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

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 microg/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 microg/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.     

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.     

Modulation of gastric distension-induced sensations by small intestinal receptors

Duodenal lipid exacerbates gastrointestinal sensations during gastric distension. Using luminal application of the local anesthetic benzocaine, we investigated the role of intestinal receptors in the induction of these sensations. Nine healthy subjects were studied on five occasions, during which isotonic saline or 20% lipid (2 kcal/min), combined with (duodenal or jejunal) 0.75% benzocaine or vehicle at 2.5 ml/min, was infused intraduodenally before and during gastric distension. Intragastric pressures and volumes, gastrointestinal sensations, and plasma CCK levels were determined. Duodenal lipid combined with vehicle increased gastric volume (in ml: saline, -10 +/- 18; lipid/vehicle, 237 +/- 30) and plasma CCK [mean levels (pmol/l): saline, 2.0 +/- 0. 2; lipid/vehicle, 8.0 +/- 1.6] and, during distensions, induced nausea (scores: saline, 3 +/- 2: lipid/vehicle, 58 +/- 19) and decreased pressures at which fullness and discomfort occurred. Duodenal but not jejunal benzocaine attenuated the effect of lipid on gastric volume, plasma CCK, and nausea during distension (135 +/- 38 and 216 +/- 40 ml, 4.6 +/- 0.6 pmol/l and not assessed, and 37 +/- 12 and 64 +/- 21 for lipid + duodenal benzocaine and lipid + jejunal benzocaine, respectively) and on pressures for sensations. In conclusion, intestinal receptors modulate gastrointestinal sensations associated with duodenal lipid and gastric distension. There is also the potential for local neural mechanisms to regulate CCK release and thereby reduce afferent activation indirectly.     

Capsaicin-sensitive vagal fibres and 5-HT3-, gastrin releasing peptide- and cholecystokinin A-receptors are involved in distension-induced inhibition of gastric emptying in the rat.

The present study was undertaken to investigate how the activation of gastric mechanoreceptors by distension of the stomach in conscious gastric fistula rats influences gastric emptying; and the roles of capsaicin sensitive vagal afferent fibres and the 5-HT3, GRP and CCK-A receptors involved in mediating these responses. To activate mechanoreceptors by non-nutrient dependent pathways, methylcellulose in saline was used to distend the stomach (5 cm H2O) and the subsequent emptying of saline was examined immediately, and at 3, 5 and 10 min following distension. Prior distension delayed the subsequent emptying of saline instilled into the stomach compared with non-distended controls (2.28+/-0.09 ml/5 min; P < 0.001). Topical application of capsaicin, completely abolished the distension-induced inhibition of gastric emptying when compared with vehicle treated rats (2.82+/-0.09 vs. 2.38+/-0.04 ml/5 min; P < 0.001). Peripheral administration of a GRP antagonist (2258 U89UJ, 1 mg/kg), and a 5-HT3 antagonist (BRL4369UA, 50 microg/kg) significantly reversed (2.56+/-0.14 ml/5 min; P < 0.05 and 2.61+/-0.07 ml/5 min; P < 0.01; respectively) the delay in gastric emptying induced by distension. When the rats were treated with the CCK-A antagonist, gastric emptying of saline following distension was also significantly facilitated (2.56+/-0.07 ml/5 min; P < 0.001). In contrast, the CCK-B/gastrin receptor antagonist had no significant effect on the distension induced delay in gastric emptying (1.95+/-0.12 ml/5 min). The present results suggest that gastric distension in conscious gastric fistula rats delays gastric emptying by activating capsaicin-sensitive extrinsic afferent nerve fibres. Moreover, the results also indicate that distension-induced mechanisms involve GRP, 5-HT3 and CCK-A receptors, but not CCK-B receptors.     

