Effects of vagal and splanchnic section on food intake, weight, serum leptin and hypothalamic neuropeptide Y in rat

Truncal vagotomy can cause reduced food intake and weight loss in humans and laboratory animals. In order to investigate some of the factors that might contribute to this effect, we studied changes in ingestive behaviour, whole body and organ weights, serum leptin and hypothalamic neuropeptide Y in rats with bilateral vagal section, bilateral splanchnic nerve section and combined vagotomy plus splanchnectomy. Pyloromyotomy was combined with vagotomy to lessen effects of vagotomy on gastric emptying. Animals with vagotomy or vagotomy plus splanchnectomy lost weight and decreased their daily food intake relative to animals with splanchnectomy alone, rats with bilateral sham exposure of one or both nerve, or rats with pyloromyotomy alone. Serum leptin and white fat mass, 4 weeks after vagotomy, were about 20% of the values in the sham-operated animals at this time. No effect for splanchnic nerve section alone was observed. Pyloromyotomy caused no reduction in weight or fat mass, but reduced serum leptin. Following vagotomy with or without splanchnic nerve section, neuropeptide Y was elevated in the arcuate nucleus relative to values for the other four groups. Changes in neuropeptide Y were inversely correlated with levels of serum leptin. It is concluded that the effect of vagotomy could be due to the loss of a feeding signal carried by vagal afferent neurons, or to changed humoral signals, for example, increased production of a satiety hormone. However, it cannot be attributed to signals that reduce feeding (for example, gastric distension) reaching the central nervous system via the splanchnic nerves. The changes were sufficient to cause weight loss even though serum leptin was decreased, a change that would be expected to increase food intake.     

Oxytocin reduces satiety scores without affecting the volume of nutrient intake or gastric emptying rate in healthy subjects

Background Oxytocin is expressed throughout the gastrointestinal tract and is released in response to a fatty meal. Administration of an oxytocin receptor antagonist prolongs the gastric emptying rate. The aim of this study was to examine the effect of oxytocin on gastric accommodation, gastric emptying time, and satiety after food intake. Methods Ten healthy subjects participated in a slow satiety drinking test with a liquid meal. Every 5 min the subjects scored their sensation of satiety using a visual analogue scale (VAS) until maximum satiety was reached and the amount of liquid intake was determined. Twelve subjects participated in a gastric emptying test. They were given a standardized meal containing 20 radio‐opaque markers, after which fluoroscopy was performed and VAS was scored every hour. Both tests were performed four times during infusions of saline and three different oxytocin concentrations. Blood was collected for oxytocin concentration measurements. Key Results There were no differences in the volume of nutrient intake at maximum satiety between the three doses of oxytocin and saline. However, lower satiety scores at maximum satiety were seen after oxytocin infusion (P = 0.031), with 40 mU min^?1 being the most effective dosage (P = 0.013), and this was also true 30 min after finishing the meal (P = 0.032). There was no difference in gastric emptying time between saline and oxytocin. The oxytocin concentration in plasma was increased proportional to the oxytocin infusions. Conclusions & Inferences Infusion of oxytocin reduces satiety without affecting the volume of nutrient intake or gastric emptying in healthy subjects.     

Caloric and noncaloric controls of food intake

Hunger and satiety appear to reflect the postabsorptive and absorptive phases of caloric homeostasis, respectively. However, only some of the signals that inhibit food intake can be related to caloric homeostasis. For example, decreases in food intake also are observed after administration of nauseogenic chemical agents, treatment with cholecystokinin (CCK), or dehydration. In each case, inhibition of food intake is correlated with induced decreases in gastric motility and increases in secretion of pituitary oxytocin in rats; in primates, including humans, vasopressin but not oxytocin is secreted. In contrast, meal-induced satiety increases gastric contractions and has little or no effect on neurohypophyseal hormone secretion in rats or human subjects. Nauseogenic toxins, CCK, and dehydration stimulate very different subjective states from satiety: LiCl elicits abdominal cramps, nausea, and vomiting, as does exogenous CCK in high doses, whereas dehydration elicits thirst. Thus, inhibition of eating may not be associated with satiety or reflect changes in caloric flux; noncaloric controls of food intake exist and may be accompanied by distinctive increases in neurohypophyseal hormone secretion and loss of gastric function.     

