The stomach, cholecystokinin, and satiety

The stomach of the rhesus monkey empties liquids in a fashion that varies with the character of the solutions. Physiological saline empties exponentially. Glucose solutions empty biphasically--rapidly for the first minutes, then slowly and proportionately to glucose concentration to deliver glucose calories through the pylorus at a regulated rate (0.4 kcal/min). This prolonged and regulated second phase of gastric emptying depends on intestinal inhibition of the stomach. Cholecystokinin (CCK), a hormone released by food in the intestine, is an inhibitor of gastric emptying. In vitro receptor autoradiography demonstrates CCK receptors to be clustered on the circular muscle of the pylorus. Exogenous CCK, in doses that inhibit gastric emptying, will reduce food intake only if combined with an infusion of saline in the stomach. These observations indicate how gastric distension can be a means for provoking satiety. The variably sustained distension produced by the stomach's slow, calorically regulated emptying could prolong intermeal intervals and thus permit high-calorie meals to inhibit further caloric intake over time. CCK, by directly inhibiting gastric emptying during a meal, could promote gastric distension and so restrict the duration and size of individual meals.     

Atropine-induced gastrointestinal cytoprotection dependences to the intact of vagal nerve against indomethacin-induced gastrointestinal mucosal and microvascular damage in rats

The non-steroidal antiinflammatory drugs, such as an indomethacin (IND), cause mucosal ulceration and increase the mucosal vascular permeability in the gastrointestinal (GI) tract. Some exogenous agents, e.g. the atropine, can protect the GI mucosa against these ulcerogenic effects. The gastrointestinal functions and mucosal protection, however, are regulated by the vagal nerve. The aims of this study was to examine the dependence of atropine-induced GI cytoprotection to the vagal innervation against the development of IND-caused ulcers and microvascular damage in the mucosa of stomach and small intestine in rats. METHODS: the observations were carried out on CFY-strain rats. The mucosal damage was produced by subcutaneous administration of IND in a 20 mg/kg dose 24 h prior to the killing of animals at the same time as the start of atropine-application, which was given in a small dose (0.1 mg/kg) every 5 h. The subdiaphragmatic bilateral surgical vagotomy was done 24 h before the experiment. The vascular permeability, indicated by the microvascular endothel damage, was measured by the appearance and concentration of intravenously administered Evans blue into the GI mucosa. The number and severity of mucosal lesions and the Evans blue content of mucosa were determined in the stomach and small intestine. RESULTS: (1) The IND caused mucosal ulcers and Evans blue extravasation into the mucosa of the stomach and small intestine. (2) The IND-induced mucosal ulceration and vascular permeability significantly decreased after atropine-administration in the same parts of GI tract. (3) The extent of cytoprotective effect of atropine against the IND was decreased after bilateral surgical vagotomy. CONCLUSIONS: (1) The IND causes microvascular endothel damage in the stomach and small intestinal. (2) The atropine has a cytoprotective effect in the stomach and small intestine against the aggressive effects of IND without decrease of gastric acid secretion. (3) The intact vagal nerve is necessary to the function of cytoprotective mechanisms of atropine against the IND.     

Cholecystokinin and stomach distension combine to reduce food intake in humans

The aim of this study was to test the hypothesis that gastric distension can enhance the effect of cholecystokinin (CCK) on reduction of food intake in men and women. Eight normal-weight subjects of each gender were tested four times each with either CCK or saline infusion crossed with gastric distension or no distension. Intravenous infusion of a low dose of CCK octapeptide (CCK-8; 112 ng/min for 23 min) combined with a subthreshold gastric distension induced by a water-filled balloon (300 ml) resulted in a significant (means +/- SED: 191 +/- 61 g in men, 209 +/- 61 g in women, and 200 +/- 43 g combined) reduction in intake of a liquid meal compared with saline infusion and unfilled gastric balloon. This combined effect was the result of a large and significant CCK effect when the stomach was distended (CCK vs. saline with distension: 169 +/- 43 g) and a small and insignificant distension effect (distension vs. no distension without CCK: 31 +/- 43 g). The CCK effect alone on intake (CCK vs. saline) without distension was not significant in men (72 +/- 61 g) but was significant in women (121 +/- 61 g). These results are consistent with the hypothesis that CCK's suppression of food intake is enhanced when the stomach is distended.     