Cholecystokinin pathways modulate sensations induced by gastric distension in humans

Ingested fat releases CCK, causes gastric relaxation, delays gastric emptying, and limits meal size; however, the mechanistic link among these actions has not been established. Fatty acid release of CCK is chain-length sensitive; dodecanoic acid (C12) induces greater CCK release than decanoic acid (C10). The effect of C12 or C10 on tolerance to subsequent intragastric infusion of liquid was determined in healthy subjects, with and without the CCK(1) receptor antagonist dexloxiglumide. Gastric wall relaxation after either fatty acid was assessed by graded volume distension and by barostat; gastric emptying was measured by gastric aspiration and by a [(13)C]octanoic acid breath technique. C12 released more CCK (mean plasma CCK after vehicle, 4.7 +/- 0.8 pM; C10, 4.8 +/- 0.3 pM; C12, 8 +/- 1.2 pM; P < 0.05 C12 vs. C10 or vehicle) and reduced the volume of water (and of 5 and 25% glucose solutions) delivered at maximum tolerance compared with C10 or vehicle (volume of water tolerated after vehicle, 1,535 +/- 164 ml; C10, 1,335 +/- 160 ml; C12, 842 +/- 103 ml; P < 0.05 C12 vs. C10 or vehicle); this effect was abolished by dexloxiglumide. Intragastric volumes were always similar at the limit of tolerance, and, whereas gastric relaxation occurred to similar degrees after the fatty acids, its duration was longer after C12, which also induced a longer delay in half-gastric emptying [t(1/2)(min) after vehicle, 53 +/- 2; C10, 67 +/- 3; C12, 88 +/- 7; P < 0.05 C12 vs. C10 or vehicle]. In conclusion, ingestion of a CCK-releasing fatty acid reduces the tolerated volume of liquid delivered into the stomach, primarily via a CCK(1) receptor-mediated delay in gastric emptying.     

Relationship between increasing duodenal lipid doses, gastric perception, and plasma hormone levels in humans

Duodenal lipid causes gastric relaxation, CCK secretion, and nausea. Vasopressin has been implicated in motion sickness-related nausea. We hypothesized that increasing doses of lipid enhance gastric relaxation and CCK-vasopressin secretion, resulting in a dose-related exacerbation of nausea. Nine healthy subjects received isotonic saline or lipid (1, 2, or 3 kcal/min, L1, L2, L3) duodenally. Changes in gastric volume, sensations, and plasma hormone levels were assessed during infusions and isobaric gastric distensions. Lipid infusions increased gastric volume, plasma CCK (but not vasopressin) levels, and gastric compliance during distensions, compared with saline. Plasma CCK levels were related to the dose of lipid administered [CCK levels at 30 min (pmol/l), saline: 1.1 +/- 0.2, L1: 1.8 +/- 0.2, L2: 3.0 +/- 0.2, L3: 4.3 +/- 0.6]. During distensions, nausea increased in intensity with increasing doses of lipid [score (where 0 is no sensation and 100 is strongest sensation), saline: 7 +/- 4, L1: 19 +/- 7, L2: 44 +/- 7, L3: 66 +/- 8]; however, no further rise in plasma CCK occurred. Because neither lipid nor distension alone induced significant nausea, we conclude that the interaction between these stimuli together with a modulation by CCK is responsible for the effects observed. Vasopressin is not involved in lipid- and distension-induced nausea.     

Substrate specificity of human ABCC4 (MRP4)-mediated cotransport of bile acids and reduced glutathione

