal afferents in the regulation of food intake utilised crude measures for disrupting vagal signalling, including vagotomies and ‘selective deafferentation’ using chemical compounds, most commonly capsaicin (Schwartz, 2000). However, there are distinct limitations for these approaches. The vagotomy could lead to different effects based on where the nerves are severed. This may explain why reports on the effects of vagotomy on body weight vary considerably, with some reporting a decrease in weight (Opsahl & Powley, 1977; Stearns et al. 2012), whilst others report no difference (Kanno et al. 2010) or even an increase (Andrews et al. 1985). With regard to the application of capsaicin, it has recently been demonstrated that capsaicin also destroys vagal efferent neurons (Browning et al. 2013). Thus capsaicin lesioning can be considered at best a vagal lesion, at worse a transient receptor potential vanilloid channel 1 (TRPV1)-positive neuron lesion. Regardless of the shortcomings these early studies reveal that GI vagal afferents are certainly involved in the regulation of food intake. The use of neurotrophin knockout mice has provided the opportunity to look at the role of subclasses of GI vagal afferents in the regulation of food intake. For example, neurotrophin-4-deficient mice have a loss of vagal intraganglionic mechanoreceptors in the small intestine (Fox et al. 2001). In these mice, although long-term food intake was unaltered, meal size and meal duration were significantly greater than control mice suggesting the short-term satiety signal from the GI tract is disrupted (Fox et al. 2001). Loss of neurotrophin-3 from smooth muscle also disrupts GI vagal afferent signals; however, in mice fed ad libitum there was no associated increase in meal size although there was an increase in the size of the first daily meal (Fox et al. 2013). In contrast, intestinal brain-derived neurotrophic factor knockout mice have increased intestinal vagal afferent density (Biddinger & Fox, 2014). Meal size and duration was diminished in these mice (Biddinger & Fox, 2014), implicating an involvement of GI vagal afferents in satiety signalling.

Figure 2. Schematic representation of vagal afferent innervation of proximal gastrointestinal tract.

Figure 2

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A, gastric vagal afferents can respond to the mechanical stimuli caused by the ingestion of food to initiate feedback signals to the central nervous system through the NTS. Peptides such as leptin and ghrelin produced in specific gastric cells can be released and modulate the response of gastric vagal afferents to mechanical stimuli. B, in the small intestine luminal nutrients cause the release of appetite regulatory peptides and neurotransmitters which can act directly on local vagal endings. Together with the gastric afferents these signals can modulate a number of processes such as motor functions, satiety and food intake.

Diet-induced obesity changes gastrointestinal vagal afferent responses to mechanical stimuli

Classically it was suggested that mechanoreceptors within the stomach were the only means that the stomach had to send afferent signals to the brain; therefore the majority of the work on gastric vagal signalling has focused on the responses to mechanical stimuli such as distension (Fig.2A). There have been elegant studies which have characterised the morphology and response of gastric vagal mechanoreceptors to mechanical stimulation (Iggo, 1955; Cervero & Sharkey, 1988; Page et al. 2002). The consumption of food would exert a substantial mechanical presence which causes distension of the stomach and is perceived centrally with well-characterised feelings of fullness and satiety (Wang et al. 2008). Discrete populations of both gastric and small intestinal vagal afferent fibres have been demonstrated to respond to distension. Furthermore, in high fat DIO mice vagal afferents within the stomach (Kentish et al. 2012) and jejunum (Daly et al. 2011) have reduced abilities to respond to distension. Such reductions in the ability to detect distension may impair the satiety signals generated, particularly within the stomach. As such an isovolumetric meal will exert a smaller satiety signal, which in turn could lead to the consumption of a larger meal before satiety is perceived (Fig.1). This is consistent with the increased meal size observed in both obese humans and rodents (Westerterp-Plantenga et al. 1996; Furnes et al. 2009). Although there is reduced neuronal excitability in chronic high fat diet conditions (Daly et al. 2011), the precise mechanisms responsible for the change in mechanosensitivity have yet to be fully elucidated. Preliminary work from our group has suggested that it probably involves alteration in the action of TRPV1. In standard laboratory diet fed TRPV1 knockout mice there is a reduction in the mechanosensitivity of gastric vagal tension receptors to the same level observed in the wild-type high fat DIO mice (Bielefeldt & Davis, 2008; Page et al. 2013) (Fig.3A). These knockout mice also exhibit an increase in food consumption (Page et al. 2013), possibly due to the reduced vagal response to distension. Furthermore, there is no additional reduction in the mechanosensitivity of these afferents in DIO (Page et al. 2013). However, this is only a possibility that requires future investigations.