Behaviorally specific inhibition of sham feeding by amylin

To further characterize amylin’s inhibitory action on feeding, we examined the effects of intraperitoneal injections of amylin on sham feeding of sucrose in food-deprived male rats with chronic gastric cannulas. Thirty and 100 μg/kg amylin reduced sham feeding, but did not terminate it or elicit the behavioral sequence of satiety. Real feeding of sucrose, but not sham feeding, was reduced after injection of 10 μg/kg amylin. Amylin’s inhibitory effect on sham feeding appeared behaviorally specific because neither 30 nor 100 μg/kg amylin affected sham drinking of water in thirsty rats and because no abnormal behaviors occurred. We conclude that amylin has a behaviorally specific satiating effect on sucrose sham feeding that is insufficient to elicit satiety in absence of gastric or postgastric food stimulation.     

Bombesin elicits satiety in sham feeding rats

The satiety effect of intraperitoneal injections of the synthetic tetradecapeptide bombesin (BBS) was examined in rats equipped with chronic gastric cannulas. BBS produced potent, dose-related suppressions of both sham feeding (on days when gastric cannulas were open) and feeding (on days when gastric cannulas were closed). BBS not only suppressed sham feeding, but also elicited the behavioral sequence characteristic of normal satiety. The results demonstrate the potency of BBS in eliciting behavioral satiety under conditions in which gastric, intestinal and postabsorptive mechanisms are minimally activated by ingested food. These findings are consistent with previous reports suggesting a role for BBS in satiety.     

Cholecystokinin and bombesin act independently to decrease food intake in the rat

The satiating effects of cholecystokinin-octapeptide (CCK-8) and bombesin (BBS) when injected alone and in combination were compared in intact rats. When injected alone, both CCK-8 and BBS elicited a dose-related decrease of 30-minute food intake. Injections of BBS were less potent than the equivalent doses of CCK-8 in producing satiety. BBS reached an asymptotic level of suppression of approximately 40 percent at a dose of 2 micrograms/kg, whereas injections of 4 micrograms/kg of CCK-8 resulted in a 72 percent suppression of food intake. When the two peptides were administered in a single injection, the resulting suppression of food intake was equivalent to that which would be predicted if their effects were completely additive. These results support the hypothesis that CCK-8 and BBS act via independent mechanisms to induce satiety. A preliminary model of peptidergic satiety, based on this hypothesis, is proposed.     

Effect of protein, fat, carbohydrate and fibre on gastrointestinal peptide release in humans

Short-term regulation of food intake controls what, when and how much we eat within a single day or a meal. This regulation results from an integrated response to neural and humoral signals that originate from the brain, gastrointestinal (GI) tract and adipose tissue. In the GI tract, multiple sites including the stomach, duodenum, distal small intestine, colon, and pancreas are involved in this process. Ingested food evokes satiety by mechanical stimulation and by release of peptides in the GI tract. The intestine in particular plays a key role in satiety through various peptides secreted in response to food. Many of the intestinal peptides inhibit also gastric emptying thus enhancing gastric mechanoreceptor stimulation. In this review, the current knowledge about the effects of different macronutrients and fibre on the release of GI satiety-related peptides in humans is discussed.     