Obese CCK-1 receptor-lacking Otsuka Long Evans Tokushima fatty (OLETF) rats are hyperphagic relative to control, nonmutant Long Evans Tokushima Otsuka (LETO) rats. This study sought to assess whether the overeating observed in OLETF rats is associated with changes in gastric emptying rates or detection of gastric volume. We performed experiments in both 12- and 29-wk-old OLETF and LETO rats to address possible alterations in gastric functions during the development of increased body weight and blood glucose abnormalities in OLETF rats. Gastric emptying of a 5-g solid chow test meal was not significantly different between strains at either 1, 2, or 4 h postmeal. When rats with ad libitum access to chow were tested, there were no significant differences in gastric emptying between strains at any time period despite OLETF rats consuming significantly more chow than LETO rats. Similar to solid food, 5-min gastric emptying of a 5-ml isosmotic and hyperosmotic saline or glucose load was not significantly different between strains. When the stomach was distended with a 15-ml semisolid chow load, there was no significance difference in emptying at either 1 or 2 h. No significant differences in gastric emptying were detected between 12- and 29-wk-old rats under any conditions. Both young and old OLETF rats, however, reduced sham intake significantly less compared with LETO rats during a brief period of gastric distension by 5- or 10-ml balloon inflation. Finally, OLETF rats showed decreased Fos expression in the nucleus of the solitary tract relative to LETO rats after an 8-ml gastric distension. These findings demonstrate that OLETF rats do not express deficits in controlling gastric emptying rates; however, they exhibit decreased behavioral and vagal responsiveness to gastric distension that may contribute to the increased meal size in these animals.     

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.     

Distension of the esophagogastric junction augments triggering of transient lower esophageal sphincter relaxation

Patients with gastroesophageal reflux disease show an increase in esophagogastric junction (EGJ) distensibility and in frequency of transient lower esophageal sphincter relaxations (TLESR) induced by gastric distension. The objective was to study the effect of localized EGJ distension on triggering of TLESR in healthy volunteers. An esophageal manometric catheter incorporating an 8-cm internal balloon adjacent to a sleeve sensor was developed to enable continuous recording of EGJ pressure during distension of the EGJ. Inflation of the balloon doubled the cross-section of the trans-sphincteric portion of the catheter from 5 mm OD (round) to 5 × 11 mm (oval). Ten healthy subjects were included. After catheter placement and a 30-min adaptation period, the EGJ was randomly distended or not, followed by a 45-min baseline recording. Subjects consumed a refluxogenic meal, and recordings were made for 3 h postprandially. A repeat study was performed on another day with EGJ distension status reversed. Additionally, in one subject MRI was performed to establish the exact position of the balloon in the inflated state. The number of TLESR increased during periods of EGJ distension with the effect being greater after a meal [baseline: 2.0(0.0-4.0) vs. 4.0(1.0-11.0), P=0.04; postprandial: 15.5(10.0-33.0) vs. 22.0(17.0-58.0), P=0.007 for undistended and distended, respectively]. EGJ distension augments meal-induced triggering of TLESR in healthy volunteers. Our data suggest the existence of a population of vagal afferents located at sites in/around the EGJ that may influence triggering of TLESR.     

NMDA receptor blockade attenuates CCK-induced reduction of real feeding but not sham feeding

Systemic injection of MK-801, a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptor ion channels, increases meal size and delays satiation. We examined whether MK-801 increases food intake by directly interfering with actions of cholecystokinin (CCK). Prior administration of MK-801 (100 microg/kg ip) reversed the inhibitory effects of CCK-8 (2 and 4 microg/kg ip) on real feeding of both liquid and solid foods. MK-801 alone did not alter 30-min sham intake of 15% sucrose compared with intake after saline. Furthermore, while CCK-8 (2 or 4 microg/kg ip) reduced sham intake, this reduction was not attenuated by MK-801 pretreatment. To ascertain whether MK-801 attenuation of CCK-induced reduction of real feeding was associated with attenuated inhibition of gastric emptying, we tested the effect of MK-801 pretreatment on CCK-induced inhibition of gastric emptying of 5-ml saline loads. Ten-minute gastric emptying was accelerated after MK-801 (3.9 +/- 0.2 ml) compared with saline vehicle (2.72 +/- 0.2 ml). CCK-8 (0.5 microg/kg ip) reduced 10-min emptying to 1.36 +/- 0.3 ml. Pretreatment with MK-801 did not significantly attenuate CCK-8-induced reduction of gastric emptying (0.9 +/- 0.4 ml). This series of experiments demonstrates that blockade of NMDA ion channels reverses inhibition of real feeding by CCK. However, neither inhibition of sham feeding nor inhibition of gastric emptying by CCK is attenuated by MK-801. Therefore, increased food intake after NMDA receptor blockade is not caused by a direct interference with CCK-induced satiation. Rather, increased real feeding, either in the presence or absence of CCK, depends on blockade of NMDA receptor participation in other post-oral feedback signals such as gastric sensation or gastric tone.     

