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Intraduodenal infusion of lipid or protein potently reduces subsequent energy intake. There is evidence that the underlying mechanisms differ significantly between the two nutrients. While intraduodenal lipid stimulates glucagon-like peptide-1 and CCK much more than protein, the release of insulin and glucagon is substantially greater in response to protein. Ghrelin and PYY are both involved in short-term regulation, while leptin is a long-term regulator, of energy balance; the acute effects of nutrients on leptin release are unclear. We investigated the comparative effects of intraduodenal lipid and protein on plasma ghrelin, PYY, and leptin concentrations. Thirteen lean, young men received 90-min intraduodenal infusions of protein (whey hydrolysate) or lipid (long-chain triglyceride emulsion) at a rate of 3 kcal/min, or saline control, on three separate days. Blood samples were collected at baseline and regularly during infusions. Both lipid and protein potently suppressed plasma ghrelin compared with control (both P < 0.001), with no difference between them. While both lipid and protein stimulated plasma PYY ( P < 0.001), the effect of lipid was substantially greater than that of protein ( P < 0.001). Neither intraduodenal lipid nor protein affected plasma leptin. In conclusion, intraduodenal lipid and protein have discrepant effects on the release of PYY, but not ghrelin. When considered with our previous findings, it appears that, with the exception of ghrelin, the energy intake-suppressant effects of lipid and protein are mediated by different mechanisms.

The postprandial reduction in blood pressure (BP) is triggered by the interaction of nutrients with the small intestine and associated with an increase in splanchnic blood flow. Gastric distension may attenuate the postprandial fall in BP. The aim of this study was to determine the effects of differences in intragastric volume, including distension at a low (100 ml) volume, on BP and superior mesenteric artery (SMA) blood flow responses to intraduodenal glucose in healthy older subjects. BP and heart rate (HR; automated device), SMA blood flow (Doppler ultrasound), mesenteric vascular resistance (MVR), and plasma norepinephrine of nine male subjects (65–75 yr old) were measured after an overnight fast on 4 separate days in random order. On each day, subjects were intubated with a nasoduodenal catheter, incorporating a duodenal infusion port, and orally with a second catheter, incorporating a barostat bag, positioned in the fundus. Each subject received a 60-min ( t = 0–60 min) intraduodenal glucose infusion (3 kcal/min) and gastric distension at a volume of 1) 0 ml (V0), 2) 100 ml (V100), 3) 300 ml (V300), or 4) 500 ml (V500). Systolic BP fell ( P < 0.05) during V0, but not during V100, V300, or V500. In contrast, HR ( P < 0.01) and SMA blood flow ( P < 0.001) increased and MVR decreased ( P < 0.05) comparably on all 4 days. Plasma norepinephrine rose ( P < 0.01) in response to intraduodenal glucose, with no difference between the four treatments. There was a relationship between the areas under the curve for the change in systolic BP from baseline with intragastric volume ( r = 0.60, P < 0.001). In conclusion, low-volume (≤100 ml) gastric distension has the capacity to abolish the fall in BP induced by intraduodenal glucose in healthy older subjects without affecting SMA blood flow or MVR. These observations support the concept that nonnutrient gastric distension prior to a meal has potential therapeutic applications in the management of postprandial hypotension.

Postprandial hypotension is an important problem, particularly in the elderly. The fall in blood pressure is dependent on small intestinal glucose delivery and, possibly, changes in splanchnic blood flow, the release of glucagon-like peptide-1 (GLP-1), and sympathetic nerve activity. We aimed to determine in healthy older subjects, the effects of variations in small intestinal glucose load on blood pressure, superior mesenteric artery flow, GLP-1, and noradrenaline. Twelve subjects (6 male, 6 female; ages 65–76 yr) were studied on four separate occasions, in double-blind, randomized order. On each day, subjects were intubated via an anesthetized nostril, with a nasoduodenal catheter, and received an intraduodenal infusion of either saline (0.9%) or glucose at a rate of 1, 2, or 3 kcal/min (G1, G2, G3, respectively), for 60 min ( t = 0–60 min). Between t = 0 and 60 min, there were falls in systolic and diastolic blood pressure following G2 and G3 ( P = 0.003 and P < 0.001, respectively), but no change during saline or G1. Superior mesenteric artery flow increased slightly during G1 ( P = 0.01) and substantially during G2 ( P < 0.001) and G3 ( P < 0.001), but not during saline. The GLP-1 response to G3 was much greater ( P < 0.001) than to G2 and G1. Noradrenaline increased ( P < 0.05) only during G3. In conclusion, in healthy older subjects the duodenal glucose load needs to be > 1 kcal/min to elicit a significant fall in blood pressure, while the response may be maximal when the rate is 2 kcal/min. These observations have implications for the therapeutic strategies to manage postprandial hypotension by modulating gastric emptying.

