Serotonin type-3 receptors mediate cholecystokinin-induced satiation through gastric distension

2006 ◽  
Vol 291 (1) ◽  
pp. R115-R123 ◽  
Author(s):  
Matthew R. Hayes ◽  
Fiona M. Chory ◽  
Claire A. Gallagher ◽  
Mihai Covasa
Keyword(s):  
Food Intake ◽  
Gastric Distension ◽  
Sucrose Intake ◽  
Gastric Balloon ◽  
Sham Feeding ◽  
Balloon Distension ◽  
Type 3

We have previously shown that serotonin type-3 (5-HT3) receptors mediate cholecystokinin (CCK)-induced satiation and that this effect is dependent on postoropharyngeal feedback. However, the independent contributions of gastric and intestinal feedback in 5-HT3 receptor mediation of suppression of food intake by CCK have not been determined. Using a sham-feeding preparation combined with intraduodenal sucrose infusion, we show that blockade of 5-HT3 receptors by ondansetron (1 mg/kg ip) had no effect on suppression of sham feeding by intraduodenal 15% sucrose infusion (4 ml/10 min), CCK (2 μg/kg ip) administration, or the combination of the two treatments. In separate experiments consisting of either sham-feeding rats that received gastric distension with the use of a balloon or real-feeding rats whose stomachs were distended using gastric loads of saline after the occlusion of the pylorus, we tested the hypothesis that gastric feedback signals are necessary for activation of 5-HT3 receptors. Ondansetron significantly attenuated suppression of sham sucrose intake after a 10-ml gastric balloon distension (30.5 ± 2.2 vs. 20.2 ± 2.2 ml, respectively) and gastric distension combined with CCK (21.9 ± 1.4 vs. 12.0 ± 1.7 ml, respectively). When intestinal feedback was eliminated in a real-feeding paradigm by closing the pylorus using a cuff preparation, ondansetron attenuated suppression of sucrose intake produced by a 10-ml saline gastric load (6.8 ± 0.7 vs. 4.2 ± 0.4 ml, respectively). Finally, when CCK (1 μg/kg) was administered in combination with a 5-ml saline gastric load in a real-feeding preparation, ondansetron significantly attenuated suppression of sucrose intake by CCK (9.0 ± 0.9 vs. 6.3 ± 0.5 ml, respectively), as well as the enhanced suppression of intake by CCK plus gastric load (6.9 ± 0.6 vs. 4.6 ± 0.5 ml, respectively). These findings demonstrate that CCK-induced activation of 5-HT3 receptors requires gastric, but not intestinal feedback.

scholarly journals Serotonin-type 3 receptors mediate intestinal Polycose- and glucose-induced suppression of intake

2005 ◽  
Vol 288 (6) ◽  
pp. R1499-R1508 ◽  
Author(s):  
David M. Savastano ◽  
Melissa Carelle ◽  
Mihai Covasa
Keyword(s):  
Food Intake ◽  
Receptor Antagonist ◽  
Dose Response ◽  
Sucrose Intake ◽  
Hydrolytic Product ◽  
Intraduodenal Infusion ◽  
Time Points ◽  
Glucosidase Inhibitor ◽  
Type 3 ◽  
Response Testing

Ondansetron, a selective serotonin-type 3 (5-HT3) receptor antagonist, was used to test the hypothesis that duodenal infusion of isosmotic solutions of Polycose or its hydrolytic product glucose suppressed intake through 5-HT3 receptors. Polycose suppressed sucrose intake across both concentrations infused (132 mM, 7.6 ± 0.6 ml; 263 mM, 2.3 ± 0.5 ml), compared with intake under control conditions (12.6 ± 0.3 ml, P <0.001). Pretreatment with 1.0 mg/kg ondansetron attenuated reduction of sucrose intake induced only by the highest concentration of Polycose (4.6 ± 0.8 ml, P = 0.004). Dose-response testing revealed that suppression of food intake by 263 mM Polycose was equally attenuated by ondansetron administered at 1.0, 2.0, and 5.0 mg/kg but not when given at 0.125, 0.25, and 0.5 mg/kg. Acarbose, an α-glucosidase inhibitor, attenuated Polycose-induced suppression of food intake, and pretreatment with 1.0 mg/kg ondansetron had no further effect. Suppression of intake after 990 mM glucose but not mannitol infusion was attenuated by pretreatment with 1.0 mg/kg ondansetron. The competitive SGLT1 inhibitor, phloridzin, had no effect on 60-min 990 mM glucose-induced suppression of intake or the ability of ondansetron to attenuate this suppression of intake. Conversely, glucose-induced suppression of intake was attenuated by phloridzin at earlier time points and further attenuated when rats were pretreated with 1.0 mg/kg ondansetron. Ondansetron administration alone had no effect on intake at any dose tested. We conclude that 5-HT3 receptors participate in the inhibition of food intake by intraduodenal infusion of carbohydrate solutions through a posthydrolytic, preabsorptive mechanism.

