Intraduodenal Lipid Research Articles

Estradiol Enhances Cholecystokinin-Dependent Lipid-Induced Satiation and Activates Estrogen Receptor-α-Expressing Cells in the Nucleus Tractus Solitarius of Ovariectomized Rats

Part of the mechanism through which estradiol, acting via estrogen receptor (ERalpha) signaling, inhibits feeding in rats and mice is increasing the satiating potency of cholecystokinin (CCK) acting on peripheral CCK-1 receptors. Ingested lipid is a principal secretagogue of intestinal CCK, and intraduodenal lipid infusions elicit CCK-mediated satiation in animals and humans. Here we tested whether estradiol affects the satiating potency of intraduodenal lipid infusions in ovariectomized rats and, using c-Fos immunocytochemistry, searched for potential brain sites of ERalpha involved. Food-deprived ovariectomized rats with open gastric cannulas sham fed 0.8 m sucrose 2 d after estradiol (estradiol benzoate, 10 mug, sc) or vehicle injection. Estradiol markedly increased the satiating potency of intraduodenal infusions of Intralipid but not the satiating potency of L-phenylalanine (10 min infusions, 0.44 ml/min, 0.13 kcal/ml), which in male rats satiates via a CCK-independent mechanism. Estradiol had no significant effect in rats pretreated with the CCK-1 receptor antagonist Devazepide (1 mg/kg, ip). The effect of estradiol on intraduodenal Intralipid-induced satiation was mirrored by selective increases in the number of cells expressing c-Fos immunoreactivity in a circumscribed region of the nucleus tractus solitarius (NTS), just caudal to the area postrema (cNTS) but not elsewhere in the NTS or the hypothalamic paraventricular or arcuate nuclei. In addition, a significant proportion of cNTS c-Fos-positive cells also expressed ERalpha. These data provide behavioral and cellular evidence that estradiol-ERalpha signaling in cNTS neurons increases the satiating potency of endogenous CCK released in response to ingested lipid.

Free Fatty Acids Have More Potent Effects on Gastric Emptying, Gut Hormones, and Appetite Than Triacylglycerides

The effects of fat on gastric emptying (GE), gut hormones, and energy intake are dependent on digestion to free fatty acids (FFAs). In animals, small intestinal oleic acid inhibits energy intake more potently than the triacylglyceride (TG) triolein, but there is limited information about the comparative effects of FFA and TG in human beings. We compared the effects of FFA and TG on GE, gut hormone secretion, appetite, and energy intake in healthy males. Nine men (age, 23 +/- 2 y; body mass index, 22 +/- 1 kg/m(2)) were studied on 3 occasions to evaluate the effects of (1) 40 g oleic acid (FFA, 1830 kJ), (2) 40 g macadamia oil (TG, 1856 kJ; both 600-mL oil-in-water emulsions stabilized with 4% milk protein and labeled with 15 MBq (123)I), or (3) 600 mL 4% milk protein (control, 352 kJ), administered intragastrically, on GE, plasma cholecystokinin (CCK) and peptide-YY (PYY) levels, appetite perceptions, and subsequent energy intake. GE of FFA was much slower than that of TG (P < .05), with greater retention of FFA, than TG, in the proximal stomach (P < .001). Hunger was less (P < .05), and fullness was greater (P < .05), after FFA when compared with control and TG. Increases in plasma CCK and PYY levels were greater after FFA than TG or control (P < .05). Energy intake tended to be less after FFA compared with TG (control, 4754 +/- 610 kJ; TG, 5463 +/- 662 kJ; FFA, 4199 +/- 410 kJ). FFAs empty from the stomach more slowly, but stimulate CCK and PYY and suppress appetite more potently than TG in healthy human beings.