Postprandial hypotension occurs frequently, particularly in the elderly. The magnitude of the fall in blood pressure (BP) and rise in heart rate (HR) in response to enteral glucose are greater when gastric emptying (GE) or small intestinal infusion are more rapid. Meal ingestion is associated with an increase in splanchnic blood flow. In contrast, gastric distension may attenuate the postprandial fall in BP. The aims of this study were to evaluate, in older subjects, the comparative effects of intraduodenal glucose infusion, at a rate similar to GE of oral glucose, on BP, HR, superior mesenteric artery (SMA) flow, and blood glucose. Eight healthy subjects (5 men, 3 women, age 66–75 yr) were studied on two occasions. On day 1, each subject ingested 300 ml of water containing 75 g glucose. GE was quantified by three-dimensional ultrasonography between time t = 0–120 min, and the rate of emptying (kcal/min) was calculated. On day 2, glucose was infused intraduodenally at the same rate as that on day 1. On both days, BP, HR, SMA flow, and blood glucose were measured. The mean GE of oral glucose was 1.3 ± 0.1 kcal/min. Systolic BP ( P < 0.01), SMA flow ( P < 0.05), and blood glucose ( P < 0.01) were greater and HR less ( P < 0.01) after oral, compared with intraduodenal, glucose. There were comparable falls in diastolic BP during the study days ( P < 0.01 for both). We conclude that the magnitude of the fall in systolic BP and rise in HR are less after oral, compared with intraduodenal, glucose, presumably reflecting the “protective” effect of gastric distension.

Postprandial ghrelin suppression arises from the interaction of meal contents with the small intestine and may relate to elevations in blood glucose and/or plasma insulin. We sought to determine whether the suppression of ghrelin by small intestinal glucose is dependent on the glucose load and can be accounted for by changes in blood glucose and/or plasma insulin. Blood glucose, plasma insulin, and plasma ghrelin levels were measured in 10 healthy males (aged 32 ± 4 yr; body mass index: 25.1 ± 0.4 kg/m2) during intraduodenal glucose infusions at 1 kcal/min (G1), 2 kcal/min (G2), and 4 kcal/min (G4), as well as intraduodenal hypertonic saline (control) for 120 min. There was a progressive decrease in ghrelin with all treatments, control at 45 min and between 90 and 120 min ( P < 0.05) and G1 ( P < 0.05), G2 ( P < 0.0001), and G4 ( P < 0.0001) between 30 and 120 min to reach a plateau at ∼90 min. There was no difference in plasma ghrelin between G1, G2, or G4. Control suppressed ghrelin to a lesser extent than intraduodenal glucose ( P < 0.05). The suppression of ghrelin was not related to rises in blood glucose or plasma insulin. Suppression of ghrelin by intraduodenal glucose in healthy males is apparently independent of the glucose load and unrelated to blood glucose or insulin levels.

There is evidence from studies in animals that the effects of both fat and CCK on gastrointestinal function and energy intake are attenuated by consumption of a high-fat diet. In humans, the effects of exogenous CCK-8 on antropyloroduodenal motility, plasma CCK, peptide YY (PYY), and ghrelin concentrations, appetite, and energy intake are attenuated by a high-fat diet. Ten healthy lean males consumed isocaloric diets (∼15,400 kJ per day), containing either 44% (high-fat, HF) or 9% (low-fat, LF) fat, for 21 days in single-blind, randomized, cross-over fashion. Immediately following each diet (i.e., on day 22), subjects received a 45-min intravenous infusion of CCK-8 (2 ng·kg−1·min−1), and effects on antropyloroduodenal motility, plasma CCK, PYY, ghrelin concentrations, hunger, and fullness were determined. Thirty minutes after commencement of the infusion, subjects were offered a buffet-style meal, from which energy intake (in kilojoules) was quantified. Body weight was unaffected by the diets. Fasting CCK ( P < 0.05), but not PYY and ghrelin, concentrations were greater following the HF, compared with the LF, diet. Infusion of CCK-8 stimulated pyloric pressures ( P < 0.01) and suppressed antral and duodenal pressures ( P < 0.05), with no difference between the diets. Energy intake also did not differ between the diets. Short-term consumption of a HF diet increases fasting plasma CCK concentrations but does not affect upper gut motility, PYY and ghrelin, or energy intake during CCK-8 infusion, in a dose of 2 ng·kg−1·min−1, in healthy males.

