Abbreviations: vagal nerve stimulation (VNS), cholecystokinin (CCK), gamma amino butyric acid (GABA), gastrointestinal (GI), peptide YY (PYY), nitric oxide (NO), positron emission tomography (PET).



INTRODUCTION
The vagus nerves contain major sensory fibers innervating the organs of thoracic and abdominal cavities. Afferent fibers of this nerve are integral part of the brain-gut axis, which take part in feedback loop controlling food intake induced by presence of food in gastrointestinal tract (1). The vagal afferent system detects gastrointestinal events in the periphery and generates appropriate autonomic, endocrine, metabolic and behavioral response. Electrophysiological recording studies identified mechano-, chemo-, osmo- and temperature-receptors. Possibility of food intake control by neuromodulation of the vagus nerve activity is actually considered and seems to be promising (2-4). The vagal nerve endings in upper GI tract are partially responsible for visceral sensation and are activated by different physical and chemical stimuli (5, 6). Duodenal receptors are sensitive predominantly to chemical stimuli and spontaneously inactive and react mostly in "on-of" system (6). The nerve itself is merely a cable receiving and conducting information in the form of electrical impulses from peripheral interface to its central representation (interface) in the brain (7, 8). The presence of food in duodenum elicits specific postprandial motility and secretion modifying interdigestive vagal discharge. The chemical content of the food is most likely differentiated by duodenal vagal chemoreceptors, whereas the size of the meal and induced motility changes stimulate mechanoreceptors of all upper GI tract (7). Actual studies pointed out mostly superiority of meal size (pressure factor) over its chemical content in inducing satiety feeling, however, this action was not definitely proved (9, 10). It seems to be possible that not only the size, but also meal composition influence food intake (11). Clear and different afferent discharge in the vagus nerve resulted in the presence of chemically distinct food in the duodenum (6). The importance of hepatic glucoreception in food intake regulation is not yet clear and needs further studies. One study showed that the alimentary behavior of rats after surgical liver denervation remains unchanged (12). Others suggest important role of hepatic vagal branch dysfunction in development of obesity in diabetics (13).

The presence of unique chemoreceptors in the stomach was not proved. These units are mostly polymodal in the rat and other species (14-16). Products of triglyceride digestion given to the rat stomach inhibit food intake via release of cholecystokinin (CCK), which in turn acts on vagus nerve sensory endings (17-19). Expression of bitter taste receptors of the T2R family in the gastrointestinal tract not only in duodenum, but also in the rat stomach has been reported (20). It is thought that presence of protein G (alfa-gustducin) in taste cells is associated with induction of taste signal, which in turn affects food intake inhibition. Ligand for taste receptor, which is simply food, triggers binding GTP to alfa-gustducin and subsequently stimulates production of second messenger. In the inner layer of stomach epithelium and gut this protein expression was reported. It may indicate potential role also gastric chemoreception in food intake (21). CCK and leptin potentiate subsequent responses to distending loads causing receptor sensitization and increasing afferent vagal traffic more than either load alone or peptide stimulations alone (22).

Satiety hormones are secreted by digestive tract in low concentrations and partially uptaken by the liver. Vagal nerve terminations have receptors for some of these hormones, as PYY (23), CCK (24) and leptin (25). This hormone-nerves transduced vagal satiety information can be effectively transmitted by afferents to control food intake via the brain-gut axis. Activation of feedback loop of this axis seems to be done by food stimuli in the following sequence: size of meal in upper GI tract, its chemical content in duodenum (transduction) and activation of hepatic glucoreceptors. Sensory information collected form peripheral interface is most likely coded in quantitative and qualitative pattern and sequence of afferent vagus nerves discharge. Integrated patterns of prandial and postprandial impulsation remain to be decoded.

RAT STUDIES
Direct electrical stimulation of the ventromedial hypothalamic nuclei enhances both fat utilization and metabolic rate, which has been shown to accompany the inhibition of feeding behavior in laboratory animals (26). Vagal nerve stimulation (VNS) is much easier for safe access and for indirect than direct stimulation of satiety center. Vagal nerves contain approximately 95% of afferent and only 5 % of efferent fibers (27). Afferent signals travel in vagal nerve fibers from mechanoreceptors and chemoreceptors, which are activated by the presence of nutrients in the stomach and in the proximal small intestine that are involved in meal termination. Nutrients arriving via the portal vein may also trigger vagal afferent signals from the liver (28). All of these signals are projected to the nucleus tractus solitarius (NTS), which remains in close relationship with the arcuate nucleus (ARC). ARC has been implicated in the control of feeding behavior due to activation of neurons releasing proopiomelanocortin (POMC) and alpha-melanocyte stimulating hormone (alpha-MSH) in the satiety center in ventromedial hypothalamus. Induction of satiety is accompanied by changes in metabolism. The metabolic and visceral sensory stimuli activate the satiety center and inhibit the hunger center.