Overexpression of Apolipoprotein A-IV Enhances Lipid Secretion in IPEC-1 Cells by Increasing Chylomicron Size

Intestinal apolipoprotein A-IV expression is highly regulated by dietary lipid in newborn swine, suggesting a role in lipid absorption. Constitutive overexpression of apoA-IV in newborn swine enterocytes enhances basolateral secretion of triacylglycerol (TG) in TG-rich lipoproteins 4.9-fold (Lu, S., Yao, Y., Meng, S., Cheng, X., and Black, D. D. (2002) J. Biol. Chem. 277, 31929-31937). To investigate the mechanism of this enhancement, IPEC-1 cells were transfected with a tetracycline-regulatable expression system (Tet-On). In cells incubated with oleic acid, a dose response relationship was observed between medium doxycycline concentration and basolateral apoA-IV and TG secretion. Similarly regulated expression of apoA-I did not enhance lipid secretion. The mean diameter of TG-rich lipoproteins secreted from doxycycline-treated cells was larger than from untreated cells (87.0 nm versus 53.4 nm). Basolateral apoB secretion decreased. Using the same expression system, full-length human apoA-IV (376 amino acids); a "pig-like" human apoA-IV, lacking the C-terminal EQQQ repeats (361 amino acids); and a "chicken-like" apoA-IV, further truncated to 343 amino acids, were expressed in IPEC-1 cells. With increasing protein secretion, cells expressing the full-length human apoA-IV displayed a 2-fold increase in TG secretion; in sharp contrast, cells expressing the pig-like human apoA-IV displayed a 25-fold increase in TG secretion and a 27-fold increase in lipoprotein diameter. When human apoA-IV was further truncated to yield a chicken-like protein, TG secretion was inhibited. We conclude that overexpression of swine apoA-IV enhances basolateral TG secretion in a dose-dependent manner by increasing the size of secreted lipoproteins. These data suggest that the region in the human apoA-IV protein from residues 344 to 354 is critical to its ability to enhance lipid secretion, perhaps by enabling the packaging of additional core TG into chylomicron particles. The EQQQ-rich region may play an inhibitory or modulatory role in chylomicron packaging in humans.

Lymphatic chylomicron size is inversely related to biliary phospholipid secretion in mice

Biliary phospholipids (PL) stimulate dietary fat absorption by facilitating intraluminal lipid solubilization and by providing surface components for chylomicron (CM) assembly. Impaired hepatic PL availability induces secretion of large very-low-density lipoproteins, but it is unclear whether CM size depends on biliary PL availability. Biliary PL secretion is absent in multidrug resistance protein 2-deficient (Mdr2(-/-)) mice, whereas it is strongly increased in essential fatty acid (EFA)-deficient mice. We investigated lymphatic CM size and composition in mice with absent (Mdr2(-/-)) or enhanced (EFA deficient) biliary PL secretion and in their respective controls under basal conditions and during enteral lipid administration. EFA deficiency was induced by feeding mice a high-fat, EFA-deficient diet for 8 wk. Lymph was collected by mesenteric lymph duct cannulation with or without intraduodenal lipid administration. Lymph was collected in 30-min fractions for up to 4 h, and lymphatic lipoprotein size was determined by dynamic light-scattering techniques. Lymph lipoprotein subfractions were isolated by ultracentrifugation, and lipid composition was measured. Lymphatic CMs were significantly larger in Mdr2(-/-) mice than in Mdr2(+/+) controls either without (+50%) or with (+25%) enteral lipid administration, and molar core-surface ratios were increased [triglyceride (TG)-to-PL ratio: 4.4 +/- 1.4 in Mdr2(-/-) mice vs. 2.7 +/- 0.8 in Mdr2(+/+) mice, P < 0.001]. In contrast, EFA-deficient mice secreted lipoproteins into lymph that were significantly smaller than in EFA-sufficient controls (173 +/- 32 vs. 236 +/- 47 nm), with correspondingly decreased core-surface ratios (TG-to-PL ratio: 3.0 +/- 1.0 in EFA-deficient mice vs. 6.0 +/- 1.9 in EFA-sufficient mice, P < 0.001). CM size increased during fat absorption in both EFA-deficient and EFA-sufficient mice, but the difference between the groups persisted. In conclusion, the present results strongly suggest that the availability of biliary PL is a major determinant of the size of intestinally produced lipoproteins both under basal conditions and during lipid absorption. Altered CM size may have physiological consequences for postprandial CM processing.