Enterally administered lipid modulates antropyloroduodenal motility, gut hormone release, appetite, and energy intake. We hypothesized that these effects would be dependent on both the load, and duration, of small intestinal exposure to lipid. Eleven healthy men were studied on four occasions in a double-blind, randomized, fashion. Antropyloroduodenal motility, plasma CCK and peptide YY (PYY) concentrations, and appetite perceptions were measured during intraduodenal infusion of lipid (Intralipid) at 1) 1.33 kcal/min for 50 min, 2) 4 kcal/min for 50 min, and 3) 1.33 kcal/min for 150 min, or 4) saline for 150 min. Immediately after the infusions, energy intake was quantified. Pressure wave sequences (PWSs) were suppressed, and basal pyloric pressure, isolated pyloric pressure waves (IPPWs), plasma CCK and PYY stimulated (all P < 0.05), during the first 50 min of lipid infusion, in a load-dependent fashion. The effect of the 4 kcal/min infusion was sustained so that the suppression of antral pressure waves (PWs) and PWSs and increase in PYY remained evident after cessation of the infusion (all P < 0.05). The prolonged lipid infusion (1.33 kcal/min for 150 min) suppressed antral PWs, stimulated CCK and PYY and basal pyloric pressure (all P < 0.05), and tended to stimulate IPPWs when compared with saline throughout the entire infusion period. There was no significant effect of any of the lipid infusions on appetite or energy intake, although nausea was slightly higher ( P < 0.05) with the 4 kcal/min infusion. In conclusion, both the load, and duration, of small intestinal lipid influence antropyloroduodenal motility and patterns of CCK and PYY release.

There is evidence that CCK and glucagon-like peptide-1 (GLP-1) mediate the effects of nutrients on appetite and gastrointestinal function and that their interaction may be synergistic. We hypothesized that intravenous CCK-8 and GLP-1 would have synergistic effects on appetite, energy intake, and antropyloroduodenal (APD) motility. Nine healthy males (age 22 ± 1 yr) were studied on four separate days in a double-blind, randomized fashion. Appetite and APD pressures were measured during 150-min intravenous infusions of 1) isotonic saline (control), 2) CCK-8 (1.8 pmol·kg−1·min−1), 3) GLP-1 (0.9 pmol·kg−1·min−1), or 4) both CCK-8 (1.8 pmol·kg−1·min−1) and GLP-1 (0.9 pmol·kg−1·min−1). At 120 min, energy intake at a buffet meal was quantified. CCK-8, but not GLP-1, increased fullness, decreased desire to eat and subsequent energy intake, and increased the number and amplitude of isolated pyloric pressure waves and basal pyloric pressure ( P < 0.05). Both CCK-8 and GLP-1 decreased the number of antral and duodenal pressure waves (PWs) ( P < 0.05), and CCK-8+GLP-1 decreased the number of duodenal PWs more than either CCK-8 or GLP-1 alone ( P < 0.02). This was not the case for appetite or isolated pyloric PWs. In conclusion, at the doses evaluated, exogenously administered CCK-8 and GLP-1 had discrepant effects on appetite, energy intake, and APD pressures, and the effects of CCK-8+GLP-1, in combination, did not exceed the sum of the effects of CCK-8 and GLP-1, providing no evidence of synergism.

