Gastric stimulation for weight loss

Abstract

The prevalence of obesity is growing to epidemic proportions, and there is clearly a need for minimally invasive therapies with few adverse effects that allow for sustained weight loss. Behavior and lifestyle therapy are safe treatments for obesity in the short term, but the durability of the weight loss is limited. Although promising obesity drugs are in development, the currently available drugs lack efficacy or have unacceptable side effects. Surgery leads to long-term weight loss, but it is associated with morbidity and mortality. Gastric electrical stimulation (GES) has received increasing attention as a potential tool for treating obesity and gastrointestinal dysmotility disorders. GES is a promising, minimally invasive, safe, and effective method for treating obesity. External gastric pacing is aimed at alteration of the motility of the gastrointestinal tract in a way that will alter absorption due to alteration of transit time. In addition, data from animal models and preliminary data from human trials suggest a role for the gut-brain axis in the mechanism of GES. This may involve alteration of secretion of hormones associated with hunger or satiety. Patient selection for gastric stimulation therapy seems to be an important determinant of the treatment’s outcome. Here, we review the current status, potential mechanisms of action, and possible future applications of gastric stimulation for obesity.

Key Words: Obesity, Gastric stimulation, Gastric motility, External pacing, Gastric pacing, Intestinal pacing

INTRODUCTION

Obesity is a major public health challenge. The evolving concepts of how nutrient excess and inflammation modulate metabolism provide new opportunities for strategies to correct the damaging health consequences of obesity. The traditional approaches of caloric restriction, exercise, and behavioral therapies can each produce substantial weight loss, but it is not sustained in the majority of patients. The pharmacological agents that are currently licensed for weight loss produce only modest results and may have unwanted side effects. Clearly, a safe, effective, and durable treatment for obesity is needed.

The role of the gastrointestinal tract in regulating energy balance is now well recognized, and the expanding understanding of gut endocrinology and electrical signaling has produced a number of potentially fruitful avenues for developing obesity therapies.

In the last few years, gastric stimulation has gained attention as a possible new approach for treating obesity. Gastric electrical stimulation (GES) is a new method for invoking gastric contractions using a microprocessor controller. The effect of this long-term gastric stimulation on food intake and body weight was first studied in pigs[1,2]. Pigs treated for eight months with electrical antral stimulation showed a net decrease of food intake[1]. In other studies, a significant decrease in food intake has been noted with gastric stimulation in dogs, and a significant decrease in fat absorption has been reported in rats[3-6].

Because GES has shown promising results in several animal models, the technique has been further refined for obesity treatment in humans. In 1995, the technique of an implantable gastric pacing device was studied in 24 morbidly obese patients. The results demonstrated the safety of the method and revealed changes in eating habits that resulted in reduced food intake and weight loss[7]. In a subsequent human study, there was a reported increase in meal-related satiety and enhanced inter-meal satiety during the treatment[8]. From this information, gastric pacing was hypothesized to facilitate weight loss by enhancing neuroendocrine satiety mechanisms.

Here, we review some of the techniques and the potential mechanisms associated with using gastric stimulation for treating obesity.

ROLE OF THE GUT-BRAIN AXIS IN REGULATING APPETITE

Food intake is influenced by emotional factors, social cues, and learned behavior. These influences overlay highly conserved systems within the brain that sense and integrate signals reflecting overall energy stores, recent energy intake and the presence of specific classes of nutrients.

Signals from the gut are important for controlling appetite and for regulating energy balance and glucose homeostasis. The active brain-gut axis sets the basis for options to stimulate different brain areas or neural connections between the brain and the gut to induce sensations of satiety.

There are several potential means by which the gut and the brain are associated. Some involve connections from the gut to hormones and from hormones to the nervous system. The gut continuously sends information to the brain regarding the quality and quantity of ingested food. These signals are not only important for satiation and meal termination but also for the appetitive phase of eating behavior[9]. By acting on the brainstem and hypothalamus, this flow of sensory information from the gut to the brain generates the feeling of satisfaction that is observed after a satiating meal[9].

