Increased food intake and CCK receptor antagonists: beyond abdominal vagal afferents.
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Evidence for a physiological role for CCK in the regulation of food intake in mice.
The effects of L-364,718, a cholecystokinin receptor antagonist, on cholecystokinin octapeptide-induced inhibition of food, and its effect on food intake when given alone, were studied in mice using several different feeding paradigms. In all studies, L-364,718 (100 micrograms/kg, 1.0 mg/kg) reversed the ability of cholecystokinin octapeptide to decrease food intake. L-364,718 enhanced food consumption compared with controls in nonfasted mice (100 microgram/kg) and in prefed mice (50, 100, 250 micrograms/kg). The number of reinforcements, using a lever press, was also enhanced by L-364,718 (100 micrograms/kg) compared with control. In other paradigms, L-364,718 failed to enhance food intake. These results are compatible with the suggestion that cholecystokinin may play a physiological role in the regulation of food intake.
Animals↗
Potent cholecystokinin antagonist L 364718 stimulates food intake in rats.
The cholecystokinin (CCK) receptor antagonist L 364718 was used to examine the role of CCK in control of food intake. Effects of L 364718 (0.01-1 mg/kg ip) on the feeding response to a maximal inhibitory dose of cholecystokinin COOH-terminal octapeptide (CCK-8; 8 nmol/kg ip) and on food intake alone were determined in rats fed ad libitum during the dark cycle. CCK-8 suppressed feeding by 48%. L 364718 reversed this effect dose dependently; the minimal effective dose was 0.03 mg/kg, and complete reversal occurred at 0.1 and 0.3 mg/kg. L 364718 (0.03 mg/kg) caused a parallel, rightward shift in the dose-response curve to CCK-8 [1-128 nmol/kg, half-maximal effective dose (ED50) increased 16-fold] but did not alter the maximal response, consistent with competitive-like kinetics. L 364718 stimulated liquid and solid food intake dose-dependently by 11-35%. The minimal effective dose was 0.1 mg/kg; maximal stimulation occurred at 0.3 mg/kg. Duodenal infusion of bile-pancreatic juice did not alter the response. These results support an important role for CCK in control of food intake.
Amylases↗
Cholecystokinin-A receptor mediation of food intake in cats.
The selective cholecystokinin (CCK)-B-receptor agonist and antagonist, BC 264 and L 365260, respectively, and the CCK-A-receptor antagonist, L 364718, were used to investigate the possible involvement of different classes of CCK receptors in the control of food intake induced by exogenous CCK octapeptide (CCK-8) in the cat with gastric fistula. Intravenous infusion of CCK-8 dose dependently inhibited milk intake under sham-feeding conditions, maximal inhibition reaching 52 +/- 7% (P less than 0.001) with 0.88 nmol.kg-1.h-1. L 364718 prevented this inhibition, whereas L 365260 was ineffective over the dose range tested. The reversal effect of L 364718 on 0.88 nmol.kg-1.h-1 CCK-8-induced inhibition of milk intake was observed at doses as low as 0.44 nmol.kg-1.h-1. The selective CCK-B-receptor agonist, BC 264, in doses ranging from 0.88 to 7 nmol.kg-1.h-1, had no effect on milk intake under sham-feeding conditions, although it dose dependently stimulated gastric acid output. Furthermore, neither L 364718 nor L 365260 (88 nmol.kg-1.h-1 iv) stimulated milk intake when given in the absence of CCK-8. We conclude that exogenous CCK-8 causes satiety in the cat through activation of peripheral CCK-A receptors.
Animals↗
Gastric loads potentiate inhibition of food intake produced by a cholecystokinin analogue.