The effect of vagotomy on the increase in food intake induced by the cholecystokinin antagonist, proglumide

Cholecystokinin, secreted when ingested food enters the duodenum, may act as a satiety factor. Injection of proglumide, a specific antagonist of cholecystokinin, induced an increase in food intake. The satiety effect of administered cholecystokinin is abolished by bilateral subdiaphragmatic vagotomy. If endogenous and exogenous cholecystokinin act via the same mechanism, then vagotomy should abolish the proglumide-induced increase in food intake. Proglumide was used to block the satiety effect of a food preload in sham-operated and vagotomized rats. Proglumide induced an increase in food intake in sham-operated rats confirming earlier results. No change in meal size was observed in vagotomized rats following proglumide injection. These results suggest that vagotomy abolishes the effect of endogenous cholecystokinin on food intake. However, evidence of dumping in vagotomized rats prevents the interpretation of the data as a direct vagal involvement in endogenous CCK-induced satiety.     

Proglumide fails to increase food intake after an ingested preload

Proglumide, a selective antagonist of exogenous cholecystokinin in vitro, also inhibits the reduction of food intake induced by the systemic administration of cholecystokinin octapeptide (CCK-8) in food deprived rats. On the basis of an increase in the size of a brief test meal which followed an oral preload and treatment with a single dose of proglumide, it was suggested that a role for endogenous cholecystokinin in satiety had been demonstrated. We attempted to replicate this finding and could not under very similar experimental conditions. Subsequently, we tested whether other proglumide doses would antagonize the satiating effect of a larger oral preload on test meal intake. When these results were also found to be negative, we confirmed that proglumide (at several doses) significantly antagonized the reduction in food intake induced by exogenous CCK-8 under our conditions. Since proglumide antagonized the satiating effect of exogenous CCK-8, but did not increase food intake after oral preloads that were presumed to release endogenous CCK, we conclude that a reliable satiating effect of endogenous CCK remains to be demonstrated.     

Difference between the effect of acute and chronic surgical vagotomy on the cytoprotective action of atropine against indomethacin-induced mucosal lesions on the gastrointestinal tract in rats

The cytoprotective effect of a small dose of atropine was proved against the indomethacin (IND)-caused gastrointestinal (GI) mucosal damage. This protective effect of atropine disappeared in the acute phase of surgical vagotomy (ASV) on the vagally-innervated parts of GI tract. The aims of our observations were: 1) to examine the effect of chronic surgical vagotomy (CSV) on the cytoprotective action of atropine in the GI tract; and 2) to compare the effects of ASV and CSV on the GI cytoprotection caused by atropine against IND-induced mucosal damage and vascular permeability in rats. The IND was given s.c. 24 h prior to the killing of the animals in a dose of 20 mg x kg(-1). Bilateral surgical vagotomy or sham operation were carried out 24 h (ASV) or 14 d (CSV) before IND-application. Atropine was given i.p. every 5 h after IND-treatment in a dose of 0.1 mg x kg(-1). The number of macroscopical mucosal ulcerations was noted and its severity was calculated by semiquantitative scale in the stomach, small intestine and three equal parts of colon. Vascular permeability was measured by Evans-blue leakage into the mucosal tissue. It has been found that: 1) Tte small dose of atropine significantly decreased the IND-induced mucosal damage and vascular permeability on the stomach, small intestine and the vascular permeability on the proximal colon; 2) the small dose of atropine did not cause any changes in the appearance of IND-induced mucosal lesions and in Evans blue concentration in the mucosa after ASV, but it significantly decreased the IND-caused mucosal damage and Evans blue concentration in the mucosa of stomach, small intestine and proximal colon after CSV; 3) the IND-induced mucosal damage and vascular permeability treated with atropine (given in cytoprotective dose) were significantly smaller after CSV than that after ASV on the stomach, small intestine and proximal colon. It has been concluded that the intact vagal nerve has an essential role in the appearance of cytoprotective mechanisms of atropine in GI tract.     