Fat digestion is required for suppression of ghrelin and stimulation of peptide YY and pancreatic polypeptide secretion by intraduodenal lipid

Stimulation of cholecystokinin and glucagon-like peptide-1 secretion by fat is mediated by the products of fat digestion. Ghrelin, peptide YY (PYY), and pancreatic polypeptide (PP) appear to play an important role in appetite regulation, and their release is modulated by food ingestion, including fat. It is unknown whether fat digestion is a prerequisite for their suppression (ghrelin) or release (PYY, PP). Moreover, it is not known whether small intestinal exposure to fat is sufficient to suppress ghrelin secretion. Our study aimed to resolve these issues. Sixteen healthy young males received, on two separate occasions, 120-min intraduodenal infusions of a long-chain triglyceride emulsion (2.8 kcal/min) 1) without (condition FAT) or 2) with (FAT-THL) 120 mg of tetrahydrolipstatin (THL, lipase inhibitor), followed by a standard buffet-style meal. Blood samples for ghrelin, PYY, and PP were taken throughout. FAT infusion was associated with a marked, and progressive, suppression of plasma ghrelin from t = 60 min (P < 0.001) and stimulation of PYY from t = 30 min (P < 0.01). FAT infusion also stimulated plasma PP (P < or = 0.01), and the release was immediate. FAT-THL completely abolished the FAT-induced changes in ghrelin, PYY, and PP. In response to the meal, plasma ghrelin was further suppressed, and PYY and PP stimulated, during both FAT and FAT-THL infusions. In conclusion, in healthy humans, 1) the presence of fat in the small intestine suppresses ghrelin secretion, and 2) fat-induced suppression of ghrelin and stimulation of PYY and PP is dependent on fat digestion.

Visceral sensitivity and symptoms during fasting and intraduodenal lipid infision in patients with irritable bowel syndrome (IBS)

Visceral sensitivity and symptoms during fasting and intraduodenal lipid infision in patients with irritable bowel syndrome (IBS)

Neuropeptide Y and lipid increase apolipoprotein AIV gene expression in rat hypothalamus

Apolipoprotein AIV (apo AIV) is a circulating signal released from intestinal cells in response to lipid feeding and contributes to the anorectic effect of a lipid meal. We have demonstrated that apo AIV is also synthesized in the hypothalamus, and that hypothalamic apo AIV gene expression is regulated physiologically. Neuropeptide Y (NPY) is a hypothalamic neuropeptide with broad regulatory actions in the central nervous system. In the present studies, the effects of intracerebroventricular (i.v.t.) administration of NPY and of intraduodenal lipid infusion on hypothalamic apo AIV gene expression were determined using competitive RT-PCR in fasted rats. I.v.t. injection of NPY alone significantly increased apo AIV mRNA levels in the hypothalamus in a dose-dependent manner. Intraduodenal infusion of lipid also stimulated the gene expression of hypothalamic apo AIV, but no further significant increment occurred when i.v.t. injection of NPY was combined with lipid infusion. These results suggest that NPY and lipid may regulate apo AIV gene expression in the rat hypothalamus.

Functional characteristics of the pylorus in patients undergoing pylorus-preserving gastrectomy for early gastric cancer

Background. This study investigates the functional characteristics of the pylorus in patients undergoing pylorus-preserving gastrectomy (PPG) for early gastric cancer. Methods. In study 1, postprandial symptoms and gastric emptying were compared between 2 groups of 12 patients with early gastric cancer more than 1 year after either PPG (PPG group) or distal gastrectomy (DG) (DG group). Gastric emptying was evaluated with the dual isotope technique for liquids and solids separately. In study 2, pyloric motility was evaluated with a sleeve/sidehole manometric assembly in 7 patients undergoing PPG, which was compared with that in the preoperative patients. Results. In study 1, the overall modified Visick score of postprandial symptoms and the Sigstad dumping score were significantly lower in the PPG group compared with the DG group (P < .05). Early accelerated gastric emptying was observed in both groups for liquids, but only in the DG group for solids. In study 2, isolated pyloric pressure waves induced by intraduodenal lipid infusion and phase III-like activity induced by intravenous erythromycin infusion were preserved after PPG. Conclusions. The quantitative analysis of postoperative symptoms revealed that PPG patients were associated with better clinical conditions than DG patients. The clinical benefits of PPG are considered to be based on the function of the preserved pylorus. (Surgery 2002;131:613-24.)