The aim of this study was to determine in the marsupial Sminthopsis crassicaudata 1) the effect of leptin on food intake, body fat stores, and metabolism and 2) whether leptin can prevent a diet-induced increase in adiposity. In response to 21 days of feeding with mealworms (2.99 kcal/g, 30% fat), body weight ( P < 0.0001) and tail width ( P < 0.0001) increased, compared with control animals fed with laboratory diet (1.01 kcal/g, 20% fat). Subsequently, S. crassicaudata were randomly allocated to receive either laboratory diet or a choice between laboratory diet and mealworms. For 13 days, one-half of the animals in each dietary group received intraperitoneal human leptin (2.5 mg/kg twice daily), while the other one-half received phosphate-buffered saline. In animals receiving laboratory diet alone, leptin induced a decrease in body weight ( P < 0.0001), tail width ( P < 0.0001), and energy intake ( P < 0.01). In animals receiving both laboratory diet and mealworms, leptin had no effect on body weight or tail width, although the proportion of laboratory diet eaten was reduced ( P = 0.0001), and there was a nonsignificant fall in overall energy intake ( P = 0.07). We conclude that in S. crassicaudata, 1) a high-calorie, higher-fat diet induces an increase in adiposity and 2) leptin induces weight loss, but 3) an increase in dietary calories and fat content is associated with resistance to the actions of leptin.

The effects of volume and posture on gastric emptying and intragastric distribution of a solid meal and appetite were evaluated. Eight normal volunteers were studied on four occasions, on each of which a meal comprising ground beef mixed with tomato sauce of either 650 g (“large”) or 217 g (“small”) was eaten. Two studies were performed while the subject was lying in the left lateral decubitus position, and two studies were performed while the subject was sitting so that in each subject data were available for both meals and in both postures. Hunger and fullness were evaluated using a visual analog questionnaire. In both postures and after both meals, gastric emptying approximated a linear pattern after an initial lag phase. The lag phase was shorter for the large meal when compared with the small meal [sitting: large 13 ± 5 vs. small 29 ± 7 min; left lateral: large 16 ± 3 vs. small 24 ± 3 min, F(1,7) = 46.3, P < 0.0005]. In both postures the contents of the total [ F(1,7) = 1794.5, P < 0.0001], proximal [ F(1,7) = 203.7, P < 0.0001], and distal [ F(1,7) = 231.5, P < 0.0001] stomach were greater after the large meal when compared with the small meal. Although the 50% emptying time was greater with the large than the small meal [ F(1,7) = 40.8, P < 0.001], the postlag emptying rate (g/min) was more rapid with the large meal [sitting: large 1.7 ± 0.2 vs. small 1.1 ± 0.1 g/min; left lateral: large 1.8 ± 0.1 vs. small 1.3 ± 0.04 g/min, F(1,7) = 44.7, P < 0.0005]. There was a significant interaction between meal volume and posture for retention in the distal stomach [ F(1,7) = 7.14, P < 0.05]. Contrasts were used to evaluate the effects of volume and posture between the four studies and demonstrated an effect of posture for the large [ F(1,21) = 18.7, P < 0.005] but not the small [ F(1,21) = 0.30, P = 0.60] meal so that the retention was greater in the sitting when compared with the left lateral position. The magnitude of the postprandial increase in fullness [ F(1,7) = 7.8, P < 0.05] and reduction in hunger [ F(1,7) = 5.9, P < 0.05] was greater with the large meal. We conclude that meal volume has a major effect on gastric emptying; in contrast posture has only a minor impact on intragastric meal distribution, which is observed only after a large meal, and no effect on gastric emptying.

Little is known about feeding regulation in marsupials. Sminthopsis crassicaudata is a small nocturnal marsupial, whose tail contains approximately 25% total body fat. We have characterized the effect of gender, photoperiod, food deprivation, and tail removal (lipectomy) on food intake in S. crassicaudata. Males and females maintained in captivity on long-day (LD, 16:8-h light-dark cycle) and short-day (SD, 9:15-h light-dark cycle) light regimens were studied. Feeding patterns under LD and SD photoperiods were initially measured under conditions of ad libitum food supply and then in groups of animals exposed to 24- and 36-h periods of food deprivation. Feeding occurred predominantly in the dark. Females maintained on SD photoperiods for 5 wk ate less (P < 0.005) than females on LD or males on either SD or LD, but this reduction in food intake was not associated with a decrease either in body weight or tail width. After both 24- and 36-h fasts, total food intake in the subsequent 24 h increased (P < 0.001) up to 100% in all groups, with no gender or photoperiod effect. SD females, however, ate less (P < 0.05) than LD females in the first 6 h after refeeding. Tail width decreased (P < 0.05) in all groups of animals after the 36-h fast but only in LD animals after the 24-h fast (P < 0.05). Body weight decreased similarly in all groups of animals after fasting. The effect of tail removal was studied in LD males. The procedure, which was well tolerated, resulted in an initial decrease in body weight (P < 0.005), which recovered within 3 wk. On day 45 in the animals whose tails were removed, body fat was approximately 30% greater than body fat of controls (P < 0.02). No significant increase in food intake occurred after tail removal. These data demonstrate in Sminthopsis crassicaudata 1) a photoperiod and gender-dependent effect on food intake, 2) the ability to regulate the amount and distribution of total body fat, and 3) a dissociation between the regulation of food intake and changes in body fat stores, which suggest alterations in energy expenditure.