We have proposed that cholecystokinin's (CCK) inhibition of gastric emptying contributes to its ability to inhibit food intake. To directly test this hypothesis in rats, the effect of the presence of a 5-ml gastric saline load on the ability of a long-acting cholecystokinin analogue U-67827E (0.1-10.0 nmol/kg) to inhibit intake of a 0.5 kcal/ml glucose solution was measured. The CCK analogue alone inhibited intake at a threshold dose of 2.5 nmol/kg. Although lower doses of the CCK analogue alone had no effect on subsequent glucose intake, when combined with the gastric load such doses did significantly inhibit intake. Thus the presence of a gastric load reduced the threshold dose of the CCK analogue required to inhibit intake. Furthermore, at suprathreshold doses, the peptide-load combination suppressed intake more than the peptide alone. In addition, administration of 0.5 and 5.0 nmol/kg doses of the CCK analogue inhibited gastric emptying at 10, 20, and 30 min in a dose-dependent fashion. The CCK analogue's inhibition of food intake and gastric emptying were reversed by pretreatment with 100 micrograms/kg L364,718, indicating that the analogue was having its effects by interacting with specific type A CCK receptors. Together these data support the notion that CCK satiety derives from an integration of the visceral afferent signals generated by CCK's promotion of gastric distension and those produced directly by CCK.
Analysis of Variance↗
Intravenous infusion of CCKA-receptor antagonist increases food intake in rats.
To test the hypothesis that endogenous cholecystokinin (CCK) released from the small intestine by ingested food produces a satiating effect by acting at CCKA-receptors, we measured the effect of slow continuous intravenous infusions of three doses of MK-329, a potent and selective CCKA-antagonist, on food intake during 2.5-h tests in 13 Sprague-Dawley male rats after 1 h of food deprivation. MK-329 increased food intake significantly and the lowest dose tested (0.5 mg.kg-1.h-1) produced the most consistent effect on cumulative intake. Part of the increased food intake under these conditions was due to a decrease in the satiating effect of food ingested at the first meal on the postprandial intermeal interval. These results are consistent with, but do not prove, the hypothesis that the satiating effect of endogenous CCK released from the small intestine by ingested food is mediated by CCKA-receptors.
Animals↗
CCK-receptor antagonists attenuate suppression of sham feeding by intestinal nutrients.
To test the possibility that endogenous cholecystokinin (CCK) participates in suppression of sham feeding by intraintestinal nutrient infusions, we examined the effect of CCK-receptor antagonists on the suppression of sham feeding by intraintestinally infused oleic acid, maltose or L-phenylalanine (L-Phe). In addition, we monitored amylase activity in the intestinal lumen during some sham feeding experiments and measured plasma CCK in parallel experiments using intestinally infused animals that were not feeding. Suppression of sham feeding by oleic acid or maltose was attenuated by CCK-receptor antagonists, while suppression of sham feeding by L-Phe was not. Oleate infusion increased plasma CCK concentration and luminal amylase activity. Oleate-induced increase in luminal amylase activity was attenuated by a CCK-receptor antagonist. Intraintestinal maltose or L-Phe did not increase plasma CCK concentration or luminal amylase activity, suggesting that they did not release endocrine CCK. These results suggest 1) that endogenous CCK mediates suppression of sham feeding by oleate and maltose but not by L-Phe and 2) that CCK participating in suppression of feeding by intestinal stimuli might not be of endocrine origin.
Amylases↗
Satiety induced by endogenous and exogenous cholecystokinin is mediated by CCK-A receptors in mice.
To investigate the relative participation of peripheral (CCK-A) and central (CCK-B) cholecystokinin (CCK) receptors in satiety induced by endogenous CCK, we examined the effect of the CCK-A antagonist MK-329 (10-315 micrograms/kg) and the CCK-B antagonist L 365260 (0.1-315 micrograms/kg) on intake of a 20% sucrose solution in mildly food-deprived mice. Intraperitoneal injection of MK-329 elicited a dose-related increase in sucrose consumption with a minimal effective dose of 31.5 micrograms/kg. This dose increased sucrose intake 23% and the highest dose tested, 315 micrograms/kg, increased sucrose intake 63% above baseline. In contrast to MK-329, intraperitoneal administration of L 365260 had no effect on sucrose intake at doses up to 315 micrograms/kg. To examine the contribution of these two CCK receptor subtypes in satiety induced by exogenous CCK, CCK-8 (8 micrograms/kg) was administered alone and in combination with MK-329 and L 365260. MK-329 (10 micrograms/kg) significantly attenuated the satiety effect of CCK-8, and L 365260 (100 micrograms/kg) was without effect. These results suggest that the peripheral CCK receptor subtype mediates satiety induced by endogenous and exogenous CCK in the mouse.
