Food Intake and the Vagus Nerve

Vagus nerve innervation
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The vagus nerve innervates various visceral organs [16]

The vagus nerve (CN X) is tenth among the twelve pairs of cranial nerves. Its projections exchange sensory and motor information with various visceral organ systems. A system of particular interest is the gastrointestinal system, which sends out vagal afferents and mediates the feeling of satiety in response to mechanical and chemical signals from the gut. Abnormal vagal excitability has implications in the lack of voluntary control over food consumption behaviours. Differential vagal activity is involved in satiety thresholds, obesity, and the perpetuation of the binge-purge cycle of bulimia nervosa[1]. Vagus nerve stimulation and vagotomy procedures have been associated with weight loss [2], demonstrating the significance of the vagus nerve in the treatment of obesity.

Vagal afferent satiety signalling

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Figure 1. Satiety signalling[3]

Vagal afferents from the gut become activated in response to gastrointestinal distension and neurotransmitters. Figure 1 illustrates a simplified explanation of how these peripheral afferents communicate with the central nervous system to mediate food intake and control[3]. After ingestion of a meal, chemical and mechanical signals from the gut activate vagal afferents which project to the nodose ganglion, the structure that contains the sensory cell bodies of vagal afferent neurons[4]. Afferent signals then travel to the medulla oblongata where they synapse onto the nucleus tractus solitarius (NTS). From there, axons to the dorsal motor nucleus of the vagus (DMV) signal satiety by projecting back to the gut. Fibres from the NTS also project to the medullary reticular formation and to the forebrain; these lead to motor control activity necessary to terminate eating and to the feeling of lasting satiety, respectively. There are also modulation projections that exist between the NTS and hypothalamus [3].

Gastrointestinal distension occurs in the presence of food in the gut, which stimulates both tactile-sensitive mucosal mechanoreceptors and stretch-sensitive tension mechanoreceptors[5]. This acts as a signal for vagal afferent mechanoreceptors to induce the feeling of satiety.

Vagal chemoreceptors respond to orexigenic gastrointestinal neurotransmitters, such as ghrelin, which act to stimulate food intake[6]. Anorexigenic gastrointestinal neurotransmitters, which inhibit food intake and thus act on vagal afferents to induce satiety, include cholecystokinin (CCK), 5-hydroxytryptamine (5-HT), glucagon-like peptide-1 (GLP-1), and peptide YY (PYY)[7][6].

Diet-induced changes in vagal sensitivity

Since the vagus nerve is crucial to satiety signalling, it must also be implicated in the high satiety thresholds seen in obese individuals. A diet consisting of high-fat foods has been shown to create physiological changes in vagal afferents, thus affecting satiety thresholds. High satiety thresholds lead to metabolically unnecessary increases in food intake, and ultimately obesity. Fasting and consumption of a high-fat diet have been shown to have similar effects on vagal mechanoreceptors and chemoreceptors; both cause a decrease in signalling that normally produces satiety[7][5]. This evidence provides a strong testimony for why a high-fat diet is not only unhealthy because of its direct effects on metabolic weight gain, but that it also leads to a hyperphagia and thus to the initiation, perpetuation and exacerbation of obesity.

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Figure 2. HFF mice have considerably more body and fat mass than LFF mice[7]

A 2011 study by Daly et al. was the first to provide direct evidence for altered sensitivity of vagal afferent neurons in diet-induced obesity. The evidence of previous studies has been indirect, as they only infer the effect of diet on vagal afferents from findings such as the apparent association between decreased levels of anorexigenic peptides and obesity[7]. The researchers of the present study examined the effects of a high-fat diet to vagal afferents isolated from the nodose ganglion, as well as those projecting specifically from the jejunum. The minimum electrical current required to trigger an action potential, referred to as rheobase, in nodose and jejunal vagal afferents of high-fat fed (HFF) mice was almost twice the amount required for low-fat fed (LFF) mice. Additionally, the number of action potentials fired at twice the rheobase level was about four times less in HFF mice than in LFF mice. Therefore, a high-fat diet leads to reduced membrane excitability of vagal afferent neurons. Compared to mice fed a low-fat diet, it takes an increased amount of stimulation to elicit the same neural response[7]. In other words, it takes more food to induce satiety in subjects exposed to a chronic high-fat diet than it does in low-fat fed subjects.