Comparisons of the effects of enterostatin on food intake and gastric emptying in rats

The effects of central and peripheral administration of enterostatin (ENT) on food intake and gastric emptying of a non-nutrient liquid meal have been studied in rats. Intraperitoneal and intragastric administration of ENT at a dose of 120 nmol suppressed the intake of a high-fat diet but failed to inhibit gastric emptying in Sprague-Dawley (SD) rats. Intracerebroventricular (i.c.v.) ENT (1 nmol) reduced intake of a high-fat diet in Osborne-Mendel (OM) and SD rats but not in S5B/Pl rats, whereas it decreased gastric emptying in S5B/Pl and SD rats but not in OM rats. The data suggest that although central ENT may reduce gastric emptying rate, this effect is not related to the inhibitory effect of ENT on food intake.     

Capsaicin pretreatment attenuates multiple responses to cholecystokinin in rats

Systemic injection of the peptide hormone cholecystokinin (CCK) is known to inhibit food intake and gastric emptying, and to stimulate neurohypophyseal secretion of oxytocin (OT) in rats. Previous studies also have shown that surgical destruction of afferent fibers in the gastric vagus eliminates the inhibitory effects of CCK on food intake. The present experiments used capsaicin to destroy peripheral sensory fibers in rats, and confirmed the failure of CCK to inhibit food intake. Similarly, capsaicin pretreatment markedly attenuated the stimulatory effect of CCK on OT secretion and the inhibitory effect of CCK on gastric emptying in rats. These and other results suggest that in rats CCK acts on receptors located on afferent fibers in the gastric vagus and stimulates inhibition of gastric emptying predominantly via a vagovagal reflex arc through the brainstem.     

Gastrointestinal Regulation of Food Intake: General Aspects and Focus on Anandamide and Oleoylethanolamide

The gastrointestinal tract plays a pivotal role in the regulation of food intake and energy balance. Signals from the gastrointestinal tract generally function to limit ingestion in the interest of efficient digestion. These signals may be released into the bloodstream or may activate afferent neurones that carry information to the brain and its cognitive centres, which regulates food intake. The rate at which nutrients become systemically available is also influenced by gastrointestinal motility: a delay in gastric emptying may evoke a satiety effect. Recent evidence suggests that the endocannabinoid anandamide and the related acylethanolamide oleoylethanolamide are produced in the intestine and might regulate feeding behaviour by engaging sensory afferent neurones that converge information to specific areas of the brain. The intestinal levels of these acylethanolamides are inversely correlated to feeding, as food deprivation increases intestinal levels of anandamide (which acts in the gut as a 'hunger signal'), while it decreases the levels of oleoylethanolamide (which acts in the gut as a 'satiety signal'). Additionally, these acylethanolamides, whose gastric levels change in response to diet-induced obesity, alter gastrointestinal motility, which might contribute to their effect on food intake and nutrient absorption.     

Diazepam reverses bombesin-induced gastric spasms and food intake reduction in the rat

Bombesin (2–16 μg/kg, i.p.) produced abnormally large gastric contractions in intact rats consisting of increases in gastric pressure and motility. The effect was antagonized by diazepam (5 mg/kg, i.p.). The same dosage of diazepam abolished bombesin-induced food intake reduction. Diazepam by itself did not increase food intake above control levels. The time course of this behavioral antagonism was followed. There was no significant difference in the intake time course of diazepam-alone and diazepam-bombesin treatments, while there was a significant difference between the saline control and the bombesin-alone treatments. Intake of the saline control, the diazepam-alone and the diazepam-bombesin treatment terminated at the same level, while the bombesin-alone remained significantly different. Additionally, swift aversion to 8 μg/kg bombesin was obtained when flavored nutrient was substituted for flavored water, suggesting that the aversion developed as a consequence of interaction with the ingested diet. Abnormalities that result from bombesin are aggravated when food is substituted for water. It is concluded that food intake reduction is due to the bombesin-produced intragastric abnormalities, and not by satiety.     

Advances in the physiology of gastric emptying

There have been many recent advances in the understanding of various aspects of the physiology of gastric motility and gastric emptying. Earlier studies had discovered the remarkable ability of the stomach to regulate the timing and rate of emptying of ingested food constituents and the underlying motor activity. Recent studies have shown that two parallel neural circuits, the gastric inhibitory vagal motor circuit (GIVMC) and the gastric excitatory vagal motor circuit (GEVMC), mediate gastric inhibition and excitation and therefore the rate of gastric emptying. The GIVMC includes preganglionic cholinergic neurons in the DMV and the postganglionic inhibitory neurons in the myenteric plexus that act by releasing nitric oxide, ATP, and peptide VIP. The GEVMC includes distinct gastric excitatory preganglionic cholinergic neurons in the DMV and postganglionic excitatory cholinergic neurons in the myenteric plexus. Smooth muscle is the final target of these circuits. The role of the intramuscular interstitial cells of Cajal in neuromuscular transmission remains debatable. The two motor circuits are differentially regulated by different sets of neurons in the NTS and vagal afferents. In the digestive period, many hormones including cholecystokinin and GLP‐1 inhibit gastric emptying via the GIVMC, and in the inter‐digestive period, hormones ghrelin and motilin hasten gastric emptying by stimulating the GEVMC. The GIVMC and GEVMC are also connected to anorexigenic and orexigenic neural pathways, respectively. Identification of the control circuits of gastric emptying may provide better delineation of the pathophysiology of abnormal gastric emptying and its relationship to satiety signals and food intake.     