The vagus nerve (VN) contributes to the bidirectional communications between the gastrointestinal tract and central nervous system (CNS)[10]. Afferent neurons of the VN are important targets of gut hormones, particularly the hormones involved in controlling food intake. Vagovagal reflexes are involved in feeding homeostasis, making neuromodulation an attractive method for managing obesity[10].

Ziomber et al[10] have described the parameters of vagal neuromodulation required to decrease food intake in rats and cause a resulting reduction in body mass. Rats with solenoid electrodes placed on the left VN significantly decreased their food intake, weight gain and serum leptin concentrations. Another study has shown the suppressive effects of vagal nerve stimulation (VNS) on long-term feeding regulation in rats[11]. VNS has been shown to increase vagal afferent satiety signals, leading to reduced food intake and decreased weight gain[11]. Chronic microchip vagal stimulation significantly decreases epididymal fat pad weight and meal size in VNS rats, which causes decreased weight gain.

In addition to the VN, several other areas in the brain are involved in regulating gastrointestinal motility and satiety. The central nervous system regulates the homeostasis between nutrient intake and body reserves by sensing nutrient levels, integrating the information, and regulating energy intake and/or energy expenditure[12]. Grill et al[13] have summarized several potential mechanisms for connections between the gut and the brain. The nucleus tractus solitarius (NTS) and circuits within the hindbrain mediate the intake-inhibition effects of gastrointestinal (GI) signals. Short-term eating behavior is also controlled by the hindbrain. The NTS receives inputs from VN afferent neurons, while the area postrema is a target for circulating factors, such as amylin and glucagon-like peptide 1 (GLP-1)[14]. Classical studies have shown that when the higher inputs are surgically interrupted, the hindbrain can continue to regulate food intake in response to peripheral signals[15].

GASTRIC HORMONES ASSOCIATED WITH HUNGER AND SATIETY

The mechanisms that modulate gut-related satiety signals are now being recognized. The apparent importance of alterations in the gut hormonal milieu caused by surgical interventions in the GI tract has led to new surgical approaches and devices. Interventions (such as gastric pacing) that modulate gut-related satiety signals may offer approaches for curbing the threat of obesity to human health. The enteroendocrine cells of the GI tract act as a luminal surveillance system, responding to either the presence or absence of food in the gut lumen[16]. Their secretion products regulate the course of digestion and determine the delivery of nutrients to the gut by controlling food intake[16]. The gut is the source of numerous peptides, many of which can alter appetite. These peptides have numerous targets, including gastrointestinal exocrine glands, smooth muscles, afferent nerve terminals, and the brain[17].

GLP-1

This incretin hormone is secreted from the lower gut in response to food intake stimulates insulin secretion and inhibits gastric emptying[18,19]. Following an oral glucose load, insulin secretion is enhanced when compared with an intravenous glucose infusion in the presence of similar plasma glucose concentrations[20]. This phenomenon is referred to as the incretin effect. In patients with type 2 diabetes mellitus (T2DM), however, the incretin effect is significantly impaired and postprandial GLP-1 secretion is diminished[20]. Because both the incretin effect and postprandial GLP-1 concentrations are markedly reduced in T2DM patients[21], the first clinical studies addressed the question of whether raising GLP-1 levels by exogenous administration of the incretin hormone could help to restore normal glucose regulation. However, GLP-1 has a plasma half-life of just a few minutes because it is readily degraded by the ubiquitous enzyme dipeptidyl peptidase-IV. Although the beneficial clinical effects of GLP-1 are evident, the need to continuously infuse it have hampered its broad clinical applications. Therefore, incretin mimetic agents, such as exenatide and dipeptidyl peptidase-IV inhibitors, are used to treat patients with T2DM[22]. Some studies have indicated that this treatment also results in weight loss[23,24]. Because of its short half-life, it has been shown that peripheral administration of GLP-1 lowers postprandial glucose dysregulation by inhibiting glucagon secretion. Beta-cell function is also improved, along with increased satiety and decreased food intake, which then results in weight loss. GLP-1 stimulates insulin secretion, which also delays gastric emptying[25-27]. Obese subjects have less GLP-1 release after a meal, which may lead to less inter-meal satiety when compared with lean subjects[28]. Low postprandial levels of GLP-1 in obese children are responsible for excessive ingestion of food and decreased inhibition of gastric emptying, both of which result in obesity[29]. The ability of Roux-en-Y gastric bypass surgery to increase GLP-1 levels has been reported[30]. In gastric pacing, up to 40% of excess body weight can be lost after 2 years of treatment[31]. A limited study in morbidly obese patients has shown that gastric pacing is associated with decreased peripheral levels of GLP-1. This effect correlates with decreased food intake and the resulting weight loss. From these results, a mechanistic role for the stimulation of vagal afferents has also been propounded[8].