Nociceptin in rVLM mediates electroacupuncture inhibition of cardiovascular reflex excitatory response in rats.

Electroacupuncture (EA) at Neiguan-Jianshi acupoints through an opioid mechanism inhibits the cardiovascular pressor response induced by mechanical stimulation of the stomach. Because nociceptin also may regulate cardiovascular activity through its action in the brain stem, we hypothesized that this neuromodulator serves a role in the EA-related inhibitory effect. Blood pressure in ventilated male Sprague-Dawley rats (400-600 g) anesthetized by ketamine and alpha-chloralose was measured during balloon inflation of the stomach. Gastric distension with 6-8 ml of air induced consistent pressor reflexes of 26 +/- 1 mmHg that could be repeated every 10 min for 100 min. When nociceptin (10 nM) was microinjected into the rostral ventrolateral medulla (rVLM), the pressor response induced by gastric distension was inhibited by 68 +/- 6%. Thirty minutes of EA also decreased the reflex response by 75 +/- 11%; microinjection of saline into the rVLM did not alter the inhibitory effect of EA. In contrast, microinjection of a nociceptin receptor antagonist into the rVLM promptly reversed the EA response. Pretreatment with the opioid receptor antagonist naloxone did not influence the EA-like inhibitory effect of nociceptin on the distension-induced pressor reflex (22 +/- 1 to 8 +/- 2 mmHg). Furthermore, a mu-opioid receptor agonist microinjected into the rVLM after microinjection of a nociceptin receptor antagonist during EA promptly reversed the nociceptin receptor antagonist-related inhibition of the EA effect. Thus, in addition to the classical opioid system, nociceptin, through opioid receptor-like-1 receptor stimulation in the rVLM, participates in the modulatory influence of EA on reflex-induced increases in blood pressure.     

Loxiglumide, a CCK-A receptor antagonist, stimulates calorie intake and hunger feelings in humans

Exogenous cholecystokinin (CCK) induces early satiety when infused into humans. Whether alimentary CCK (CCK-A) receptor blockade stimulates food intake in humans is, however, uncertain. The aim of the present investigation was, therefore, to establish the effect of CCK-A receptor blockade on satiety and eating behavior in healthy volunteers. To further explore the role of endogenous CCK, the effects of the specific CCK-A receptor antagonist loxiglumide (Lox; 22 micromol. kg(-1). h(-1)) on satiety and eating behavior were investigated in healthy men and compared with saline infusions (as placebo) in a series of randomized, double-blind, placebo-controlled, crossover studies. Lox produced a slight (7%), but not significant (P = 0.104), increase in food intake that was accompanied by a modest (10%), but significant (P < 0.004), increase in calorie intake. Fluid ingestion was not affected by Lox. Subjects experienced more hunger and delayed fullness during Lox infusion than during saline infusion (P < 0.05). This study provides further evidence that CCK is an endogenous physiological satiety signal acting through CCK-A receptor-mediated mechanisms. Repeated-dose studies comparing hunger and satiety responses after CCK-A receptor blockade in healthy subjects and patients with eating disorders may help clarify the possible involvement of endogenous CCK in these conditions.     