Altered response to mechanical stimulation

In line with the finding of reduced neuronal membrane excitability, a high-fat diet has been linked to a decreased response of vagal afferent mechanoreceptors to gastrointestinal distension. Recordings from afferents during induced distension of jejunal segments revealed significantly impaired responses of low-threshold mechanoreceptive afferents in HFF mice compared to responses in LFF mice[7]. Afferents responsive to low distension are of vagal origin while afferent responses to high distension are of spinal origin[8]. No difference was found between HFF and LFF mice in response to high distension, indicating that diet selectively affects vagal afferents[7].

Altered response to orexigenic and anorexigenic neuropeptides

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Figure 3. a) Labelled vagal afferent fibre; b) Labelled epithelial cells containing ghrelin;
c) Superimposed images of a) and b), demonstrating ease at which ghrelin is able to act
locally on vagal afferent fibres. [5]

The response of vagal afferent mucosal receptors has been found to be reduced similarly in fasted and HFF diet mice, due to the altered sensitivity to the orexigenic peptide ghrelin. Ghrelin in gastric mucosa epithelial cells is able to exert its orexigenic effects by acting on nearby vagal afferents (see Figure 3) [5]. The response to gastric distension by tension receptors is significantly reduced in both food-deprived and HFF mice. Obese subjects therefore do not respond adequately to mechanical satiety signals. Furthermore, the mucosal receptors of both fasted and HFF mice show significant reductions in responses to tactile stimulation following the introduction of ghrelin. Recall that tactile stimulation of mechanoreceptors acts as a signal to promote satiety, while the role of ghrelin is to promote food intake In the case of fasted and HFF mice, the activity of ghrelin overrides the sensitivity to mechanical stimulation; the sensitivity to ghrelin is enhanced, promoting food intake despite the presence of tactile signals[5]. There is, however, one difference between the increase in ghrelin sensitivity in HFF and food-deprived mice. In fasted mice, there is a marked increase in the expression of the ghrelin receptor GHS (growth hormone secretagogue), which can be found on gastric vagal afferents. This effect is not observed in HFF mice, so the effect of increased ghrelin receptor expression is specific to the occurrence of food-deprivation[5].

The response output of jejunal afferents in HFF mice to the anorexigenic neurotransmitters 5-HT and CCK is significantly reduced when compared to LFF mice. They also possess a considerably lower number of nodose neurons sensitive to 5-HT and CCK. Hence, in obese subjects the effects of satiety-mediating neurotransmitters are impeded due to both altered sensitivity and reduced target neurons[7]. The result is a further contribution to increased satiety thresholds and hyperphagia.

The importance of genetic susceptibility to obesity can also be demonstrated by the presence of orexigenic factor receptors that act on vagal afferents. Expression of these receptors in the nodose ganglion is increased only in HFF mice that have a susceptible genotype for obesity; HFF mice with the resistant phenotype did not exhibit such increase in receptor expression[9]. Thus, the development of obesity is not solely dependent on a diet’s fat content.

Binge-purge cycle of bulimia

The “vagal hypothesis” regarding bulimia nervosa[1] posits that the binge-purge cycle is due to an abnormal increase in vagal activity. In the early stages of the disorder, individuals voluntarily engage in binging and purging behaviours. Eventually these behaviours manifest uncontrollably and they become difficult to resist, due to the induced changes on vagal activity. Satiety thresholds become elevated and the act of vomiting becomes easier, hence the perpetuation of the binge-purge behaviours. Blockage of the 5-HT3 receptor by the serotonin antagonist ondansetron results in the inhibition of excitatory neuronal activity of the vagus nerve. In concordance with the hypothesis that the binge-purge cycle is contributed to by increased vagal activity, ondansetron has been shown to decrease the binge-purge symptoms of bulimia. In addition to the reduction of these symptoms after ondansetron treatment, satiety thresholds are normalized[1].

Treatment of obesity by vagal mechanisms

Vagal Block Therapy[15]

Vagotomy and vagal de-afferentation have been shown to reduce abdominal fat mass and weight gain in animal subjects[10]. However, human subjects who have undergone vagotomy usually only demonstrate a short-term decrease in appetite and weight loss[11].
A recently developed therapy known as VBLOC vagal blocking therapy makes use of implanted electrodes, which cause timed blocking of vagal activity. Clinical research findings have shown that this therapy is associated with safe loss of excess weight and lower satiety thresholds[11]. Effectiveness is proportional to the amount of time the device is in use[12].