Effects of the Nitric Oxide Synthase Inhibitor NG-Nitro-L-Arginine Methyl Ester (L-NAME) on Antropyloroduodenal Motility and Appetite in Response to Intraduodenal Lipid Infusion in Humans

Background: Studies in animals indicate that endogenous nitric oxide (NO) is an important inhibitory neurotransmitter in the gastrointestinal tract and that it modulates food intake. We evaluate the role of NO mechanisms in mediating the effects of small intestinal nutrients on antropyloroduodenal motility and appetite in humans. Methods: On 2 separate days, 8 healthy adult men received intravenous L-NAME 180 µg/kg/h or 0.9% saline (0-150 min); between 30 min and 120 min, an intraduodenal lipid infusion (2 kcal/min) was administered, and at 120 min subjects were offered a buffet meal (120-150 min). Antropyloroduodenal pressures were measured with a sleeve/sidehole manometric assembly. During the infusions, perceptions of hunger and fullness were assessed with visual analog questionnaires and amount and macronutrient content of food consumed at the buffet meal were quantified. Blood pressure and heart rate were monitored at regular intervals. Results: Intraduodenal lipid infusion was associated with increases in fullness (P < 0.05) and in frequency of isolated pyloric pressure waves (P < 0.05) and basal pyloric pressure (P < 0.05); and decreases in hunger (P < 0.05) and in frequency of antral (P < 0.05) and duodenal (P < 0.05) pressure waves. L-NAME increased diastolic blood pressure (P = 0.08) and decreased heart rate (P < 0.05), but had no effect on antropyloroduodenal pressures or food intake. Conclusions: Intravenous administration of the systemic NO synthase inhibitor, L-NAME, in a dose that affects cardiovascular function in healthy humans does not modify the antropyloroduodenal motor and appetite responses to intraduodenal lipid infusion.

The stimulation of antral motility by erythromycin is attenuated by hyperglycemia

OBJECTIVE: Diabetic gastroparesis is usually treated with prokinetic drugs, of which the most potent, when given intravenously during euglycemia, is erythromycin. Recent studies have demonstrated that the gastrokinetic effects of erythromycin are attenuated by hyperglycemia. The aim of this study was to determine whether the effects of erythromycin on antropyloroduodenal motility, including the organization of antral pressure waves, are modified by hyperglycemia. METHODS: A total of eight healthy male volunteers (median age 24 yr) were studied on 2 days each in randomized order. A manometric assembly, incorporating six antral, two pyloric, and seven duodenal sideholes and a pyloric sleeve sensor, was positioned with the sleeve spanning the pylorus. The blood glucose concentration was stabilized at about 5 mmol/L (euglycemia) or 15 mmol/L (hyperglycemia). After 30 min (T = 0), an intraduodenal lipid infusion (1.5 kcal/min) was commenced and continued until the end of the study. At T = 20 minutes, erythromycin (200 mg) as the lactobionate was infused intravenously over 20 min, followed by 100 mg over the next 40 min. RESULTS: Intravenous erythromycin increased the amplitude of antral waves during intraduodenal lipid infusion at both blood glucose concentrations ( p < 0.01 for euglycemia and p < 0.05 for hyperglycemia). After erythromycin (T = 20 to T = 80), the frequency ( p < 0.05) and amplitude ( p < 0.01) of antral waves were less during hyperglycemia than euglycemia. Both propagated ( p < 0.0005) and nonpropagated ( p < 0.01) antral waves were decreased by hyperglycemia, but the suppression of propagated waves was greater ( p < 0.05). Erythromycin reduced the frequency ( p = 0.09) but increased the amplitude ( p < 0.05) of phasic pyloric pressures, and decreased basal pyloric pressure ( p < 0.0005). The frequency ( p = 0.06) and amplitude ( p < 0.05) of phasic pyloric waves during erythromycin infusion were slightly less during hyperglycemia than euglycemia, whereas there was no effect of the blood glucose concentration on basal pyloric pressure. Erythromycin increased the amplitude ( p < 0.001) but not the frequency of duodenal waves; the frequency and amplitude of duodenal waves did not differ between the two blood glucose concentrations. CONCLUSIONS: Hyperglycemia attenuates the stimulation of antral pressures and propagated antral sequences by erythromycin, but not the effects of erythromycin on pyloric or duodenal motility.

Effects of glucagon-like peptide-1(7-36)amide on antro-pyloro-duodenal motility in the interdigestive state and with duodenal lipid perfusion in humans

BACKGROUNDGlucagon-like peptide-1(7-36)amide (GLP-1) is a gut hormone released postprandially. Synthetic GLP-1 strongly inhibits gastric emptying in healthy subjects and in patients with diabetes mellitus.AIMSTo investigate the effects of GLP-1 on...