Leptin

The nervous system regulates energy balance at the whole-body level by constantly adjusting energy intake, expenditure, and storage[32,33]. The ob gene encodes the protein leptin, which is an adipose tissue-derived circulating hormone. Since the identification of ob as the first example of human monogenic obesity, it has become clear that leptin plays a key role in controlling mammalian food intake and body fat stores[34,35]. A leptin deficiency in mice homozygous for a mutant ob gene (ob/ob mice) causes morbid obesity and diabetes. Leptin replacement leads to decreased food intake, normalized glucose homeostasis and increased energy expenditure[36-39]. Leptin induces transcriptional changes for several genes via the JAK/STAT3 pathway, and rapid changes in cellular activity and membrane potential may underlie the acute actions of leptin[40]. Leptin resistance limits its utility in ordinary obesity, as reflected by the increased levels of leptin in obese subjects relative to their increased body fat[41]. Therefore, while the actions of leptin in peripheral tissues have been identified, studies in genetically modified mice have demonstrated that leptin action in the CNS is sufficient to regulate body weight, feeding, energy expenditure, and glucose metabolism[42-44]. The effect of leptin on metabolism is supported by neurons distributed in the hypothalamus, midbrain, and brainstem. It has been suggested that morphological changes progressively develop in the brain during obesity[45-47], and further inquiry into the cellular mechanisms linking obesity, neural plasticity, and food cravings are needed. Certain gut peptides (e.g., ghrelin) act in an additive manner with leptin to regulate energy balance[48], which has led to the development of combination therapies to enhance leptin sensitivity in obese states. Roux-en-Y gastric bypass in obese patients is associated with a decrease in leptin levels after only minimal changes in BMI have occurred[49]. Gastric pacing in morbidly obese patients results in significant weight loss that correlates with a decrease in leptin levels[8].

Peptide YY

The gut hormone peptide YY (PYY) belongs to a family of peptides that includes pancreatic polypeptide and neuropeptide Y (NPY). It is secreted by the L cells of the lower intestine after ingesting a meal and is released into the circulation[50], where it exists in two endogenous forms: PYY _1-36 and PYY _3-36[51]. PYY _1-36 is the major form of PYY in the fasting state[51]. The latter form is produced by the action of the dipeptidyl peptidase-IV enzyme in response to food intake[52]. Between 1% and 10% of PYY is also found in the esophagus, stomach, duodenum and jejunum[53]. PYY exerts its action through NPY receptors. PYY inhibits gastric motility and increases water and electrolyte absorption in the colon[54].

Endogenous PYY may be involved in the long-term regulation of body weight. PYY enhances a reduction in hunger and food intake[55]. Peripheral administration of PYY _1-36 decreases food intake in rodents. PYY _3-36 also markedly inhibits food intake in rodents[56,57] In humans, an intravenous infusion of physiological levels of PYY_3-36 reduces caloric intake in both normal weight[56] and obese subjects[58]. This effect is not achieved exclusively by affecting energy intake; there is evidence that PYY may have some effects on energy expenditure and lipid metabolism[59]. PYY levels are higher in rats treated with solenoid electrodes placed on the left VN than in untreated controls[10]. PYY may also be associated with the rapid improvement in carbohydrate homoeostasis observed after bypass surgery. This improvement is secondary to an increase in insulin sensitivity rather than an increase in insulin secretion, which occurs later[60]. Increases in the secretion of GLP-1 and PYY are involved in the disappearance of hypertriglyceridemia and decreases in the levels of circulating fatty acids[60]. Some studies have reported that Roux-en-Y gastric bypass surgery increases PYY levels[30].