Gastric control of food intake

Inhibition of gastric emptying leads to enhanced satiety and this mechanism may contribute to the undereating observed after administration of cholecystokinin (CCK) and fenfluramine, and in patients with anorexia nervosa. Pyloric smooth muscle bears specific CCK receptors and the evidence suggests that a major site of action for CCK satiety is in the periphery. CCK receptors are widespread in the neonatal rat stomach but not in the brain and over the first two weeks of life binding in the stomach decreases and that in the brain increases. This and the finding that independent ingestion as well as gastric emptying are inhibited by CCK at birth suggest the stomach as its likely site of action in the neonatal rat. Fenfluramine inhibits feeding in animals and in patients with bulimia nervosa. In monkeys, fenfluramine inhibits gastric emptying and this action correlates with its feeding inhibition. Patients with anorexia nervosa who are acutely starving and rats maintained on a restricted diet have delayed gastric emptying. Anorexic patients showed abnormal reporting of both hunger and satiety, and, together with those with bulimia nervosa, often associated gastric contents with symptoms of eating disorder, indicating disturbed interpretation of gastric signals.     

Evidence for a role of the sodium pump of hepatocytes in the control of food intake

To test the hypothesis that the sodium pump of hepatocytes is involved in the control of food intake, we investigated the effect of ouabain, an inhibitor of the sodium pump, on feeding in intact and hepatic vagotomized rats. Ouabain (2 mg/kg b.wt.), injected intraperitoneally during the bright phase of the lighting cycle, stimulated feeding in intact and sham-vagotomized rats, but not in hepatic vagotomized rats. Atropinization did not block ouabain's hyperphagic effect. Ouabain did not affect portal blood glucose level. Rats started to eat sooner than normal when ouabain was injected, while their meal size and duration was unchanged. The results are consistent with a role of the sodium pump of hepatocytes in the control of food intake.     

Dietary self-selection in diabetic rats: An overview

The literature concerning dietary self-selection patterns of diabetic rats is reviewed and compared with new data. There is agreement among the various investigators as to the dietary choices observed following induction of diabetes, regardless of the diabetogenic treatment used. That is, moderately diabetic rats select a high fat, low carbohydrate diet, whereas more severely diabetic animals consume high protein, low carbohydrate diets with little change in fat consumption relative to nondiabetic controls. Even very midly diabetic rats reduce carbohydrate intake. Evaluation of metabolic status of diabetics suggests that with severe diabetes, the beneficial reduction of plasma glucose seen with consumption of a high fat diet may be offset by extreme elevations in ketone and triglyceride levels. Moreover, the hypothesis that diabetic rats are insensitive to carbohydrate calories seems weakened by evidence of reduced food intake following carbohydrate consumption either in solutions or as a gastric load. These findings are discussed in terms of "dietary wisdom" as first proposed by Richter.     

Delay in meal termination follows blockade of N-methyl- -aspartate receptors in the dorsal hindbrain

We have reported that rats increased their intake of food, but not water, following an intraperitoneal injection of MK-801, a non-competitive antagonist of N-methyl- -aspartate (NMDA)-activated ion channels. The antagonist appears to specifically interfere with signals that participate in meal termination (satiety), thereby prolonging the meal and increasing its size. The anatomical site at which MK-801 acts to increase food intake is not known. However, vagal sensory neurons are known to participate in satiation for food. Furthermore, NMDA receptor immunoreactivity is present in the caudal nucleus of the solitary tract (NTS) where vagal sensory fibers terminate. Therefore, we hypothesized that MK-801 might increase food intake by blocking NMDA receptors in the NTS. To test this hypothesis, we microinjected MK-801 directly into the hindbrain, immediately prior to a deprivation-induced meal of 15% sucrose. We found that sucrose intake was significantly increased following injection of MK-801 (2 μg/3 μl) into the fourth ventricle. When MK-801 was injected directly into the caudomedial NTS, intake was increased significantly by doses as small as 198 ng/30 nl, while equivalent injections into other hindbrain areas or the fourth ventricle did not increase food intake. These data are consistent with control of food intake by endogenous glutamate and NMDA-type glutamate receptors located in the caudomedial NTS.     