Satiety: the roles of peptides from the stomach and the intestine

Rats were surgically prepared to allow perfusions of anatomically limited portions of the gastrointestinal (GI) surface during test meals. The results demonstrated that at least one potent satiety signal was generated when ingested food accumulated in the stomach and did not enter the small intestine. This gastric satiety signal did not require the vagus nerve for its operation. In addition, at least one other potent satiety signal was generated when food perfused the small intestine. This intestinal satiety signal did not require gastric distension for its operation. We tested a variety of GI peptides to determine whether any met the criteria imposed by this evidence for regionally specific satiety signals. Bombesin (BBS), a peptide present in high concentration in the stomach, was a potent and behaviorally specific inhibitor of food intake. Its satiating effect was not altered by subdiaphragmatic vagotomy. Cholecystokinin (CCK), a peptide hormone that is released from the small intestine by food, was also a potent and behaviorally specific inhibitor of food intake; its satiating effect did not require gastric distension for its expression, but its satiating effect was markedly reduced or abolished by subdiaphragmatic vagotomy. Thus, BBS and CCK may mediate at least part of the satiating effect of food acting in the stomach and in the small intestine, respectively.     

Effect of peripherally administered ghrelin on gastric emptying and acid secretion in the rat

Ghrelin is a gut peptide that is secreted from the stomach and stimulates food intake. There are ghrelin receptors throughout the gut and intracerebroventricular ghrelin has been shown to increase gastric acid secretion. The aim of the present study was to examine the effects of peripherally administered ghrelin on gastric emptying of a non-nutrient and nutrient liquid, as well as, basal and pentagastrin-stimulated gastric acid secretion in awake rats. In addition, gastric contractility was studied in vitro. Rats equipped with a gastric fistula were subjected to an intravenous infusion of ghrelin (10-500 pmol kg(-1) min(-1)) during saline or pentagastrin (90 pmol kg(-1) min(-1)) infusion. After administration of polyethylene glycol (PEG) 4000 with 51Cr as radioactive marker, or a liquid nutrient with (51)Cr, gastric retention was measured after a 20-min infusion of ghrelin (500 pmol kg(-1) min(-1)). In vitro isometric contractions of segments of rat gastric fundus were studied (10(-9) to 10(-6) M). Ghrelin had no effect on basal acid secretion, but at 500 pmol kg(-1) min(-1) ghrelin significantly decreased pentagastrin-stimulated acid secretion. Ghrelin had no effect on gastric emptying of the nutrient liquid, but significantly increased gastric emptying of the non-nutrient liquid. Ghrelin contracted fundus muscle strips dose-dependently (pD2 of 6.93+/-0.7). Ghrelin IV decreased plasma orexin A concentrations and increased plasma somatostatin concentrations. Plasma gastrin concentrations were unchanged during ghrelin infusion. Thus, ghrelin seems to not only effect food intake but also gastric motor and secretory function indicating a multifunctional role for ghrelin in energy homeostasis.     

Influence of sildenafil on gastric sensorimotor function in humans

After a meal, the proximal stomach relaxes probably through the activation of nitrergic neurons in the gastric wall. Nitric oxide-induced smooth muscle relaxation involves activation of soluble guanylate cyclase, with cGMP production, which is then degradated by phosphodiesterase-5 (PDE-5). The aim of this study was to investigate the effect of sildenafil, a selective PDE-5 inhibitor, on fasting and postprandial proximal gastric volume and on gastric emptying rates in humans. A gastric barostat was used to study gastric compliance and perception to isobaric distension in healthy subjects before and after placebo (n = 13) or sildenafil, 50 mg (n = 15). In 10 healthy subjects, two gastric barostat studies were performed in randomized order to study the effect of placebo or sildenafil on postprandial gastric relaxation. Similarly, solid and liquid gastric emptying rates were studied in 12 healthy subjects. Sildenafil significantly increased fasting intragastric volume (141 +/- 15 vs. 163 +/- 15 ml, P < 0.05) and volumes of first perception. Sildenafil induced a higher and prolonged gastric relaxation either at 30 min (357 +/- 38 vs. 253 +/- 42 ml, P < 0.05) or 60 min (348 +/- 49 vs. 247 +/- 38 ml, P < 0.05) after the meal. Sildenafil did not alter solid half-emptying time but significantly delayed liquid emptying (43 +/- 4 vs. 56 +/- 4 min, P < 0.01). In conclusion, sildenafil significantly increases postprandial gastric volume and slows liquid emptying rate, confirming that meal-induced accommodation in humans involves the activation of a nitrergic pathway. The effect of sildenafil on gastric fundus suggests a therapeutic potential for phosphodiesterase inhibitors in patients with impaired gastric accommodation.     