Intraduodenal lipid inhibits central vagal stimulation of gastric acid secretion through activation of CCK a receptor in rats

Background: Intestinal lipids inhibit gastric acid secretion induced by meal in dogs and gastric emptying in rats via CCK and vagal capsaicin-sensitive afferent pathway (Lloyd et al: Gastroenterology, 102: 131,1992. Holzer et al: Am J Physiol267: G625, 1994). Intracisternal injection (ic) ofTRH is widely used to stimulate vagal efferent activity and mimics the cephalic phase of acid secretion. Aim: To investigate I) whether intraduodenal lipids inhibit central vagal gastric acid stimulation-induced by ic TRH analog; 2) whether CCK receptors are involved in these responses. Methods: Male SD rats (270-310 g) fasted for 24 h were anesthetized with urethane. Gastric acid secretion was induced by ic TRH analog, RX 77368 (5 ng) and measured by flushing the stomach through a gastric cannula. Intraduodenal (id) intralipid (0.5 ml) was administered through a duodenal fistula. Results: RX 77368 ic induced a net acid output of 56.8 ± 8.0 /Lmo1/90 min. CCK-8S (0.5 and 1 nmol/kg/h) iv infusion started 10 min before the ic RX 77368 inhibited the acid secretion by 23% and 82% respectively. The inhibitory action of CCK-8S was completely prevented by the CCK A receptor antagonist devazepide (l mg/kg) injected iv 10 min before the CCK-8S infusion. Intraduodenal intralipid (5%, 10% and 20%) administered 20 min before ic RX 77368 dose-dependently reduced by 24%, 83% and 100% the acid response and the inhibitory effect of intralipid was completely prevented by devazepide(l mg/kg). The CCK B receptor antagonist L-365260 (l mg/kg) had no effect on the inhibitory effect of intraduodenal lipid (Table). Conclusion: Intraduodenal lipid inhibits central TRH-induced gastric acid secretion through releasing endogenous CCK and the inhibitory action is mediated by CCK A receptors.

Effects of cisapride on antral area and fullness during intraduodenal lipid infusion

Effects of cisapride on antral area and fullness during intraduodenal lipid infusion

Long-term effects of pyloromyotomy on pyloric motility and gastric emptying in humans.

The aim of this study was to determine the long term effects of pyloromyotomy for infantile hypertrophic pyloric stenosis (IHPS) on gastric emptying and pyloric motility. Concurrent measurements of gastric emptying and antropyloroduodenal pressures were performed in six volunteers (aged 24-26 yr) who had had pyloromyotomy performed in infancy because of IHPS, and in six normal subjects. Subjects were studied on 2 days, once sitting and once in the left lateral position. Gastric emptying of 300 ml 25% dextrose labeled with 20 MBq 99mTc sulfur colloid was measured. Antropyloroduodenal motility was evaluated with a sleeve/multiple sidehole manometric assembly, which was also used to deliver an intraduodenal triglyceride infusion at 1.1 kcal/min for 60 min, starting 30 min after ingestion of the dextrose. In both body positions, gastric emptying and intragastric distribution of the drink did not differ between the two groups. In both groups and postures, the amount emptied was less during intraduodenal lipid infusion. The number (p<0.01) and amplitude (p<0.02) of isolated pyloric pressure waves (IPPWs) was greater in the control subjects, whereas basal pyloric pressure was greater in the pyloromyotomy subjects (p<0.02). In both groups, the rate of gastric emptying in the sitting position was related to the number of IPPWs (r> or =0.40, p<0.05), but not to basal pyloric pressure. These results indicate that, in adults who have had pyloromyotomy for IHPS in infancy, patterns of pyloric motility are abnormal; pyloric tone is higher, whereas the number and amplitude of phasic pyloric pressure waves are less. In contrast, the overall rate of gastric emptying of a nutrient liquid meal is normal. These observations are consistent with the concept that the stomach has the capacity to compensate for changes in pyloric motility to minimize effects on gastric emptying.