Cholecystokinin

Cholecystokinin (CCK) is the major hormone responsible for gallbladder contraction and pancreatic enzyme secretion. Like other gastrointestinal hormones, CCK is produced in discrete endocrine cells that line the mucosa of the small intestine. CCK stimulates vagal afferent neuron discharge and controls the expression of G-protein coupled receptors and peptide neurotransmitters in these neurons[16,61]. A gatekeeper function is attributed to CCK because its presence or absence influences the capacity of vagal afferent neurons to respond to other neuro-hormonal signals[16]. CCK reduces food intake by exerting an effect on the CCK-1 receptors residing in the VN[62].

During fasting, plasma CCK concentrations are low and vagal afferent neurons express cannabinoid CB1 and melanin concentrating hormone (MCH)-1 receptors, which stimulate food intake[16]. Post-prandial release of CCK down-regulates the expression of both receptors and stimulates the expression of Y2 receptors in neurons projecting to the stomach. In fasting, there is increased expression in the neurons of the appetite-stimulating neuropeptide transmitter MCH, along with decreased expression of the satiety-peptide cocaine and amphetamine-regulated transcript (CART). The secretion of CCK decreases the expression of MCH and increases the expression of CART. At low plasma concentrations of CCK, vagal afferent neurons exhibit increased capacity for appetite-stimulation, while post-prandial concentrations of CCK lead to enhanced capacity for satiety signaling[16].

CCK antagonists induce hunger, leading to larger meals sizes. CCK also delays the rate at which food empties from the stomach[62]. CCK expression can be altered by prolonged gastric stimulation. Following 14 d of GES, the number of CCK-immunoreactive neurons in the hippocampus increased compared with a control group[63]. In another study performed on morbidly obese patients treated with gastric pacing, the gastric pacing resulted in decreased CCK levels[8].

Ghrelin

Ghrelin was the first identified circulating hunger hormone[64]. In contrast to the GI peptide hormones (such as GLP-1, PYY and others) that increase satiety through CNS-mediated pathways[65,66], the gastric hormone ghrelin stimulates hunger through a different CNS-mediated pathway[65]. Ghrelin is produced primarily by cells in the oxyntic glands of the stomach and intestines[67] and is secreted into the bloodstream. Ghrelin is a potent stimulator of growth hormone (GH) secretion and is the only circulatory hormone known to potently enhance feeding and weight gain and to regulate energy homeostasis following central and systemic administration. When administered either peripherally or centrally to rodents, ghrelin increases food intake and body weight[68-70] and stimulates gastric motility and acid secretion[71]. In humans, there is a pre-prandial rise in plasma ghrelin levels[72,73]. When administered to rodents at supra-physiological doses, ghrelin is able to activate hypothalamic neuropeptide Y agouti-related protein neurons and increase both food intake and body weight. Ghrelin participates in meal initiation. When administered either peripherally or centrally to rodents, ghrelin rapidly increases food intake and body weight[48]. Therapeutic intervention with ghrelin in catabolic situations enhances food intake and increases gastric emptying and nutrient storage. These effects, coupled with an increase in GH, link nutrient partitioning with growth and repair processes. Ghrelin-based compounds may have therapeutic utility for treating the malnutrition and wasting that are induced by various sub-acute and chronic disorders. Conversely, compounds that inhibit ghrelin action may be useful for preventing or treating components of the metabolic syndrome, such as obesity, impaired lipid metabolism and insulin resistance.