Load-dependent effects of duodenal lipid on antropyloroduodenal motility, plasma CCK and PYY, and energy intake in healthy men

Both load and duration of small intestinal lipid infusion affect antropyloroduodenal motility and CCK and peptide YY (PYY) release at loads comparable to and higher than the normal gastric emptying rate. We determined 1) the effects of intraduodenal lipid loads well below the mean rate of gastric emptying on, and 2) the relationships between antropyloroduodenal motility, CCK, PYY, appetite, and energy intake. Sixteen healthy males were studied on four occasions in double-blind, randomized fashion. Antropyloroduodenal motility, plasma CCK and PYY, and appetite perceptions were measured during 50-min IL (Intralipid) infusions at: 0.25 (IL0.25), 1.5 (IL1.5), and 4 (IL4) kcal/min or saline (control), after which energy intake at a buffet meal was quantified. IL0.25 stimulated isolated pyloric pressure waves (PWs) and CCK release, albeit transiently, and suppressed antral PWs, PW sequences, and hunger (P < 0.05) but had no effect on basal pyloric pressure or PYY when compared with control. Loads >/= 1.5 kcal/min were required for the stimulation of basal pyloric pressures and PYY and suppression of duodenal PWs (P < 0.05). All of these effects were related to the lipid load (R > 0.5 or < -0.5, P < 0.05). Only IL4 reduced energy intake (in kcal: control, 1,289 +/- 62; IL0.25, 1,282 +/- 44; IL1.5, 1,235 +/- 71; and IL4, 1,139 +/- 65 compared with control and IL0.25, P < 0.05). In conclusion, in healthy males the effects of intraduodenal lipid on antropyloroduodenal motility, plasma CCK and PYY, appetite, and energy intake are load dependent, and the threshold loads required to elicit responses vary for these parameters.     

Meal fatty acid uptake in adipose tissue: gender effects in nonobese humans

We tested for gender differences in dietary fatty acid metabolism in 12 nonobese men and 12 nonobese women using the meal fatty acid tracer/adipose tissue biopsy study design. In addition to determining body composition, measurements of regional adipose tissue lipoprotein lipase activity, blood flow, and fat cell size were performed to place the meal fatty acid kinetic studies in perspective. Twenty-four hours after ingesting the test meal, the concentration of meal fatty acids was greater (P < 0.05) in abdominal subcutaneous than in thigh adipose tissue in both men (0. 61 +/- 0.12 vs. 0.45 +/- 0.09 mg/g) and women (0.59 +/- 0.10 vs. 0. 43 +/- 0.05) but was not different between men and women. A greater percentage of dietary fat was stored in subcutaneous adipose tissue in women than in men (38 +/- 3 vs. 24 +/- 3%, respectively, P < 0. 05), and a greater portion of meal fatty acid disposal was unaccounted for in men. Significant gender differences in regional adipose tissue blood flow after meal ingestion were noted; the differences were in the direction that could support greater nutrient storage in lower body fat in women.     