Effects of CCK on gastrointestinal function in lean and obese Zucker rats

Cholecystokinin (CCK), a hormone affecting several gastrointestinal functions, has also been shown to elicit satiety and affect daily meal patterns. Since Zucker obese rats are less sensitive to the satiety effects of CCK, two experiments were designed to determine if they are also less sensitive to the gastric emptying and intestinal transit rate effects of CCK. In the first experiment phenol red was administered to 5.5 hr fasted rats 15 minutes after intraperitoneal injection of CCK-8 or saline. Rats were sacrificed after 30 minutes, the stomach and small intestine were removed, and phenol red content was measured. More phenol red was in the stomach of obese but not lean rats treated with CCK-8. The rate of transit of the contents of the small intestine was increased by CCK-8 and the percent of phenol red in the fourth quarter of the small intestine was greater in obese than lean rats (91 vs 37%, p<0.05). In the second experiment gastrointestinal transit of ferric oxide was measured during the light and dark phases of the diurnal cycle, and when obese rats were ad lib or yoke-fed to lean pair-mates. Total gastrointestinal transit time of the ferric oxide was decreased 15% when CCK-8 was administered to yoke-fed obese rats in either the light or dark portions of the diurnal cycle but was not affected in ad lib-fed obese rats or lean rats. Thus, while Zucker obese rats are less sensitive to satiety effects of CCK, they appear to be more sensitive to the gastrointestinal effects of CCK, and therefore it is not clear what role these gastrointestinal responses have on the feeding behavior responses.     

Abdominal vagal mediation of the satiety effects of CCK in rats

CCK type 1 (CCK1) receptor antagonists differing in blood-brain barrier permeability were used to test the hypothesis that satiety is mediated in part by CCK action at CCK1 receptors on vagal sensory nerves innervating the small intestine. Devazepide penetrates the blood-brain barrier; A-70104, the dicyclohexylammonium salt of N alpha-3-quinolinoyl-D-Glu-N,N-dipentylamide, does not. At dark onset, non-food-deprived control rats and rats with subdiaphragmatic vagotomies received a bolus injection of devazepide (2.5 micromol/kg i.v.) or a 3-h infusion of A-70104 (3 micromol.kg(-1).h(-1) i.v.) either alone or coadministered with a 2-h intragastric infusion of peptone (0.75 or 1 g/h). Food intake was determined from continuous computer recordings of changes in food bowl weight. In control rats both antagonists stimulated food intake and attenuated the anorexic response to intragastric infusion of peptone. In contrast, only devazepide was effective in stimulating food intake in vagotomized rats. Thus endogenous CCK appears to act both at CCK1 receptors beyond the blood-brain barrier and by a CCK1 receptor-mediated mechanism involving abdominal vagal nerves to inhibit food intake.     

Species-specific effects of bombesin on gastric emptying and neurohypophyseal secretion

Previous reports have demonstrated that systemic injection of cholecystokinin (CCK) in rats produces dose-related decreases in food intake, increases in neurohypophyseal secretion of oxytocin (OT), and decreases in gastric emptying. The present studies determined whether systemic injection of bombesin (BBS), another peptide that potently reduces food intake in rats, had similar effects on OT secretion and gastric emptying. Although BBS produces a dose-dependent inhibition of food intake, even very high doses did not significantly affect plasma OT levels and only slightly decreased rates of gastric emptying. Consequently, despite their similar inhibitory effects on food intake, BBS does not appear to activate the same network of central nervous system pathways as does CCK in rats. However, parallel studies in monkeys demonstrated that systemic injection of BBS was effective in stimulating neurohypophyseal secretion of vasopressin rather than OT, in a pattern both qualitatively and quantitatively analogous to the effects of CCK in this species. Together with previous findings that BBS more potently inhibits gastric emptying in primates than in rats, these results therefore also suggest the presence of significant species differences in the central mechanisms by which BBS acts to reduce food intake.     