Peripheral blood ghrelin levels were studied one month prior to gastric pacing, one month following implantation, and six months after activation of the electrical stimulation. Ghrelin levels were decreased significantly in response to food intake at all these evaluations. After activating the pacemaker, ghrelin levels were significantly increased above their levels prior to activation. The weight loss was significantly correlated with the increased ghrelin levels[74]. A decrease in the number of ghrelin-immunoreactive neurons in the hypothalamic paraventricular nucleus and in the supraoptic nucleus has been reported after a short period of gastric stimulation in rats[63]. In Roux-en-Y gastric bypass surgery, the total fasting plasma ghrelin levels were nearly identical between the subjects and the matched controls[30].

METHODS OF GASTRIC STIMULATION FOR THE TREATMENT OF OBESITY

Many aspects of cell functioning are controlled by intrinsic or extrinsic electrical activity. In the normal physiological state, an action potential is generated and then causes a cellular response. When electrical signals are applied externally, they increase the rate at which this response occurs, which is called electrical pacing. Nevertheless, if the electrical signal is applied during the refractory period of the normal action potential, it does not increase the response rate. However, it has been shown in several studies that application of the electrical signal is still able to change the biochemistry of the cell, which leads to greatly increased responses to the next normal action potential[75]. Stimulating the stomach, the sub-diaphragmatic sympathetics, the vagal nerve (with or without unilateral vagotomy), and the intestines are some of the pacing approaches that have been used for treating obesity[76].

Gastric pacing with short pulse width and high frequency for the treatment of obesity

Dilatation of the stomach by food ingestion sends afferent signals through the VN to the CNS and increases satiety, thus regulating food intake[77,78-80]. Because of the many neuro-hormonal functions of the stomach and the modification of these hormones by food ingestion, modifying the function of the stomach has been hypothesized to be a potential mechanism for treating obesity.

Several methods have been used to electrically stimulate the stomachs of obese patients[76]. Changes in the intensity of the stimulus, the duration of the pacing, and the anatomical site of stimulation determine the effect of the treatment. The responses to gastric pacing are dependent on the stimulus intensity, with shorter duration stimuli being sufficient when the impulse strength is increased. The antrum can be paced to significantly higher frequencies than the more proximal gastric regions.

GES is a method for invoking gastric contractions. The main effect of the technique was originally thought to be longer retention of food in the stomach that induces early satiety and diminishes food intake. The first clinical use of gastric pacing in the early 1990s was preceded by an exploration of gastric electrical physiology in the 1980s[81] Human GES for obesity began in 1995. There have now been more than 500 subjects treated for obesity with gastric pacing. With proper screening, the weight loss can be in the range of 40% of the excess body weight[76,82].

GES uses an electrical device called a gastric pacemaker to provide mild electrical stimulation to the lower abdominal nerves. Utilizing minimally-invasive surgical techniques, the gastric pacemaker is placed subcutaneously in the abdomen. It is intended to induce early satiety through electrical stimulation of the gastric wall. Several gastric stimulation protocols have demonstrated their weight-reduction efficacy in animal obesity models and in patients with morbid obesity. The implantable gastric stimulator (IGS) induces stomach expansion via electrical stimulation of the VN. This type of stimulation induces neurobiological responses by using brain circuits that lead to decreased food intake[83].

IGS has been used for the treatment of obesity[84]. IGS reduces appetite and increases satiety. Its efficacy is attributed to its inhibitory effects on gastric motility and its direct effects on the central nervous system and hormones related to satiety and/or appetite[84]. Chronic gastric stimulation impairs intrinsic gastric myoelectrical activity in the fed state, induces gastric distention in the fasting state and inhibits postprandial antral contractions[84]. The impairment of gastric myoelectrical activity and contractions are associated with impaired digestion and emptying of the stomach, which leads to early satiety and reduced food intake. The induction of gastric distention in the fasting state results in activation of stretch receptors, causing satiety[84]. Modulation of neuronal activities and the release of certain hormones in response to an IGS may also explain the reduction in appetite and increase in satiety.