Figure 3. Involvement of TRPV1 channels and endocannabinoids in the vagal signalling.

Figure 3

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A, genetic knockout of TRPV1 reduces the gastric vagal afferent response to stretch. B, typical trace illustrating that application of cannabinoid receptor 1 (CB1) agonist WIN55,212-2 reduces the response of gastro-oesophageal vagal afferents to mechanical stimulation indicating a potential ability for endocannabinoids to act via CB1 to reduce vagal satiety signals. C, schematic diagram demonstrating that endocannabinoids such as anandamide are able to freely diffuse into cells and activate TRPV1 channels, whilst also being able to activate CB1 receptors, which can inhibit TRPV1 channels. Endocannabinoids that have crossed the cell membrane will eventually be bound to fatty acid binding protein (FABP), which then shuttles to the endoplasmic reticulum where the endocannabinoid is hydrolysed by fatty acid amide hydrolase (FAAH).

It is interesting to note that a similar reduction or change in the response of gastric vagal afferents to mechanical stimuli and appetite-regulating peptides (discussed in a later section) occurs in both DIO and acutely fasted mice (Kentish et al. 2012, 2013a). This suggests that something in the development of obesity is triggering a potential perception of a perpetual fasted state irrespective of the abundance of energy stores.

Little has been done to identify whether the changes in mechanosensitivity of GI vagal afferents to mechanical stimuli is a cause or effect of obesity and whether it is the high fat content of the diets they were exposed to. Future studies are urgently needed to address this issue. However, we have previously presented evidence that the reduction, at least in gastric vagal afferent mechanosensitivity, is preserved after the removal of the high fat diet for 12 weeks (Kentish et al. 2014). Whilst these mice could only consume a much lower fat and calorie-dense chow diet they exhibited a marked increase in the volume of food consumed such that they were consuming equal calories compared to mice that were being fed a high-fat diet (Kentish et al. 2014). The observed hyperphagia resulted in the regain of weight lost as a result of the diet change. This highlights that disruption to vagal afferent signalling is resistant to being restored by simple dietary change and may represent a mechanism that contributes to a reduction in satiety signalling in obesity serving to both maintain and defend the obese state (Fig.1).

Diet-induced obesity changes gastrointestinal vagal afferent responses to chemical stimuli

The release and response of GI vagal afferents to appetite-regulating hormones from the GI tract varies depending on the site of action. In general, appetite hormones released from the stomach modulate gastric vagal afferent responses to mechanical stimuli whereas in the small intestine the hormones directly activate vagal afferent endings. Both the modulatory and direct effects of these hormones on GI afferents form part of a balance between food intake-promoting and -inhibiting signals. For example the only endogenous peripheral orexigenic peptide, ghrelin, is produced predominantly within the stomach (Seim et al. 2012). It has been suggested that ghrelin's main role is to initiate food intake and meals, as its levels rise with periods of fasting, such as between meals, and its levels quickly decrease after food consumption (Cummings et al. 2001). Both central and peripheral vagal sites of action have been demonstrated to be involved in the effect of ghrelin on food intake (Date et al. 2002). However, one study has demonstrated that ghrelin still increases food intake after a vagotomy (Arnold et al. 2006) casting doubt on the vagus being the primary pathway for its orexigenic action. This study appears to be in isolation, with peripheral ghrelin administration in vagotomised mice, rats and humans having no effect on food intake (Asakawa et al. 2001; Date et al. 2002; le Roux et al. 2005). Thus, whilst there is some controversy about the importance of the vagus in the orexigenic effect of ghrelin, the majority of the literature does support its involvement.