Gastric emptying in response to IAPP and CCK in rats with subdiaphragmatic afferent vagotomy

In the subdiaphragmatic vagal deafferentation procedure (SDA), the afferent fibers of the vagus are surgically severed unilaterally where they enter the brain stem. The technique includes a subdiaphragmal truncal vagotomy performed on the contralateral side. This procedure has been used to study the control of food intake, but it has not been used previously to investigate the role of vagal afferent fibers in the control of gastric emptying (GE). The current experiment studied the effect of SDA on the inhibition of GE by islet amyloid polypeptide (IAPP or amylin) and cholecystokinin (CCK) in awake, unrestrained rats with gastric cannulas. The experimental group underwent subdiaphragmatic vagal deafferentation; the control group had sham operations. All rats received 20-min intravenous infusions of IAPP (1, 3, 9, 27, and 81 pmol/kg/min), CCK (3, 30 and 90 pmol/kg/min), and normal saline in random order. Gastric emptying of saline was measured by the phenol red method during the last 5 min of each infusion period. CCK dose-dependently inhibited gastric emptying in both the control and SDA animals. The inhibition of GE by CCK was significantly attenuated by SDA (p<0.01). IAPP also inhibited gastric emptying dose-dependently, but the difference between the SDA and control groups was not significant. The current experiment, which used a different methodology than previous studies, provides support for the hypothesis that the inhibition of gastric emptying by CCK, but not by IAPP, is mediated partly by afferent vagal fibers.     

The endogenous CCK mediation of electroacupuncture stimulation-induced satiety in rats

A major satiety hormone, cholecystokinin (CCK) is well known to be released by electroacupuncture (EA) stimulation at certain body sites which elicits profound psychophysiological responses. Previous clinical and animal studies have shown that EA stimulation reduces food intake and body weight in both normal and obese subjects. The aim of the present study was to elucidate the satiety effect of EA stimulation and its mechanism related to CCK in rats. Here we show that EA stimulation at "Zusanli" (ST36) acupoint significantly reduced 30-min and 60-min food intake in 48-h fasted Sprague-Dawley rats, and such effect was reversed by a lorglumide (CCK-1 receptor antagonist, 10mg/kg, i.p.) pretreatment. The ST36 EA stimulation-induced satiety was not observed in CCK-1 receptor knockout, Otsuka Long-Evans Tokushima Fatty rats, but in their controls, Long-Evans Tokushima Otsuka rats. Subdiaphragmatic vagotomy also blocked the satiety effect of ST36 EA stimulation in Sprague-Dawley rats. These results suggest that ST36 EA stimulation elicits satiety in rats and this is mediated by the endogenous CCK signaling pathway.     

Peripheral and central satiety factors in neuropeptide Y-induced feeding in rats

In the first study, injection of NPY into the hypothalamic paraventricular nucleus (PVN) caused a robust feeding effect that was attenuated by intravenous infusions of glucose, but not fructose. It is suggested that increased blood glucose has a direct central effect on NPY feeding mechanisms. In a second study, and contrary to a previous report, peripheral administration of CCK-8 had a marked satiety effect in NPY-treated rats. Thus, NPY-induced feeding is, at least for a short time, possibly subject to the satiating action of prandially-released CCK. In a final study, NPY was shown to be without effect on gastric emptying of a solid test meal.     

Gastrointestinal satiety signals I. An overview of gastrointestinal signals that influence food intake

An overview is presented of those signals generated by the gastrointestinal (GI) tract during meals that interact with the central nervous system to create a sensation of fullness and satiety. Although dozens of enzymes, hormones, and other factors are secreted by the GI tract in response to food in the lumen, only a handful are able to influence food intake directly. Most of these cause meals to terminate and hence are called satiety signals, with CCK being the most investigated. Only one GI signal, ghrelin, that increases meal size has been identified. The administration of exogenous CCK or other satiety signals causes smaller meals to be consumed, whereas blocking the action of endogenous CCK or other satiety signals causes larger meals to be consumed. Satiety signals are relayed to the hindbrain, either indirectly via nerves such as the vagus from the GI tract or else directly via the blood. Most factors that influence how much food is eaten during individual meals act by changing the sensitivity to satiety signals. This includes adiposity signals as well as habits and learning, the social situation, and stressors.     