Animal studies suggest that aging is associated with anorexia and disordered gastrointestinal transit. To determine whether there is a relationship between the effects of aging on appetite and gastrointestinal transit in humans, 19 young (age 23-50 yr) and 14 elderly (age 70-84 yr) normal volunteers underwent measurements of 1) desire to eat, hunger, and fullness (visual analog scales); 2) gastric emptying (scintigraphy); 3) orocecal transit (breath hydrogen); 4) total gut transit (radiopaque markers); and 5) autonomic nerve function (cardiovascular reflexes). We found that, postprandially, elderly subjects had less desire to eat (P < 0.05) and less hunger (P < 0.05), but not a significantly greater fullness than younger subjects. Gastric emptying (50% emptying time) for solid (182 +/- 26 vs. 127 +/- 13 min, P < 0.05) and liquid (47 +/- 4 vs. 35 +/- 3 min, P < 0.05) meal components was slower in elderly subjects. Postprandial hunger was inversely related (r = -0.39, P < 0.05) to solid gastric emptying. There were no significant differences in orocecal and total gut transit times between the two groups. Autonomic nerve function was abnormal in 11 elderly but none of the young subjects (P < 0.01). We conclude that aging is associated with 1) diminished desire to eat and hunger, 2) slowing of solid and liquid gastric emptying, 3 no change in orocecal and total gut transit, and 4) autonomic nerve dysfunction. The slowing of gastric emptying may contribute to anorexia in aging subjects.

Amylin has been demonstrated to produce anorexia in rodents. Its mechanism of action is unknown. We have studied the effect of amylin on food intake in mice in a variety of paradigms to determine whether it inhibits food intake by a peripheral mechanism of action. In addition, we determined its effect in genetically obese mice models and whether its effects differed in aged mice. Cholecystokinin is the prototypic satiety agent. The effects of amylin on reducing food intake were not attenuated by the cholecystokinin antagonist L-364718, suggesting that it does not produce its effect through the release of cholecystokinin. A number of gastrointestinal peptides produce anorexia by stimulating ascending vagal fibers. For this reason, we studied the effect of truncal vagotomy on the suppression of feeding induced by amylin. Vagotomy did not prevent amylin from inhibiting food intake. Amylin was equally effective at reducing food intake in genetically obese (ob/ob) and lean (ob/c) mice and in diabetic (db/db) and lean (db/c) mice. Amylin effectively suppressed food intake in mice over the age of 4-22 mo. These studies further support the role of the pancreatic hormone amylin as a peripherally acting satiety agent.

The effect of thermal dehydration (37 degrees C) on the integrated response of the circulation was studied in conscious laboratory rats and in the desert species Psammomys obesus, the latter being studied prior to and following acclimation to heat. Cardiac output (CO) and its distribution were measured using labeled microspheres with the reference organ technique. At low dehydration (7-9% body wt loss) rats showed peripheral vasodilation coincidentally with splanchnic vasoconstriction, whereas the desert species exhibited an increased CO and peripheral vasodilation with no change in splanchnic blood perfusion. At severe dehydration (10-18% body wt loss), closure of skin arteriovenous anastomoses together with splanchnic vasodilation was observed in both species. These changes were discussed in relation to plasma volume conservation mechanism and its deterioration. Acclimation to heat resulted in no change in CO, whereas blood flow to splanchnic and skin capillaries increased remarkably. Dehydration in heat-acclimated P. obesus (5-10% body wt loss) brought about a significant fall in CO. However, most organs maintained relatively stable blood flow. This might contribute to better survival during heat stress.