Opposing the function of ghrelin is the well-studied anorexigenic peptide leptin. Leptin, which is predominantly released from white adipose tissue, is also produced within the stomach (Bado et al. 1998; Cinti et al. 2001). Gastric leptin is released in response to food intake suggesting that it is involved in generating a post-prandial food intake termination signal (Bado et al. 1998). Thus, a similar model to ghrelin and leptin acting in balance to regulate food intake by acting on the arcuate nucleus may exist in gastric vagal afferents. Both leptin- and ghrelin-containing gastric epithelial cells have been shown to be located close to vagal afferent endings (Kentish et al. 2012, 2013a), which suggests a potential in vivo functional relationship between local sites of production and action. In support of this, ghrelin causes an inhibition of gastric vagal afferent firing in response to mechanical stimulation, specifically tension-sensitive afferent responses to stretch (Murray et al. 2006; Page et al. 2007). In contrast, leptin causes a potentiation of mucosal vagal afferent mechanosensitivity (Kentish et al. 2013a). Both of these modulations are supportive of ghrelin and leptin utilising local vagal afferent endings to increase or reduce food intake, respectively.

The vagal route for acute food intake regulation by leptin is supported by infusion of leptin into the proximal GI tract blood circulation reducing acute sucrose intake, whereas central administration had no effect (Peters et al. 2006). This suggests that the acute effect of leptin on food intake is probably due to its ability to activate or modulate the activity of vagal afferents (Wang et al. 1997; Gaige et al. 2002). Additionally, recent evidence indicates that selective knockout of the leptin receptor in visceral afferents (including vagal afferents) causes hyperphagia and leads to increased weight gain further affirming that vagal leptin signalling is important in the regulation of energy homeostasis (de Lartigue et al. 2014).

In obesity it has been proposed that there is central ghrelin (Briggs et al. 2010) and leptin resistance. However, ghrelin still increases energy intake in obese humans (Druce et al. 2005) and vagal afferent expression of the ghrelin receptor is increased in DIO rats (Paulino et al. 2009). This suggests that there is the capacity for maintained or even increased ghrelin signalling through vagal pathways in obesity. We have shown that the vagal modulatory action of ghrelin is increased in high fat DIO, with mucosal afferents becoming sensitive to the inhibitory effect of ghrelin, in addition to the tension receptors (Kentish et al. 2012). This increase in vagal afferent inhibition has the potential to increase the potency of the effect of ghrelin on food intake through a vagal pathway.

On the other hand it has been suggested, in addition to the proposed central resistance, that vagal afferents also become leptin resistant (de Lartigue et al. 2012). However, we have previously reported that DIO causes a switch in the effect of leptin; in lean mice leptin potentiates the mechanosensitivity of gastric vagal mucosal mechanoreceptors, in DIO mice leptin has no effect on mucosal receptors, but instead causes an inhibition of tension-sensitive mechanoreceptors (Kentish et al. 2013a). The discrepancy between these finding may be explained by the mechanism by which de Lartgiue et al. (2012) defined leptin activation. Their study used the commonly accepted method of measuring phosphorylation of the signal transducer and activator of transcription (STAT) 3 protein (de Lartigue et al. 2012), which is integral in the well-defined Janus kinase (JAK)/STAT pathway of leptin action. However, we demonstrated that the effect of leptin on gastric vagal afferents involved the activation of phosphoinositide 3-kinase (PI3K) (Kentish et al. 2013a). Previously, it was shown that leptin-induced activation of PI3K in pro-opiomelanocortin (POMC) neurons does not require STAT3 phosphorylation (Xu et al. 2005). Thus, it is possible that using STAT3 phosphorylation as a sole marker of activation could lead to a false assumption of loss of receptor pathway activation. Alternatively, given that gastric vagal afferents, specifically tension-sensitivity afferents, represent a minority of the total nodose population it is likely that alterations in the activity of this discrete population of neurons would be missed when looking at the whole population of neurons. As an aside, the latter is a common issue as there seems to be widespread assumption that changes in the whole vagal afferent population are representative of signals involved in specific processes such as the regulation of food intake. It is almost impossible to believe that neurons of vagal afferents innervating the lungs or heart will behave the same as those from the GI tract.