Comparative effects of CCK-8 on feeding, sham feeding, and exocrine pancreatic secretion in rats

1986 ◽  
Vol 251 (1) ◽  
pp. R97-R105 ◽  
Author(s):  
R. D. Reidelberger ◽  
T. E. Solomon
Keyword(s):  
Food Intake ◽  
Pancreatic Secretion ◽  
Gastric Distension ◽  
Exocrine Pancreatic Secretion ◽  
Humoral Factors ◽  
Sham Feeding ◽  
Hormonal Mechanism ◽  
Satiety Hormone ◽  
Feeding Effect ◽  
Normal Feeding

Cholecystokinin (CCK) is thought to be a hormonal regulator of exocrine pancreatic secretion and is postulated to be a satiety hormone. We compared the dose-response effects of CCK octapeptide (CCK-8) on feeding, sham feeding, and pancreatic secretion to gauge whether the feeding effect might be physiological. Pancreatic responses to intravenous CCK-8 (40, 200, 1,000, or 4,000 pmol . kg-1 . h-1) in fasted unanesthetized rats were compared with effects of CCK-8 (0, 200, 1,000, or 4,000 pmol . kg-1 . h-1) on ingestion of liquid diet in fasted rats with gastric cannulas either closed (normal feeding) or open (sham feeding). Maximal pancreatic amylase output occurred at 200 pmol . kg-1 . h-1 of CCK-8; output declined at higher doses. Food intake was significantly inhibited only at 1,000 and 4,000 pmol . kg-1 . h-1 of CCK-8; the effect was similar when gastric cannulas were closed and open. These results, together with available data on the low postprandial levels of plasma CCK, suggest that circulating levels of CCK normally present after food intake are not sufficient to produce satiety. Furthermore, suppression of feeding by CCK does not appear to be mediated solely by a mechanism that senses gastric distension, because CCK-8 had similar effects in the presence and absence of gastric distension. Whether CCK interacts with other neural or humoral factors to produce satiety by a hormonal mechanism remains to be determined.

Oral-pharyngeal-esophageal and gastric cues contribute to meal-induced c-fos expression

1995 ◽  
Vol 268 (1) ◽  
pp. R223-R230 ◽  
Author(s):  
K. A. Fraser ◽  
E. Raizada ◽  
J. S. Davison
Keyword(s):  
Area Postrema ◽  
Receptor Activation ◽  
Gastric Distension ◽  
Motor Nucleus ◽  
Gastric Fistula ◽  
Gastric Balloon ◽  
Sham Feeding ◽  
Dorsal Motor Nucleus ◽  
Caudal Level

We recently demonstrated that a meal induces c-fos immunoreactivity in the dorsal motor nucleus of the vagus (DMV), the nucleus of the tractus solitarius (NTS), and the area postrema (AP) of the rat brain stem. This response was not eliminated by the cholecystokinin A (CCK-A) antagonist L-364,718, a finding suggesting that feeding induces c-fos immunoreactivity by a pathway that is largely independent of CCK-A receptor activation. Consequently, the role of alternative gastrointestinal cues in the induction of c-fos was investigated. The induction of c-fos after oral-pharyngeal and esophageal stimuli was examined by use of a sham-feeding procedure via a gastric fistula. Gastric fistula-closed and fed rats displayed c-fos immunoreactivity similar to that of meal-fed rats seen previously. Fistula-open and fed rats showed the same degree of staining in the more rostral section of NTS examined as fistula-closed and fed rats, but fewer c-fos-positive nuclei in the more caudal level of the NTS. The potential for gastric distension to induce c-fos was assessed after the inflation of a gastric balloon. Physiological inflation of the balloon produced marked c-fos induction primarily in the medial NTS.