The first studies of GES as a treatment for obesity employed the Transcend™ Implantable Gastric Stimulator. In 2002, Favretti and colleagues showed that the Transcend device was safe and effective at inducing and maintaining weight loss in 20 morbidly obese patients[85]. The pacemaker was implanted laparoscopically below the pes anserinus, 3 cm from the edge of the lesser gastric curvature and 6 cm from the pylorus. The lead was fixed within a tunnel in the gastric muscular wall by a suture, and gastroscopy was performed to ensure that the lead did not perforate the stomach wall. The operative time was less than an hour, and the stimulator was activated 30 d after its implantation. The stimulus parameters were an amplitude of 10 mA, a pulse width of 208 ms, and a frequency of 40 Hz with 2 s on and 3 s off[85]. The Transcend device blocks vagal efferents and delays gastric emptying, leading to a 40% loss of excess body weight[76]. The pacemaker delivers 2 s pulse trains with a 40-100 Hz frequency, 3-10 mA of current, and a short pulse duration of 0.18-0.4 ms, with intervening 3 s periods of no stimulation[7,86]. In another study, two electrode positions along the lesser curvature of the stomach were used, with the low insertions 6 cm proximal to the pylorus and the high insertions just distal to the esophageal-gastric junction. Short-term weight loss has been achieved in a subset of these patients[86]. The clinical response is most often defined by the excess weight lost (EWL) in these studies; however, improvements in symptoms, quality of life and nutritional status have also been reported by most open-labeled studies[87].

Gastric pacing with long pulse width and low frequency for obesity

Other types of stimuli have been tested in animal models and in humans. In dogs, retrograde stimulation through two electrode pairs positioned proximal to the pylorus for 8 s at a frequency of 50 Hz and a voltage of 16 V with intervening periods of no stimulation elicits retrograde contractions, reduces food intake and promotes weight reduction[88]. In another animal study, electrical stimulation has been shown to reduce food intake and increase gastric volume[89]. Studies in dogs using a pulse width in milliseconds at a frequency of six cycles per minute induced gastric relaxation when the pacing occurred in the proximal stomach but not when it occurred in the distal stomach[90]. These studies demonstrated the ability to inhibit gastric contractions and delay gastric emptying[90,91]. Temporary retrograde pacing with a mucosal electrode placed endoscopically on the greater curvature of the stomach, 5 cm above the pylorus, was performed in 12 normal volunteers. The gastric slow waves were entrained at nine cycles per minute, and the symptoms of satiety, bloating, discomfort, and nausea were linearly correlated with the energy stimulation in milliamps[92]. Later, 12 normal volunteers were studied for 3 d using temporary electrodes endoscopically placed on the greater curvature stomach, 5 cm above the pylorus. Retrograde gastric pacing at nine cycles per minute resulted in retrograde propagation of electrical waves from the antrum. These waves disrupted the normal electrical waves that propagate distally and caused gastric hypomotility. Food intake decreased by 16% and gastric retention of solids increased by 15% during this retrograde pacing. These changes were accompanied by tolerable dyspeptic symptoms[92]. Another study in 12 normal volunteers using a stimulus intensity below the threshold that induces dyspepsia was able to delay gastric emptying, decrease food intake, and decrease water intake compared with sham controls. These results suggested the possibility of performing longer stimulations to treat obesity[93].

VNS for weight loss

The VN has a role in regulating hippocampal activity, and the hippocampus has a role in modulating eating behaviors[83]. Studies with the Transcend gastric pacemaker have suggested that blocking the efferent vagal impulses can reduce gastric tone, which is accompanied by slower gastric emptying, decreased food intake, and weight loss. A laparoscopically implanted electrical device that intermittently blocked both VNs near the esophageal-gastric junction led to EWL in obese patients[94]. A vagal blocking algorithm with a duration of 90-150 s was associated with greater EWL than were either shorter- or longer-duration algorithms[94]. An association was found between the number of 90-150 s algorithms delivered daily and greater EWL. In a study conducted in rabbits, the animals had a microchip implanted on the posterior vagus by laparotomy. Over a 4-wk period, body weight decreased by 12%, food intake decreased by 40%, and pulse rate decreased. Heart rate changes suggested stimulation of the afferent vagus in addition to blocking of the efferent vagus[95]. In another study, pigs were implanted with microchips on both vagal nerves by laparotomy. At an amplitude of 170 mV, a frequency of 1 Hz, and a 170-ms impulse duration, their food intake was decreased and their body weight gain was reduced with no observable side effects. Normogastria was reduced and tachygastria was increased, which is consistent with reduced efferent vagal transmission[96]. The human data on weight loss through VN stimulation comes from trials using VN stimulators for treating epilepsy. These patients had cervical vagal stimulation, which caused hoarseness, cough, throat pain, and dyspnea. Thirty-two patients were evaluated and 17 lost weight[97].