Given that obesity is associated with increased circulating leptin in both humans and rodents (Dagogo-Jack et al. 1996; Kentish et al. 2013b), and that leptin can inhibit the response of tension-sensitive vagal afferents (Kentish et al. 2013a), this suggests that at least with regard to gastric vagal afferent signalling leptin has the potential to act as an orexigenic signal. Whilst specific experiments to evaluate this need to be performed, mice lacking the leptin receptor only in visceral afferents exhibit a significantly lower body weight when fed a high fat diet compared to wild-type counterparts (de Lartigue et al. 2014). This suggests that leptin signalling in vagal afferents probably has the ability to encourage hyperphagia and weight gain. Unfortunately, this study did not present data on the food intake of these conditional knockout mice when being fed the high fat diet, so an actual cause of the lower body weight still needs to be determined. Centrally, leptin has been reported to depolarise neuropeptide Y/Agouti-related peptide/GABA neurons of the arcuate nucleus of postnatal mice, which would support an orexigenic action for leptin (Baquero et al. 2014). This depolarisation is lost and replaced by a hyperpolarisation in perinatal mice (Baquero et al. 2014). Together there is mounting evidence which suggests that classical anorexigenic peptides, such as leptin, have the ability to act in an opposite fashion under specific physiological situations.

Within the small intestine appetite hormones appear to exhibit nutrient-specific release and function, consistent with the small intestine being the predominant site of food digestion and nutrient absorption. All known peptides released from the small intestine have been shown to be anorexigenic, which, considering their release is triggered by nutrients, is a logical relationship. Cholecystokinin (CCK) is a peptide released from I cells primarily within the duodenum and proximal jejunum. Its release is mediated through the presence of luminal nutrients (Fig.2B) with a preference for digestion products of amino acids and fatty acids rather than those of carbohydrates (Rehfeld, 1978; Cummings & Overduin, 2007; Liou et al. 2011). Peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) are thought to be predominantly released from the ileum, although GLP-1 is also present in the duodenum and proximal jejunum suggesting that release of GLP-1 may have an effect throughout much of the small intestine (Kuhre et al. 2014). GLP-1 release like CCK is triggered by luminal fatty acids; however, carbohydrate and amino acids are also potent regulators of GLP-1 release.

CCK, PYY and GLP-1 have all been shown to increase vagal afferent activity and reduce food intake. The CCK receptor (CCK1R), PYY receptor Y2 and GLP-1 receptor GLP-1R have all been shown to be expressed in the nodose ganglia, which suggest they have the potential to act directly on vagal afferents. However, no study has sought to map the distribution of the receptor-positive endings to particular regions of the GI tract and this is something which needs to be addressed. The ability for these peptides to reduce food intake are lost after a vagotomy, suggesting that vagal afferents are the primary anorexigenic pathways for CCK, PYY and GLP-1 (Sullivan et al. 2007; Brennan et al. 2008). However, in addition to termination of vagal afferent signalling, vagotomy exerts a number of physiological effects, including the termination of vagal efferent signalling, which could also influence food intake. Of significance is that these anorexigenic–vagal afferent signalling pathways are compromised to varying degrees in high fat DIO.