Serotonin-type 3 receptors mediate intestinal lipid-induced satiation and Fos-like immunoreactivity in the dorsal hindbrain

2007 ◽  
Vol 292 (3) ◽  
pp. R1063-R1070 ◽  
Author(s):  
David M. Savastano ◽  
Matthew R. Hayes ◽  
Mihai Covasa
Keyword(s):  
Small Intestine ◽  
Food Intake ◽  
Receptor Antagonist ◽  
Sucrose Solution ◽  
Receptor Activation ◽  
Sucrose Intake ◽  
Neuronal Responses ◽  
Vehicle Injection ◽  
Dorsal Hindbrain ◽  
Type 3

Several gastrointestinal stimuli, including some intestinal nutrients, have been shown to exert their satiating effect via activation of serotonin type-3 (5-HT3) receptors. The presence of lipids in the small intestine potently suppresses food intake; however, whether 5-HT3 receptors play a role in this response has not been directly examined. Therefore, using the selective 5-HT3 receptor antagonist ondansetron, we tested the hypothesis that duodenal infusion of lipid suppresses intake of both sucrose solution and chow through 5-HT3 receptor activation. Rats duodenally infused with 72 and 130 mM Intralipid suppressed 1-h 15% sucrose intake by 33 and 67%, respectively. Suppression of sucrose intake by 72 mM Intralipid was significantly attenuated by ondansetron at all doses tested (0.5, 1.0, 2.0, and 5.0 mg/kg ip), whereas the lowest effective dose of ondansetron to attenuate suppression of intake by 130 mM Intralipid was 1.0 mg/kg. Furthermore, infusion of 130 mM Intralipid suppressed 1- and 4-h chow intake by 35 and 20%, respectively. Ondansetron administered as low as 0.5 mg/kg significantly attenuated 1-h Intralipid-induced suppression of chow intake and completely reversed the suppression by 4 h. Administration of ondansetron alone did not alter sucrose or chow intake compared with vehicle injection at any time. Finally, to test whether Intralipid-induced neuronal activation of the dorsal vagal complex is mediated by 5-HT3 receptors, Fos-like immunoreactivity (Fos-LI) was quantified in ondansetron-pretreated rats following intestinal lipid infusion. Ondansetron (1 mg/kg) significantly attenuated duodenal intralipid-induced Fos-LI in the dorsal hindbrain. These data support the hypothesis that 5-HT3 receptors mediate both satiation, as well as hindbrain neuronal responses evoked by intestinal lipids.

Reduction of food intake by intestinal macronutrient infusion is not reversed by NMDA receptor blockade

2000 ◽  
Vol 278 (2) ◽  
pp. R345-R351 ◽  
Author(s):  
M. Covasa ◽  
R. C. Ritter ◽  
G. A. Burns
Keyword(s):  
Oleic Acid ◽  
Nmda Receptor ◽  
Food Intake ◽  
Intraperitoneal Injection ◽  
Receptor Blockade ◽  
Sucrose Intake ◽  
Sham Feeding ◽  
Mk 801 ◽  
Intraduodenal Infusion ◽  
Nmda Receptor Blockade

Rats increase their intake of food, but not water, after intraperitoneal injection of MK-801, a noncompetitive antagonist of N-methyl-d-aspartate-activated ion channels. We hypothesized that MK-801 might enhance intake by interfering with intestinal chemosensory signals. To test this hypothesis, we examined the effect of the antagonist on 15% sucrose intake after an intraduodenal infusion of maltotriose, oleic acid, or phenylalanine in both real- and sham-feeding paradigms. MK-801 (100 μg/kg) significantly increased sucrose intake regardless of the composition of the infusate during real feeding. Furthermore, MK-801 had no effect on reduction of sucrose intake by intestinal nutrient infusions in sham-feeding rats. These results indicate that MK-801 does not increase meal size and duration by interfering with signals activated by intestinal macronutrients.