Krolczyk et al showed a significant decrease in body weight and food intake induced by VNS in rats compared to controls (2). The same authors published interesting study on pathomechanism of VNS. Authors suggest that VNS effects are partially attenuated by baclofen and are related to GABA(B) receptors (29). Baclofen alone did not significantly change neither food intake nor diurnal body weight. In turn baclofen significantly reduced effect of vagal neuromodulation. This study showed also significant decrease in leptin and glucose levels due to VNS.


PIG AND DOG STUDIES
Gastric pacing was proposed for the treatment of obesity (30, 31). The idea of gastric stimulation for treating obesity was based on the artificial creation of anti-peristaltic motility in the porcine stomach (32). From a physiological point of view, the generation of anti-peristaltic motility induces rather nausea-like condition than satiety. It should be also noted that satiety signals are generated mainly in proximal stomach (33), which plays a role of temporary reservuar for ingested food. Moreover, satiety signals generated by gastric mechanoreceptors (mucosal "touch" receptors, muscular tension receptors, and serosal receptors) are not the unique source of physiological information provided by the digestive tract. Duodenal chemoreceptors and hepatic glucoreceptors are of the same importance as the others (34). Time, diversity and sequence of afferent information is important for the completing of satiety.

According to the physiology of food intake, activation of vagal afferents seems to be logic consequence for induction of satiety. Two approaches to electrode implantation have been proposed. Sobocki et al implanted electrodes by laparotomy access (35), and Roslin et al performed thoracotomy for electrode implantation (36).

Matyja et al used autonomic microchip for vagal stimulation, implanted by laparoscopy. Stimulated animals demonstrated continuous decrease in body weight gain during 8 weeks of experiment, compared to controls. Electrogastrogaphic recording showed decrease in percent of normogastria mostly at cost of tachygastria (37). Reduced percent of normogastria suggests delayed gastric emptying. Despite of this, food intake was not significantly affected, but body weight in stimulated pigs decreased. This discrepancy suggests predominant importance of central rather than peripheral effects of vagal stimulation and lacks the side effects. Tachygastria is often associated with nausea, vomiting and early satiety (38). In this study, however, no vomiting or symptoms related to nausea were noted.

VNS modifies not only centropetal afferent input, but also peripheral output of the both vagal nerves. Studies on recording of mass vagal nerve activity showed two kinds of activity, high amplitude low frequency and high frequency low amplitude signals (39).

Peripheral effects of VNS includes effects on all gastrointestinal functions. Krolczyk et al have shown decreased NO dependent gastric emptying and secretion in rats (2). Similar results were published by Ouyang and coworkers (40). They found that electrical field gastric stimulation (EFS) in dogs with long pulsed exerts protracted effects on gastric emptying, gastric contractility and vagal activity. Long term gastric stimulation in dogs decreased significantly food intake and body weight.

Some interesting data have been published recently on the VNS regarding its pathomechanism of action, influence of hormonal activity, metabolic rate, body composition, and incidence of adverse effects (41). In this study VNS attenuated body weight gain, reduced subcutaneous fat gain and intramuscular fat gain. VNS resulted in lower fat/fat free body mass ratio. No significant change in metabolic rate was observed. In this study laparoscopic technique of electrode implantation was described.

The study of Laskiewicz et al (39), have shown that bilateral VNS is more effective than unilateral stimulation, and suggested that anterior vagal stimulation with posterior vagotomy was as effective as bilateral stimulation. The anterior vagal trunk is suggested for stimulation for at last two reasons: firstly it activates hepatic branch (which play an important role in sensation of satiety), secondly VNS induces weight loss in humans, where electrode is habitually implanted on the left side (42). Bilateral electrode implantation is preferred by Roslin et al (36).


CLINICAL PERSPECTIVE
VNS can control body mass not only in experimental animals but also in humans. Burneo et al published that VNS is capable to decrease body mass in humans, as a side effect of treatment of epilepsy within 6 and 12 months after implantation (42). The pathway of this action involves hypothalamic centers. It was shown by PET-imaging that the application of VNS for treating epilepsy induces hypometabolism of the hypothalamus (43). Consequently, VNS may involve the brain center of satiety and induce a cascade of metabolic and behavioral changes. So far only one report of few implanted cases has been published by Roslin et al. Results of this pilot study were mixed. Significant lost of body weight was achieved only in two of 6 implanted patients.

Due to promising results of experimental studies, clinical trials are expected in the near future.


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