In high fat DIO mice there is reduced ability of CCK to activate intestinal vagal afferents (Daly et al. 2011) and reduce food intake suggesting that the loss of the anorexigenic effect of CCK is due to a loss of its vagal activation ability. This is supported by studies investigating the effect of exogenous CCK on vagal afferent activation of neurons in the NTS and area postrema. Induction of Fos (a marker for neural activation) immunoreactivity within these regions in response to exogenous CCK is reduced in high fat DIO rats (Covasa et al. 2000). In addition, the CCK-induced reduction in food intake was attenuated (Covasa & Ritter, 1998; Covasa et al. 2000). The mechanism(s) behind the reduction in CCK-induced satiety is not clear. However, expression of CCKR1 in the nodose ganglia is reduced in DIO, but not DIO-resistant rats (Duca et al. 2013b). Furthermore, there is a reduced lipid-induced release of CCK from the small intestine and a reduced potency for CCK to reduce food intake in high fat DIO but not high fat DIO-resistant rats (Duca et al. 2013b). Together these data suggest that the accumulation of adiposity and not the high intake of fat is responsible for impaired CCK satiety signalling observed in obesity.

In obese humans there is a reduction in post-prandial release of PYY, which is accompanied by an increase in calories required to reach satiation (Meyer-Gerspach et al. 2014). DIO rats also exhibit reduced plasma PYY (Rahardjo et al. 2007). There is also a reduction in Y2 receptors in vagal afferent neurons of obese rats (de Lartigue et al. 2012), which together suggest that in obesity there may be blunted intestinal satiety signals conveyed via PYY. However, exogenous administration is still able to reduce food intake in obese mice (le Roux et al. 2006). Thus, whether the endogenous role of PYY acting on vagal afferents is truly compromised due to the impaired release still remains to be conclusively determined.

Similar to PYY, exogenous GLP-1 can still reduce food intake, but there is also a reduction in nodose ganglia GLP-1R and proximal intestine GLP-1 content in DIO rats (Näslund et al. 1999; Duca et al. 2013a). Furthermore, a reduction in GLP-1 receptor expression has been linked with a reduced ability for the GLP-1 analogue, extendin-4, to reduce food intake (Duca et al. 2013a). Thus, if vagal afferent activation is the major pathway by which GLP-1 reduces food intake it is likely that this ability is compromised in obesity. However, whether the high fat intake or the increased adiposity of the rats is responsible for the observed changes in GLP-1 action remains to be determined.

In conclusion, it is likely that changes in the effect of small intestinal peptides on food intake are, at least in part, due to altered small intestinal vagal afferent signalling. However, the importance of this signalling pathway compared to the central effects of these hormones remains to be determined.

Whilst many chemical mediators from the GI tract are peptides there are other chemicals which play potentially very important roles in food intake regulation, including endocannabinoids. Exogenous cannabinoids such as Δ9-tetrahydrocannabinol (Δ9-THC) have long been observed to have potent orexigenic effects (Williams et al. 1998). Such effects lead to the development of cannabinoid (CB) receptor antagonists and inverse agonists including rimonabant as potential anti-obesity therapies (Christopoulou & Kiortsis, 2011). Whilst it has now been removed from the market rimonobant did show a modest weight loss effect, illustrating that the cannabinoid system is involved in regulating food intake and weight (Curioni & André, 2006). There is a high density of CB receptors within the brain, particularly CB1 in hedonic centres (Mahler et al. 2007), the brain stem where they are involved in modulation of vagal neurocircuit functions (Partosoedarso et al. 2003; Van Sickle et al. 2003; Derbenev et al. 2004, 2006) and the gastrointestinal tract (Lin et al. 2013). However, of importance for this review it has also been demonstrated that CB1 is present within the nodose ganglia (Paulino et al. 2009).