Acotiamide hydrochloride (Z-338), a novel prokinetic agent, restores delayed gastric emptying and feeding inhibition induced by restraint stress in rats

Abstract  Acotiamide hydrochloride (Z-338) is a member of new class prokinetic agents currently being developed for the treatment of functional dyspepsia (FD). DNA microarray analysis showed that acotiamide altered the expressions of stress-related genes such as γ -aminobutyric acid (GABA) receptors, GABA transporters and neuromedin U (NmU) in the medulla oblongata or hypothalamus after administration of acotiamide. Therefore, effects of acotiamide on stress-related symptoms, delayed gastric emptying and feeding inhibition, in rats were examined. Acotiamide significantly improved both delayed gastric emptying and feeding inhibition in restraint stress-induced model, but did not affect both basal gastric emptying and feeding in intact rats, indicating that acotiamide exerted effects only on gastric emptying and feeding impaired by the stress. On the other hand, mosapride showed significant acceleration of gastric emptying in intact and restraint stress-induced model, and itopride showed no effect on restraint stress-induced delayed gastric emptying. In addition, gene expression of NmU increased by restraint stress was suppressed by administration of acotiamide, while acotiamide had no effect on delayed gastric emptying induced by an intracerebroventricular administration of NmU, suggesting that the suppressive effect of acotiamide on gene expression of NmU might be important to restore delayed gastric emptying or feeding inhibition induced by restraint stress. These findings suggest that acotiamide might play an important role in regulation of stress response. As stress is considered to be a major contributing factor in the development of FD, the observed effects may be relevant for symptom improvement in FD.     

Centrally injected kisspeptin reduces food intake by increasing meal intervals in mice

Kisspeptin is distributed not only in brain areas for regulating reproduction but also in nuclei involved in feeding control. Whether kisspeptin alters food intake is unknown in mice. We examined how kisspeptin-10 influences feeding after intracerebroventricular injection in mice using automated monitoring. Kisspeptin-10 (0.3, 1, and 3 μg/mouse) dose-dependently inhibited the feeding response to an overnight fast by 50, 95, and 90% respectively, during the 2-3 h period postinjection. The 1μg/mouse dose reduced the 4-h cumulative food intake by 28% whereas intraperitoneal injection (10 μg/mouse) did not. The decreased 4-h food intake was due to reduced meal frequency (-45%/4 h), whereas meal size and gastric emptying were not altered. These data suggest that kisspeptin may be a negative central regulator of feeding by increasing satiety.     

Evidence for a vagally mediated satiety signal derived from hepatic fatty acid oxidation

To test the possibility that vagally mediated signals derived from hepatic fatty acid oxidation affect feeding, we investigated the influence of selective hepatic vagotomy on the acute hyperphagic effect of the fatty acid oxidation inhibitor 2-mercaptoacetate (MA) in rats kept on a medium fat diet (18% fat). An i.p. injection of MA (400 mumol/kg b.wt.) stimulated feeding in sham-vagotomized rats clearly more than in vagotomized rats. A high dose of MA (800 mumol/kg b.wt.) initially increased food intake in sham-vagotomized but not in vagotomized rats and later decreased food intake similarly in both surgical groups. MA retained its potency to stimulate feeding after an i.p. injection of atropine methylnitrate (5 mg/kg b.wt.). These results indicate that hepatic fatty acid oxidation provides a satiety signal that is mediated by vagal afferents.     

Intracerebroventricular leptin inhibits gastric emptying of a solid nutrient meal in rats

The effects of leptin injected intracerebroventricularly (i.c.v.) or i.p. on food intake and gastric emptying of a solid nutrient meal were studied in fasted Long-Evan rats. Leptin (3 microg, i.c.v.) reduced the 5 h cumulative food intake by 39% and gastric transit by 50% while i.p. leptin (300 microg) resulted in a 35% decrease in food intake and no change in gastric transit after 5 h. Lower i.p. doses of leptin (30 or 3 microg) did not alter food intake. These results show that central, unlike peripheral, injection of leptin inhibits gastric transit of an ingested meal; such a central action of leptin may contribute to the greater potency of i.c.v. than i.p. leptin to suppress food intake.     