Vagus nerve stimulation

As previously discussed, vagal membrane excitability is reduced in obese subjects. So, it is a logical assumption to make that perhaps stimulation of the vagus nerve should help to treat obesity. Vagus nerve stimulation (VNS) is normally used in the treatment of epilepsy and depression. The effects of VNS in obese humans is not conclusive however, as observations of weight loss have only been made from epileptic and depressed subjects[2]. Animal studies have shown that VNS leads to decreased weight gain, continually decreased food intake, and a reduction in preference for high-caloric foods[2][13]. Similar to the a finding in obese minipigs[2], VNS-treated human patients with depression show a selective decrease in craving for sweet foods[14]. This finding seems to be associated less with vagal fibres of the gastrointestinal tract and more with reward systems in the brain.

1. Faris, P. L., Eckert, E. D., Kim, SW., Meller, W. H., Pardo, J. V., Goodale, R. L., & Hartman, B. K. (2006). Evidence of a vagal pathophysiology for bulimia nervosa and the accompanying depressive symptoms. Journal of Affective Disorders, 92, 79-90.
2. Val-Laillet, D., Biraben, A., Randuineau, G. & Malbert C. H. (2010). Chronic vagus nerve stimulation decreased weight gain, food consumption and sweet craving in adult obese minipigs. Appetite, 55, 245-252.
3. Berthoud, HR. (2008). The vagus nerve, food intake and obesity. Regulatory Peptides, 149, 15-25.
4. Buyse, M., Ovesjö, M-L., Goïot, H., Guilmeau, S., Péranzi, G., Moizo, L., Walker, F., Lewin, M. J. M., Meister, B., & Bado, A. (2001). Expression and regulation of leptin receptor proteins in afferent and efferent neurons of the vagus nerve. European Journal of Neuroscience, 14, 64-72.
5. Kentish, S., Li, H., Philp, L. K., O'Donnell, T. A., Isaacs, N. J., Young, R. L., Wittert, G. A., Blackshaw, L. A., & Page, A. J. (2012). Diet-induced adaptation of vagal afferent function. The Journal of Physiology, 590, 209-221.
6. Dockray, G. J. (2009). The versatility of the vagus. Physiology & Behavior, 97, 531-536.
7. Daly, D. M., Park, S. J., Valinsky, W. C., & Beyak, M. J. (2011). Impaired intestinal afferent nerve satiety signalling and vagal afferent excitability in diet induced obesity in the mouse. The Journal of Physiology, 589, 2857-2870.
8. Booth, C. E., Shaw, J., Hicks, G. A., Kirkup, A. J., Winchester, W., & Grundy, D. (2008). Influence of the pattern of jejunal distension on mesenteric afferent sensitivity in the anaesthetized rat. Neurogastroenterology and Motility, 20, 149-158.
9. Paulino, G., de la Serre, C. B., Knotts, T. A., Oort, P. J., Newman, J. W., Adams, S. H., & Raybould, H. E. (2009). Increased expression of receptors for orexigenic factors in nodose ganglion of diet-induced obese rats. American Journal of Physiology - Endocrinology and Metabolism, 296, E898-E903.
10. Steams, A. T., Balakrishnan, A., Radmanesh, A., Ashley, S. W., Rhoads, D. B., & Tavakkolizadeh, A. (2012). Relative Contributions of Afferent Vagal Fibers to Resistance to Diet-Induced Obesity. Digestive Diseases and Sciences, 57, 1281-1290.
11. Camilleri, M., Toouli, J, Herrera, M. F., Kulseng, B., Kow, L., Pantoja, J. P., Marvik, R., Johnsen, G., Billington, C. J., Moody, F. G., Knudson, M. B., Tweden, K. S., Vollmer, M., Wilson, R. R., & Anvari, M. (2008). Intra-abdominal vagal blocking (VBLOC therapy): Clinical results with a new implantable medical device. Surgery, 143, 723-731.
12. Sarr, M. G., Billington, C. J., Brancatisano, R., Brancatisano, A., Toouli, J. et al. (2012). The EMPOWER Study: Randomized, Prospective,Double-Blind, Multicenter Trial of Vagal Blockade to Induce Weight Loss in Morbid Obesity. Obesity Surgery, 22, 1771-1782.
13. Banni, S., Carta, G., Murru, E., Cordeddu, L., Giordano, E., Marrosu, F., Puligheddu, M., Floris, G., Asuni, G. P., Cappai, A. L., Deriu, S., & Follesa, P. (2012). Vagus Nerve Stimulation Reduces Body Weight and Fat Mass in Rats. PLoS ONE, 7(9): e44813.doi:10.1371/journal.pone.0044813
14. Bodenlos, J. S., Kose, S., Borckardt, J. J., Nahas, Z., Shaw, D., O'Neil, P. M., & George, M. S. (2007). Vagus nerve stimulation acutely alters food craving in adults with depression. Appetite, 48, 145-153.
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