Peripheral endocannabinoid signalling has been demonstrated to be of significance in the control of food intake and weight gain with centrally administered rimonabant having no effect on food intake (Gomez et al. 2002). Furthermore, the orexigenic effects of cannabinoids and the anorexigenic effect of rimonabant are lost after capsaicin treatment (Gomez et al. 2002). This supports the notion that peripheral, probably vagal, cannabinoid signalling is important in the overall regulation of food intake. This was further substantiated by a report that administration of a CB1 receptor antagonist, unable to cross the blood–brain barrier, reduced food intake and body weight in genetic leptin-deficient obese ob/ob mice (LoVerme et al. 2009). Preliminary data from within our group indicate that the CB1 agonist WIN55,212-2 causes an inhibition of both gastric tension and mucosal vagal afferents (Fig.3B) (A. J. Page & L. A. Blackshaw, unpublished observations), which further supports vagal afferents as an orexigenic pathway for endocannabinoids.

In DIO rats there is an increase in expression of CB1 in the nodose ganglia (Paulino et al. 2009), which could lead to increased endocannabinoid-induced food intake. GI endocannabinoid levels are also altered with consistent reports of increased 2-arachidonoylglycerol in DIO (Izzo et al. 2009) and reports of both increased and decreased levels of anandamide (AEA). If vagal CB1 receptors are involved in the regulation of food intake the increase in CB1 receptors itself may be sufficient to increase food intake independent of the presence of a ligand as the CB1 receptor has been shown to be constitutively active (Fioravanti et al. 2008).

Whilst there is favourable evidence for vagal pathway-mediated endocannabinoid signalling in the regulation of food intake there are also caveats which cast doubt on the paradigm. In rats and mice which had undergone a subdiaphragmatic vagotomy, rimonabant reduced the intake of both chow and a highly palatable diet (Ensure) (Madsen et al. 2009). Secondly, selective vagal CB1 knockout mice exhibit normal body weight and respond similarly to the administration of CB1 inverse agonists in terms of food intake and body weight (Vianna et al. 2012). Together this suggests that vagal CB1 signalling may not be of physiological significance in terms of regulation of food intake (Vianna et al. 2012). However, the CB1 vagal knockout mice did show increased GI motility, suggesting that GI endocannabinoids probably use a CB1 vagal pathway to regulate motility (Vianna et al. 2012).

It is worth noting that, in addition to being ligands for the CB1 and -2 receptors, endocannabinoids, including AEA, are modulators for TRPV1 channels which are also expressed in vagal (as well as other sensory) neurons (Horie et al. 2005). Activation of these channels through administration of exogenous agonists such as capsaicin has an anti-obesity effect in rodents (Zhang et al. 2007). In humans, consumption of red pepper (a source of capsaicin) along with caffeine significantly reduced energy intake (Yoshioka et al. 2001). Therefore, it is plausible that TRPV1 may play a role in regulating food intake, but to date the data on the role of TRPV1 in the regulation of food intake is limited (Ahern, 2013).

AEA can both activate and inactivate TRPV1 channels (via CB1) (Fig.3C), thus resolving the importance of these channels in general and specifically on vagal afferents in modulating food intake is not clear. It is likely that the net effect of endocannabinoids on cells is dependent on the presence of CB1 and the rate at which endocannabinoids are shuttled by fatty acid binding protein (FABP) to the endoplasmic reticulum to be hydrolysed by fatty acid amide hydrolase (FAAH) (Fig.3C). However, given the orexigenic nature of AEA and the fact that CB1 is highly expressed in vagal afferents it is likely that if vagal TRPV1 channels are involved in the food modulatory effect of endocannabinoids AEA would have an overall inhibitory effect on TRPV1.

Interactions between the gut microbiota and gastrointestinal vagal afferents in health and obesity

Recent attention has focused on the role of the gut microbiota in obesity. The microbiota comprises a highly dynamic range of bacteria that can be influenced by factors such as diet and stress. It has an important role in breaking down substances which the human GI tract cannot (Kau et al. 2011). Through this breakdown there is formation of short chain fatty acids (SCFAs) (Kau et al. 2011). There is evidence that SCFAs can act on G-protein receptor (GPR)41 and GPR43 on L-cells within the GI tract (Tolhurst et al. 2012) which could lead to release of GLP-1 and PYY that can subsequently act on vagal afferents to increase satiety, as described earlier. Of interest is the SCFA butyrate which can directly activate jejunal vagal afferents (Lal et al. 2001). The 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 (Bergman, 1990; Roy et al. 2006), suggesting a local site of action. There is vagal innervation of the colon (Berthoud & Powley, 1992) and, in addition, L-cells have been located in the colon (Berthoud & Powley, 1992; Hansen et al. 2013). Therefore SCFAs could act on vagal afferents in the colon either directly or via action on L-cells.