Peripheral administration of GLP-2 to humans has no effect on gastric emptying or satiety

Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are secreted in parallel to the circulation after a meal. Intravenous (IV) GLP-1 has an inhibitory effect on gastric emptying, hunger and food intake in man. In rodents, central administration of GLP-2 increases satiety similar to GLP-1. The aim of the present study was to assess the effect of IV administered GLP-2 on gastric emptying and feelings of hunger in human volunteers. In eight (five men) healthy subjects (age 31.1+/-2.9 years and BMI 24.1+/-1.0 kg m(-2)), scintigraphic solid gastric emptying, hunger ratings (VAS) and plasma concentrations of GLP-2 were studied during infusion of saline or GLP-2 (0.75 and 2.25 pmol kg(-1) min(-1)) for a total of 180 min. Concentrations of GLP-2 were elevated to a maximum of 50 and 110 pmol l(-1) for 0.75 and 2.25 pmol kg(-1) min(-1) infusion of GLP-2, respectively. There was no effect of GLP-2 on either the lag phase (29.5+/-4.4, 26.0+/-5.2 and 21.2+/-3.6 min for saline, GLP-2 0.75 or 2.25 pmol kg(-1) min(-1), respectively) or the half emptying time (84.5+/-6.1, 89.5+/-17.8 and 85.0+/-7.0 min for saline, GLP-2 0.75 or 2.25 pmol kg(-1) min(-1), respectively). The change in hunger rating after the meal to 180 min was also unaffected by infusion of GLP-2. GLP-2 does not seem to mediate the ileal brake mechanism.     

Gastric distension attenuates the hypotensive effect of intraduodenal glucose in healthy older subjects

Postprandial hypotension occurs frequently, and current management is suboptimal. Recent studies suggest that the magnitude of the fall in postprandial blood pressure (BP) may be attenuated by gastric distension. The aim of this study was to determine the effect of gastric distension on the hypotensive response to intraduodenal (ID) glucose. Eight healthy subjects (5 males, 3 females, aged 65-76 years) received an ID infusion of either 1) 50 g glucose in 300 ml saline (ID glucose) over 60 min (t=0-60 min), 2) 50 g glucose in 300 ml saline over 60 min and intragastric (4) infusion of 500 ml water between t=7-10 min (IG water and ID glucose), or 3) ID saline (0.9%) infusion over 60 min and IG infusion of 500 ml water (IG water and ID saline) all followed by ID saline infusion for another 60 min (t=60-120 min) on three separate days. BP and heart rate (HR) were measured. Gastric emptying (GE) of the IG water was quantified by two-dimensional ultrasonography. Between t=0-60 min, systolic and diastolic BP was greater (P<0.05 for both) with IG water and ID saline compared with IG water and ID glucose, and less (P<0.05 for both) with ID glucose compared with IG water and ID glucose. These effects were evident at relatively low IG volumes (approximately 300 ml). GE was faster with IG water and ID saline when compared with IG water and ID glucose. We conclude that, in healthy older subjects, IG administration of water markedly attenuates the hypotensive response to ID glucose, presumably as a result of gastric distension.     

Intraluminal modulation of gastric sensitivity to distension: effects of hydrochloric acid and meal

Conscious sensations in response to gut distensions may be modulated by temporospatial interactions among different stimuli. This study investigated whether symptoms induced by gastric distension may be modified by hydrochloric acid (HCl) gastric infusion and meal ingestion. In nine healthy subjects, fixed pressure (isobaric) and fixed volume (isovolumetric) distensions were performed during continuous (4 ml/min) intragastric saline or HCl infusion, during fasting and after meal ingestion, until the maximal distension step defined as discomfort or a predefined maximal volume. During fasting isobaric distensions, the maximal distension step was significantly decreased during HCl compared with saline. The intragastric volumes were not significantly different, but the wall tension was significantly lower during HCl than saline. HCl increased gastric compliance. Meal ingestion relaxed the stomach and decreased the pressure at the maximal distension step during saline, but HCl did not further decrease it compared with fasting. During isovolumetric distensions, HCl also increased gastric compliance, but in both fasted and fed states it did not modify the maximal distension steps. In conclusion, sensations in response to gastric isobaric distensions, but not to isovolumetric distensions, are influenced by gastric acid infusion and meal ingestion. The effects of HCl might be related to a sensitization of mucosal mechanoreceptors.