Stimulation during the electrical refractory period to treat obesity

Stimulating the gastric antrum in rats during the absolute refractory period increases the strength of gastric contractions and increases vagal afferent firing, similar to its effects on gastric distension[98]. Pyloric stimulation in dogs decreases food intake, decreases antral contractions, and delays gastric emptying[99]. The Tantalus system (MetaCure Ltd.) is implanted laparoscopically for gastric stimulation that does not exhibit malabsorptive or restrictive characteristics[100]. It was developed to electrically stimulate the gastric antral muscle immediately following the entrance of food into the stomach. It increases antral muscular contractions and delays gastric emptying by delivering stimulation during the absolute refractory period[76]. The Tantalus system has a pulse generator and three bipolar leads. Two pairs of electrodes are implanted in the gastric antrum and two pairs in the gastric fundus. The electrodes in the gastric fundus sense the beginning of a meal and signal the pulse generator to stimulate the antral electrodes during the absolute antral refractory period, which enhances spontaneous gastric contractions and sends a signal through the afferent vagus that the stomach is distended. The device applies gastric contractility modulation signals to the gastric antrum. The system is designed to automatically detect when eating begins and to only then deliver GES sessions using electrical pulses that are synchronized to the intrinsic antral slow waves[100,101]. This method involves surgical placement of three electrode pairs; one pair in the fundus detects food ingestion, and two pairs in the antrum detect the intrinsic slow waves and deliver stimuli in synchrony with these signals[102]. The gastric stimulation begins when food enters the stomach, so it is only delivered postprandially. The device is believed to work by increasing antral contractions. This stimulated phased motor activity enhances the satiety that is normally elicited by postprandial gastric distention[98]. The stimulation parameters that enhance the phased antral contractions include a frequency of 80 Hz, a pulse width of 1-2 s, and a current of 0.5-1 mA[98]. Because of its energy requirements, the device must be recharged weekly by an external charger.

A trial in 12 obese subjects demonstrated that the fundal electrodes were able to sense the start of a meal > 75% of the time. The subjects lost 10 kg over 20 wk, and 9 subjects who continued till week 52 lost an additional 7 kg, for a total of 30.5% of their excess body weight lost[102]. In a European multicenter, open-label study, thirteen T2DM obese patients were laparoscopically implanted with the Tantalus device. The thirteen subjects that completed 3 mo of treatment showed a significant reduction in weight that was accompanied by glycemic improvement[100]. In the eleven patients that completed 6 mo of therapy, HbA1c was significantly reduced. However, the improvement in glucose control did not correlate with weight loss[101]. The data support the hypothesis that GES can improve glucose metabolism and induce weight loss in obese diabetic patients[103].

Intestinal electrical pacing for obesity

Intestinal electrical stimulation (IES) may have promising applications for treating motility disorders associated with altered intestinal contractile activity. However, recent studies have also revealed possible applications of intestinal electrical stimulation in obesity treatment[104]. IES applied to the duodenum reduces postprandial blood glucose levels by modulating gastric emptying and the intestinal flow rate[105]. Both vagal and extra-vagal pathways are involved in the modulatory effects of IES on the central neurons of the satiety center[106]. Electrical stimulation of the stomach, intestine, or colon with long pulses has an inhibitory effect on gastric tone[107]. IES has been reported to alter intestinal slow waves, contractions and transit, effects that are mediated by both vagal and adrenergic pathways[108]. Duodenal stimulation in 12 healthy human volunteers did not induce dyspepsia, but it did reduce water intake and slowed gastric emptying[43]. Intestinal stimulation in dogs using seven sequential electrodes with a frequency of 24 cycles per minute, a pulse duration of 50 ms, and a pulse amplitude of 1-3 mA entrains the intestinal pacesetter. This treatment is effective at stimulating intestinal transit, even in the face of fat in the distal small intestine[109]. Intestinal stimulation in rats accelerates intestinal transit and reduces fat absorption[110]. Clinical trials of intestinal pacing in humans have yet to be reported.