Experience with the high-intensity sweetener saccharin impairs glucose homeostasis and GLP-1 release in rats

Previous work from our lab has demonstrated that experience with high-intensity sweeteners in rats leads to increased food intake, body weight gain and adiposity, along with diminished caloric compensation and decreased thermic effect of food. These changes may occur as a result of interfering with learned relations between the sweet taste of food and the caloric or nutritive consequences of consuming those foods. The present experiments determined whether experience with the high-intensity sweetener saccharin versus the caloric sweetener glucose affected blood glucose homeostasis. The results demonstrated that during oral glucose tolerance tests, blood glucose levels were more elevated in animals that had previously consumed the saccharin-sweetened supplements. In contrast, during glucose tolerance tests when a glucose solution was delivered directly into the stomach, no differences in blood glucose levels between the groups were observed. Differences in oral glucose tolerance responses were not accompanied by differences in insulin release; insulin release was similar in animals previously exposed to saccharin and those previously exposed to glucose. However, release of GLP-1 in response to an oral glucose tolerance test, but not to glucose tolerance tests delivered by gavage, was significantly lower in saccharin-exposed animals compared to glucose-exposed animals. Differences in both blood glucose and GLP-1 release in saccharin animals were rapid and transient, and suggest that one mechanism by which exposure to high-intensity sweeteners that interfere with a predictive relation between sweet tastes and calories may impair energy balance is by suppressing GLP-1 release, which could alter glucose homeostasis and reduce satiety.     

The metabolic bases for “paradoxical” and normal feeding

Hexoses infused slowly into the duodenum or hepatic-portal vein reduce feeding. However, hexoses can increase food intake following rapid infusion via either of these two routes. Insulin responses and resultant glycemic changes differ following fast and slow duodenal glucose infusion. This is unlikely to be the primary explanation, because fructose affects feeding but is not a secretagogue of insulin under our testing conditions. In follow-up studies, we infused glucose or fructose into the hepatic-portal vein at the fast or the slow rate, and measured 14C incorporation into liver mitochondria and glycogen, and tritiated water uptake into hepatic lipids. Fast infusion of glucose or fructose increased lipid formation, reducing mitochondrial uptake and glycogen formation, and was associated with hunger enhancement. Slow hexose infusion was associated with substrate uptake into mitochondria and glycogen, with reduced uptake into hepatic fat. These findings all are consistent with the previously observed positive correlation seen between mitochondrial oxidation and satiety (28).     

The metabolic bases for "paradoxical" and normal feeding

Hexoses infused slowly into the duodenum or hepatic-portal vein reduce feeding. However, hexoses can increase food intake following rapid infusion via either of these two routes. Insulin responses and resultant glycemic changes differ following fast and slow duodenal glucose infusion. This is unlikely to be the primary explanation, because fructose affects feeding but is not a secretagogue of insulin under our testing conditions. In follow-up studies, we infused glucose or fructose into the hepatic-portal vein at the fast or the slow rate, and measured 14C incorporation into liver mitochondria and glycogen, and tritiated water uptake into hepatic lipids. Fast infusion of glucose or fructose increased lipid formation, reducing mitochondrial uptake and glycogen formation, and was associated with hunger enhancement. Slow hexose infusion was associated with substrate uptake into mitochondria and glycogen, with reduced uptake into hepatic fat. These findings all are consistent with the previously observed positive correlation seen between mitochondrial oxidation and satiety (28).     

Delayed gastric emptying and enteric nervous system dysfunction in the rotenone model of Parkinson's disease

Gastrointestinal (GI) dysfunction is the most common non-motor symptom of Parkinson's disease (PD). Symptoms of GI dysmotility in PD include early satiety and weight loss from delayed gastric emptying and constipation from impaired colonic transit. Understanding the pathophysiology and treatment of these symptoms in PD patients has been hampered by the lack of investigation into GI symptoms and pathology in PD animal models. We report that the parkinsonian neurotoxin and mitochondrial complex I inhibitor rotenone causes delayed gastric emptying and enteric neuronal dysfunction when administered chronically to rats in the absence of major motor dysfunction or CNS pathology. When examined 22-28 days after initiation of rotenone infusion by osmotic minipump (3 mg/kg/day), 45% of rotenone-treated rats had a profound delay in gastric emptying. Electrophysiological recording of neurally-mediated muscle contraction in isolated colon from rotenone-treated animals confirmed an enteric inhibitory defect associated with rotenone treatment. Rotenone also induced a transient decrease in stool frequency that was associated with weight loss and decreased food and water intake. Pathologically, no alterations in enteric neuron numbers or morphology were apparent in rotenone-treated animals. These results suggest that enteric inhibitory neurons may be particularly vulnerable to the effects of mitochondrial inhibition by parkinsonian neurotoxins and provide evidence that parkinsonian gastrointestinal abnormalities can be modeled in rodents.