Gastric distension induces c-Fos in medullary GLP-1/2-containing neurons

2003 ◽  
Vol 285 (2) ◽  
pp. R470-R478 ◽  
Author(s):  
Niels Vrang ◽  
Curtis B. Phifer ◽  
Michele M. Corkern ◽  
Hans-Rudolf Berthoud
Keyword(s):  
Food Intake ◽  
Mechanical Stimulus ◽  
Gastric Distension ◽  
Neural Pathways ◽  
Appetite Control ◽  
Balloon Distension ◽  
Different Types ◽  
Inhibit Food Intake ◽  
Freely Moving ◽  
Caudal Medulla

A group of neurons in the caudal nucleus of the solitary tract (NTS) processes preproglucagon to glucagon-like peptides (GLP)-1 and -2, peptides that inhibit food intake when administered intracerebroventricularly. The GLP-1/2-containing neural pathways have been suggested to play a role in taste aversion and nausea because LiCl activates these neurons, and LiCl-induced suppression of food intake can be blocked by the GLP-1 receptor antagonist exendin-9. As many gastrointestinal signals related to both satiety and nausea/illness travel via the vagus nerve to the caudal medulla, the present study assessed the capacity of different types of gastric distension (a purely mechanical stimulus) to activate GLP-1 neurons in the caudal NTS. Gastric balloon distension (1.4 ml/min first 5 min, 0.4 ml/min next 5 min, 9 ml total, held for 60 min) in nonanesthetized, freely moving rats produced 12- and 17-fold increases in c-Fos-expressing NTS neurons when distension was mainly in the fundus or corpus, respectively. Fundus and corpus distension increased the percentage of c-Fos-activated GLP-1 neurons to 21 ± 9% and 32 ± 5% compared with 1 ± 1% with sham distension ( P < 0.01). Thus gastric distension that may be considered within the physiological range activates GLP-1/2-containing neurons, suggesting some role in normal satiety. The results support the view that the medullary GLP system is involved in appetite control and is activated by stimuli within the behavioral continuum, ranging from satiety to nausea.

Cholecystokinin (CCK-8) affects gastric pressure and ratings of hunger and fullness in women

1992 ◽  
Vol 263 (2) ◽  
pp. R452-R456 ◽  
Author(s):  
P. M. Melton ◽  
H. R. Kissileff ◽  
F. X. Pi-Sunyer
Keyword(s):  
Food Intake ◽  
Neural Activity ◽  
Pressure Rise ◽  
Gastric Distension ◽  
Gastric Balloon ◽  
Maximum Volume ◽  
Gastric Pressure ◽  
Gastric Contractions ◽  
Distended Stomach

Cholecystokinin (CCK) may affect food intake by augmenting neural activity from the distended stomach, thereby amplifying satiety signals. To test the hypothesis that subjects would report more fullness and less hunger with gastric distension when CCK-8 (112 ng/min) was infused than when saline was infused, a gastric balloon was inflated in the stomachs of four women. When the balloon was inflated to 500 ml, there was no difference in gastric pressure between the CCK-8 and saline conditions. Nonetheless, ratings of fullness were higher with CCK-8 administration. When the balloon was inflated to the maximum volume tolerated, the pressure rise was significantly smaller with CCK-8 infusion. In addition, fullness ratings rose and hunger ratings declined more steeply in relation to gastric pressure when CCK-8 was infused. In all conditions, gastric contractions were practically abolished with CCK-8 infusion. CCK-8 relaxed the stomach and concurrently sensitized the subjects to gastric pressure.