CCK enhances response to gastric distension by acting on capsaicin-insensitive vagal afferents

Capsaicin treatment destroys vagal afferent C fibers and markedly attenuates reduction of food intake and induction of hindbrain Fos expression by CCK. However, both anatomical and electrophysiological data indicate that some gastric vagal afferents are not destroyed by capsaicin. Because CCK enhances behavioral and electrophysiological responses to gastric distension in rats and people, we hypothesized that CCK might enhance the vagal afferent response to gastric distension via an action on capsaicin-insensitive vagal afferents. To test this hypothesis, we quantified expression of Fos-like immunoreactivity (Fos) in the dorsal vagal complex (DVC) of capsaicin-treated (Cap) and control rats (Veh), following gastric balloon distension alone and in combination with CCK injection. In Veh rats, intraperitoneal CCK significantly increased DVC Fos, especially in nucleus of the solitary tract (NTS), whereas in Cap rats, CCK did not significantly increase DVC Fos. In contrast to CCK, gastric distension did significantly increase Fos expression in the NTS of both Veh and Cap rats, although distension-induced Fos was attenuated in Cap rats. When CCK was administered during gastric distension, it significantly enhanced NTS Fos expression in response to distension in Cap rats. Furthermore, CCK's enhancement of distension-induced Fos in Cap rats was reversed by the selective CCK-A receptor antagonist lorglumide. We conclude that CCK directly activates capsaicin-sensitive C-type vagal afferents. However, in capsaicin-resistant A-type afferents, CCK's principal action may be facilitation of responses to gastric distension.     

The influence of cadmium (CdCl2) on the canine plasma levels of gastrin,cholecystokinin (CCK), and pancreatic polypeptide (PP)

The influence of cadmium on basal and stimulated plasma levels of gastrin, cholecystokinin (CCK), and pancreatic polypeptide (PP) was investigated in conscious dogs using three doses of cadmium (0.15, 0.5, and 0.75 mg Cd/kg-h). Levels of gastrointestinal (GI) hormones were stimulated with bombesin (BBS), a peptide known to stimulate GI hormone release. Plasma cadmium was measured employing atomic absorption spectrophotometry and GI hormone levels were measured with specific radioimmunoassays (RIA). Basal plasma levels of hormones (pg/mL) in the dogs were in the range (mean ± SE): 38±5 to 44±6 for gastrin, 80±25 to 107±17, for CCK and 120±5 to 142±5 for PP; these levels did not change with cadmium. Significant increases above basal levels in all three hormones were found with infusions of BBS and with BBS plus cadmium. Gastrin levels remained steady during Cd and saline after BBS; however, CCK and PP levels dropped to values that were 68 and 73% less than their stimulated peak levels. With reinfusion of BBS, gastrin, CCK, and PP were significantly elevated above basal; however, the peak values for CCK and PP, but not gastrin, were less than those found during the first BBS infusion. The data suggest that in response to bombesin, cadmium has little or no effect on the release of gastrin, but that is exerts a latent effect on the release of both CCK and PP.     

Peripheral factors in the mediation of cholecystokinin-induced satiety as assessed by comparative potencies of cholecystokinin antagonists.

Cholecystokinin COOH-terminal octapeptide (CCK-8) produces a satiating effect in the rat and other animals upon peripheral administration. Although it has been demonstrated that the receptors which mediate this action are located in the periphery and are of the CCK-A subtype, their anatomical location has not been firmly established. A dense population of CCK receptors in the pyloric sphincter has been suggested as a candidate. We here quantify the potency of several CCK antagonists to inhibit the contractile effect of CCK-8 on the rat pyloric sphincter in vitro. The potent and selective antagonist MK-329 has a Schild pK of 8.85; the less potent but selective antagonist lorglumide (CR-1409) a pK of 6.37; the related antagonist phenoxyacetylproglumide (phi oAc proglumide) a pK of 5.1; and the weak parent compound proglumide a pK of about 3.3. These data can be compared with the potencies of these compounds to inhibit the actions of CCK-8 to produce satiety in the rat; this comparison supports the contention that CCK receptors of the rat pyloric sphincter could in part mediate the satiety effect produced by exogenous CCK-8.