Long-term effects of pyloromyotomy on pyloric motility and gastric emptying in humans

OBJECTIVE: The aim of this study was to determine the long term effects of pyloromyotomy for infantile hypertrophic pyloric stenosis (IHPS) on gastric emptying and pyloric motility. METHODS: Concurrent measurements of gastric emptying and antropyloroduodenal pressures were performed in six volunteers (aged 24–26 yr) who had had pyloromyotomy performed in infancy because of IHPS, and in six normal subjects. Subjects were studied on 2 days, once sitting and once in the left lateral position. Gastric emptying of 300 ml 25% dextrose labeled with 20 MBq 99mTc sulfur colloid was measured. Antropyloroduodenal motility was evaluated with a sleeve/multiple sidehole manometric assembly, which was also used to deliver an intraduodenal triglyceride infusion at 1.1 kcal/min for 60 min, starting 30 min after ingestion of the dextrose. RESULTS: In both body positions, gastric emptying and intragastric distribution of the drink did not differ between the two groups. In both groups and postures, the amount emptied was less during intraduodenal lipid infusion. The number ( p < 0.01) and amplitude ( p < 0.02) of isolated pyloric pressure waves (IPPWs) was greater in the control subjects, whereas basal pyloric pressure was greater in the pyloromyotomy subjects ( p < 0.02). In both groups, the rate of gastric emptying in the sitting position was related to the number of IPPWs (r ≥ 0.40, p < 0.05), but not to basal pyloric pressure. CONCLUSIONS: These results indicate that, in adults who have had pyloromyotomy for IHPS in infancy, patterns of pyloric motility are abnormal; pyloric tone is higher, whereas the number and amplitude of phasic pyloric pressure waves are less. In contrast, the overall rate of gastric emptying of a nutrient liquid meal is normal. These observations are consistent with the concept that the stomach has the capacity to compensate for changes in pyloric motility to minimize effects on gastric emptying.

Effect of Intraduodenal Lipid on Parabrachial Gustatory Coding in Awake Rats

Intestinal fat differentially suppresses sham feeding of liquid diets and preferred gustatory stimuli. Although the behavioral effect is robust, no electrophysiological evidence exists to account for its neural basis. Therefore, we investigated the effect of intestinal fat on gustatory coding in the pontine parabrachial nuclei (PBN) by recording from single neurons in awake rats before, during, and after intraduodenal infusions of lipid (Intralipid; 10 ml, 5 kcal). Intraduodenal lipid did not alter the response profiles of PBN taste neurons. It did, however, produce an overall decrease in response magnitude (-16.25%; n = 43), with the largest reduction to sucrose (-30%; n = 43). The most pronounced suppression occurred in sucrose-best neurons in response to sucrose (-55%; n = 19), and this effect was largest for the sucrose-specific cells (-77%; n = 3). After lipid infusions, nonspecific neurons in both the sucrose-best and NaCl-best categories also responded less to their best stimulus (sucrose, -46%; n = 16; NaCl, -35%; n = 13). In contrast, no significant changes were found in NaCl-specific cells in response to NaCl. All effects appeared with short latency ( approximately 5 min) and were reversible within the time frame of a meal. In controls, duodenal infusions of saline did not cause any changes in taste responsiveness. These results suggest that intestinal fat has specific effects on taste coding in the PBN that may contribute to the intake suppression of palatable food observed in behavioral studies. The similar, short latency of both the behavioral and neural effects supports the hypothesis of a preabsorptive site of action.

Effects of age on concentrations of plasma cholecystokinin, glucagon-like peptide 1, and peptide YY and their relation to appetite and pyloric motility

Aging is associated with a decrease in appetite and a slowing of gastric emptying. The gastrointestinal hormones cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), and peptide YY (PYY) may mediate these changes. We investigated whether aging influenced the secretion of CCK, GLP-1, and PYY and their effects on appetite and pyloric motility. Eight healthy older (65-80 y) and 7 younger (20-34 y) men received isoenergetic (12.1 kJ/min) intraduodenal infusions of lipid and glucose for 120 min on separate days. Plasma CCK, GLP-1, and PYY concentrations were measured. Plasma CCK concentrations were higher in older than in younger subjects (P = 0.004) as a result of higher baseline values (4.7+/-0.2 compared with 3.2+/-0.2 pmol/L; P < 0.0001) and a greater rise during lipid infusion (increase from baseline: 7.1+/-0.5 compared with 5.3+/-0.6 pmol/L; P = 0.048). Plasma GLP-1 and PYY concentrations were not significantly different between groups. The decrease in hunger during intraduodenal lipid infusion was inversely related to the increase in CCK, GLP-1, and PYY in younger but not older subjects. During intraduodenal lipid infusion, the increase in isolated pyloric pressure wave (IPPW) frequency was positively related to GLP-1 and PYY and the increase in IPPW amplitude was positively related to CCK in older but not younger subjects, whereas the increase in IPPW amplitude and pyloric tone was negatively related to GLP-1 and PYY in younger subjects. Human aging is associated with increased CCK concentrations, which may contribute to the slowing of gastric emptying, mediated by increased pyloric motility. The role of increased plasma CCK concentrations in mediating the age-related decrease in appetite remains to be established.