Meal-stimulated absorption of water and electrolytes in canine jejunum

1990 ◽  
Vol 259 (3) ◽  
pp. G402-G409
Author(s):  
C. J. Yeo ◽  
J. A. Bastidas ◽  
R. E. Schmieg ◽  
M. J. Zinner
Keyword(s):  
Gastric Acid ◽  
Acid Output ◽  
Gastric Distension ◽  
Gastric Balloon ◽  
Gastric Acid Output ◽  
Standard Meal ◽  
Jejunal Absorption ◽  
Balloon Distension ◽  
Cephalic Phase ◽  
Independent Mechanism

After a meal, the absorption of water and electrolytes from the jejunal lumen increases. This meal-induced jejunal absorption occurs in jejunal segments out of normal gastrointestinal continuity. The experimental model used 25-cm proximal jejunal Thiry-Vella loops in awake dogs (n = 72 observations) to evaluate the mechanisms involved in meal-induced jejunal absorption, seeking to define the source or sources of the proabsorptive signal. Specifically, we evaluated the jejunal absorptive response to a standard meal, a standard meal plus cholinergic blockage using atropine, a sham-fed meal, a gavage-fed meal, and gastric distension with balloon and gavage water. Both the standard meal and the gavage-fed meal induced a prompt, sustained, and significant (P less than 0.0001) increase in the absorption of H2O, Na+, and Cl-. Atropine significantly reduced the magnitude of the postmeal absorptive response (P less than 0.05) compared with the standard meal alone. The sham-fed meal, gastric balloon distension, and gavage water did not alter jejunal absorption. Vagal nerve integrity after cervical esophageal manipulation was verified by gastric acid output and gastrin response to stimuli. These data support a role for cholinergic modulation of meal-stimulated jejunal absorption via a cephalic-phase-independent and gastric-distension-independent mechanism.

Cholecystokinin and stomach distension combine to reduce food intake in humans

2003 ◽  
Vol 285 (5) ◽  
pp. R992-R998 ◽  
Author(s):  
Harry R. Kissileff ◽  
Julie C. Carretta ◽  
Allan Geliebter ◽  
F. Xavier Pi-Sunyer
Keyword(s):  
Food Intake ◽  
Intravenous Infusion ◽  
Low Dose ◽  
Normal Weight ◽  
Saline Infusion ◽  
Gastric Distension ◽  
Reduce Food Intake ◽  
Gastric Balloon ◽  
Men And Women ◽  
Liquid Meal

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.

5-HT3receptors participate in CCK-induced suppression of food intake by delaying gastric emptying

2004 ◽  
Vol 287 (4) ◽  
pp. R817-R823 ◽  
Author(s):  
Matthew R. Hayes ◽  
Rachael L. Moore ◽  
Samit M. Shah ◽  
Mihai Covasa
Keyword(s):  
Gastric Emptying ◽  
Food Intake ◽  
Feedback Control ◽  
Negative Feedback ◽  
Intraperitoneal Administration ◽  
Liquid Diet ◽  
Solid Meal ◽  
Sham Feeding ◽  
Negative Feedback Control ◽  
Type 3

Serotonin type 3 (5-HT3) receptors have been shown to participate in the negative-feedback control of food intake. We previously reported that cholecystokinin (CCK)-induced suppression of food intake is partly mediated through 5-HT3receptors when rats were tested on a preferred liquid diet, but whether such an effect occurs when they are tested on a solid maintenance diet is unknown. In the present study, we examined the effects of ondansetron, a selective 5-HT3antagonist, on CCK-induced suppression of solid chow intake. Intraperitoneal administration of ondansetron significantly attenuated 30- and 60-min CCK-induced reduction of food intake, with suppression being completely reversed by 120 min. It is not known whether 5-HT3receptors directly mediate CCK-induced satiation or whether their participation depends on CCK acting as part of a feedback cascade to inhibit ongoing intake. Because CCK-induced inhibition of sham feeding does not depend on additive gastric/postgastric-feedback signals, we examined the ability of ondansetron to reverse CCK-induced satiation in sham-feeding rats. Ondansetron did not attenuate reduction of sham feeding by CCK, suggesting that ondansetron does not directly antagonize CCK-satiation signals. CCK suppresses real feeding through a delay in gastric emptying. Ondansetron could attenuate CCK-induced reduction of food intake by reversing CCK-induced inhibition of gastric emptying. We found that blockade of 5-HT3receptors attenuates CCK-induced inhibition of gastric emptying of a solid meal, as well as saline and glucose loads. We conclude that 5-HT3receptors mediate CCK-induced satiation through indirect mechanisms as part of a feedback cascade involving inhibition of gastric emptying.

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