In addition to nutrient production, the gut microbiota also releases bioactive molecules, some of which can cross the epithelium. Endotoxin lipopolysaccharide (LPS) is one such molecule and vagal afferent neurons within the GI tract express the receptor for LPS, toll-like receptor 4 (TLR4) (Hosoi et al. 2005). Within cultured vagal neurons LPS treatment inhibits leptin signalling (de Lartigue et al. 2011), suggesting that the microbiota can modulate the action of endogenous peptides. There is strong evidence that bacterial products, including LPS, have food modulatory effects with LPS administration causing reductions in food intake (Aubert et al. 1997). However, the actual mechanism behind this modulation has yet to be determined. 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 (Liu et al. 2007), supporting the theory that vagal afferents are involved in the transmission of microbiota-induced signals.

Plasma LPS levels are elevated after consumption of a high fat diet (de La Serre et al. 2010). Furthermore, a high fat diet causes changes in the resident gut microbiota (de La Serre et al. 2010). Given that obesity is associated with a chronic low grade inflammation it is not surprising that there is an accompanying increase in systemic LPS. 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 (Cani et al. 2007a,b; Murphy et al. 2010).

Conclusion

It is becoming abundantly clear that the ability of GI vagal afferents to signal is vastly disrupted in obesity. Based on the evidence currently available it appears that obesity causes an increase in orexigenic and a decrease in anorexigenic signalling capacity. Given how concerted these changes are they probably serve a purpose for encouraging the acquisition or maintenance of increased weight. Currently much of the work is either too broad or too focused and there is very little which allows conclusive links to be drawn from molecular changes to signalling changes and ultimately to behavioural changes. This is the biggest challenge because unless we get a conclusive idea about how a system works, not just in isolation, but in an already compromised environment, then establishing viable targets for the treatment of obesity is difficult. However, for now we believe it is most likely that obesity is characterised by changes both at the level of the primary site of sensory detection, at the peripheral vagal afferent ending, and also at the level of information integration within the CNS, which together create the stubborn condition of obesity.

Glossary

Abbreviations

AEA

anandamide

CB

cannabinoid

CCK

cholecystokinin

DIO

diet-induced obesity

GI

gastrointestinal

GLP-1

glucagon-like peptide 1

LPS

lipopolysaccharide

NTS

nucleus of the solitary tract

PYY

peptide YY

SCFAs

short chain fatty acids

TRPV1

transient receptor potential vanilloid channel 1

Biography

Inline graphic A/Prof Amanda Page is senior researcher and group leader of the Vagal Afferent Research Group. Dr Stephen Kentish is a National Health and Medical Research Council Early Career Fellow. They both work at the Centre for Nutrition and Gastrointestinal Diseases, University of Adelaide where they have made major contributions in the development of current concepts in gastric vagal afferent satiety signalling in health and obesity. This includes pioneering studies on the phenotypic specialisation of vagal sensory endings: a classification that has been adopted worldwide and extended to other regions of the gut, and innovative approaches to demonstrate that satiety signals originating in the stomach can be modulated by appetite hormones including leptin and ghrelin. Together, these studies have highlighted the importance of the stomach in the regulation of food intake, the complex interplay between appetite hormones and vagal afferent activity and the changes that occur in high fat diet-induced obesity

Additional information

Competing interests

None declared.

Funding

The Australian National Health and Medical Research Council (NHMRC) and the Australian Research Council (ARC).

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