Physiological changes in blood glucose affect appetite and pyloric motility during intraduodenal lipid infusion.

We evaluated the effects of varying blood glucose concentration within the normal postprandial range and its interaction with small intestinal nutrients on antropyloric motility and appetite. Eight healthy males (19-40 yr) underwent paired studies, with a blood glucose level of 5 or 8 mmol/l. Manometry and visual analog scales were used to assess motility and appetite, during fasting and intraduodenal lipid infusion (1.5 kcal/min). In the fasting state, antral waves were suppressed at 8 mmol/l compared with 5 mmol/l (P = 0.018). However, pyloric motility was no different between the two blood glucose concentrations. Hunger was no different at 5 mmol/l compared with 8 mmol/l, but fullness was greater at 8 mmol/l (P = 0. 01). During intraduodenal lipid infusion, antral waves were suppressed (P < 0.035) and isolated pyloric pressure waves (IPPWs) were stimulated (P < 0.02) compared with during the fasting state, with no difference between blood glucose concentrations, although the temporal patterning of IPPWs varied between blood glucose concentrations. The amplitude of IPPWs was greater at 5 mmol/l compared with 8 mmol/l (P < 0.001), and hunger decreased at 8 mmol/l compared with 5 mmol/l (P = 0.02). We conclude that "physiological" hyperglycemia modifies gastric motor and sensory function and that synergy exists between blood glucose concentration and small intestinal nutrients in modulating gastric motility and appetite.

Differential 5-HT3 mediation of human gastrocolonic response and colonic peristaltic reflex.

Colonic motor function is modulated by extended and local neural reflexes involving unknown mediators. To test the role of serotonin (5-HT3) pathways, increases in colonic tone during antral distension and duodenal lipid perfusion (gastrocolonic responses) and changes in orad and caudad colonic tone in response to local colonic distension (peristaltic reflex) were measured after double-blind granisetron (10 microg/kg) or placebo infusion in healthy human volunteers. Antral distension evoked increases in colonic tone, which were blunted by granisetron (P < 0.05) without effects on antral compliance. Intraduodenal lipid perfusion also evoked increased colonic tone, which was reduced by granisetron (P < 0.05). In contrast, orad colonic contractions and caudad relaxations and contractions during colonic distension were unaffected by granisetron. In conclusion, 5-HT3 receptor antagonism blunts both the mechano- and chemoreceptor components of the human gastrocolonic response without altering antral compliance. In contrast, 5-HT3 pathways play no role in the ascending or descending components of the colonic peristaltic reflex. These findings demonstrate different roles for 5-HT3 receptors in the control of colonic motor function by the proximal gastrointestinal tract and by local neural reflexes.

Food Intake Responses to Upper Gastrointestinal Lipid Infusions in Humans

CASTIGLIONE, K. E., N. W. READ AND S. J. FRENCH. Food intake responses to upper gastrointestinal lipid infusions in humans. Physiol Behav 64(2) 141–145, 1998. Previous studies in humans and animals have shown that the presence of lipid in the small intestine can reduce food intake. Studies that have combined intraduodenal lipid infusions with gastric distension produced a greater reduction in food intake than when these two stimuli were separated. In this study, subjects received duodenal lipid (Intralipid 20%) infusions for varying periods before and during the consumption of a liquid test meal. The aim of this procedure was to maximise the interaction between intestinal nutrient stimulation and gastric distension. A dose-dependent decrease in food intake was observed that corresponded to the duration of infusion; 90- (180 kcal) and 45-min (90 kcal) infusions but not 15-min (30 kcal) infusions significantly reduced intake compared to saline. These results show that concomitant intestinal nutrient stimulation and gastric distension is an effective test for the measurement of suppression of food intake by intestinal nutrients.