Some potential mechanisms for the effect of gastric pacing in obesity

Obesity is the result of an imbalance between nutrient consumption, absorption, and energy expenditure[111]. GI motility regulates the rates at which nutrients are processed and absorbed and participates in controlling appetite and satiety via mechanical and neuro-hormonal pathways. The relatively extensive information on gastric pacing for motility disorders has shed light on the possible mechanisms of this treatment’s beneficial effects on obesity. The effects of pacing may depend on the stimulus parameters and stimulation sites. Both the entrainment of intrinsic gastric electrical activity, eliciting propagating contractions and reducing symptomatology in patients with gastroparesis and reducing appetite and food intake in morbid obesity were suggested[112]. Additionally, gastric stimulation parameters have extra-gastrointestinal effects, including altering systemic hormonal and autonomic neural activity and modulating afferent nerve pathways projecting to the central nervous system[112].

Obesity that is induced by hypothalamic damage is associated with increased vagal tone, increased insulin secretion, increased food intake, and weight gain[113]. Performing a vagotomy below the diaphragm reverses the obesity caused by hypothalamic damage in rodents. Because trials have shown that placing a gastric pacemaker is the safest and simplest surgical treatment for morbid obesity, there has been considerable interest in defining the mechanisms by which it works[31]. Obesity seems to be associated with efferent vagal stimulation, which is inhibited by the Transcend pacemaker that is currently used. Short pulse widths and high-frequency stimulation induces gastric distention, inhibits postprandial antral contractions, and slows gastric emptying, which then leads to early satiety, reduced food intake and weight loss[114]. Cholinergic vagal efferents increase gastric tone, while nitric oxide pathways decrease it[115]. Gastric stimulation blocks the efferent vagal pathway and releases nitric oxide pathways from inhibition, resulting in gastric dilatation[84,116,117].The gastric slow waves are inhibited postprandially, which may also contribute to the delayed gastric emptying and promotion of satiety[118].

The decreased levels of GI hormones may be more compatible with depressed vagal tone than with vagal electrical stimulation of the pes anserinus area (the spreading zone of the vagal branches in the lesser curvature of the stomach). However, it is also possible that gastric pacing leads to parasympathetic hyperstimulation and the depletion of stored peptides, which may explain the reduced plasma levels of certain gastrointestinal hormones[8]. GES may also affect several brain areas associated with satiety and hunger, and may exert an effect on the hormonal gut-brain axis. Information on the current metabolic state is transmitted to the appetite control centers of the brain by a diverse array of signals, such as VN activity and metabolic “feedback” factors that are derived from the pituitary gland, adipose tissue, stomach, intestines, pancreas and muscle[12]. These signals act directly on the neurons located in the arcuate nucleus of the medio-basal hypothalamus, a key integration and hunger (orexigenic) and satiety (anorexigenic) control center of the brain[12].

CONCLUSION

Obesity is an epidemic disease that is increasing in prevalence and is associated with a rising incidence of diabetes. Behavior and lifestyle therapy are safe and effective treatments for obesity in the short term, but the durability of the weight loss is limited. Although promising obesity drugs are in development, the currently available drugs lack efficacy or have unacceptable side effects. Surgery leads to long-term weight loss, but it is associated with morbidity and mortality. GES is a promising, minimally invasive, safe, and effective method for treating obesity. Patient selection for gastric stimulation therapy seems to be an important determinant of the treatment’s outcome[86,119-121]. Several approaches with different physiologic mechanisms are in various stages of development. The use of GES as an obesity treatment should produce exciting new developments in the foreseeable future.