Animals↗
CCK-A receptors mediate the effect of cholecystokinin on vasopressin but not on cortisol in pigs.
Bolus intravenous injections of cholecystokinin (CCK) octapeptide induce a rapid rise in plasma vasopressin and a later increase in cortisol in the prepubertal pig. To determine whether these endocrine responses involve CCK-A or CCK-B receptors, this experiment investigated the effect of CCK (1 microgram/kg) in pigs (n = 7) pretreated with the CCK-A antagonist L 364718 (70 microgram/kg) or the CCK-B antagonist L 365260 (10 ng/kg and 10 micrograms/kg). The animals were prepared with jugular vein catheters and given the antagonist vehicle, L 364718, or L 365260 10 min before administration of CCK or saline. Analysis of hormone concentrations in blood samples taken 2, 5, 10, and 20 min after the second injection indicated that an abrupt rise in vasopressin, detectable within 2 min of CCK administration, occurred after vehicle or L 365260 pretreatment but not when CCK was preceded by L 364718. In contrast, the rise in plasma cortisol that was observed approximately 15 min after CCK injection was not prevented by either antagonist. Thus peripherally administered CCK induces vasopressin release by CCK-A receptor activation, in agreement with its inhibitory effect on food intake in this species. However, the effect of CCK on cortisol secretion does not appear to involve either CCK-A or CCK-B receptors.
Animals↗
Abdominal vagal mediation of the satiety effects of exogenous and endogenous cholecystokinin in rats.
The hypothesis that peripherally administered cholecystokinin C-terminal octapeptide (CCK-8) and endogenous CCK act by the same abdominal vagal mechanism to produce satiety was tested by injecting rats with CCK-8 or the type A CCK receptor antagonist MK-329 after they had received bilateral subdiaphragmatic vagotomies. CCK-8 (8 nmol/kg ip) inhibited 1-h food intake by 60%; vagotomy and MK-329 (0.5 mg/kg sc) each completely blocked this effect. In contrast, vagotomy did not alter the stimulatory effect of MK-329 (0.5 mg/kg sc) on feeding; 3-h cumulative intake in control and vagotomized animals was increased by 25 and 34%, respectively. These results suggest that satiety is mediated in part by an endogenous CCK action that is independent of abdominal vagal innervation.
Abdomen↗
CCK satiety is differentially mediated by high- and low-affinity CCK receptors in mice and rats.
Cholecystokinin-JMV-180 (JMV-180) is an analogue of cholecystokinin C-terminal octapeptide (CCK-8), which has been shown to be an agonist at the proposed CCK pancreatic high-affinity site and a functional antagonist at the pancreatic low-affinity site in rats and to have agonist activity at both high- and low-affinity sites in the mouse. In this study we used JMV-180 to evaluate the potential participation of these two CCK-A sites in the satiety effect of CCK-8 in rats and mice. When tested at doses that ranged from 0.01 to 9.2 mumol/kg, JMV-180 did not reliably affect food intake of solid or liquid test diets in rats. When combined with CCK-8 (3.2 or 8.5 nmol/kg) JMV-180 dose dependently reversed the satiety effect of CCK-8. In contrast to these results in the rat, both JMV-180 (3.7-14.8 mumol/kg) and CCK-8 (1.7-6.8 nmol/kg) dose dependently reduced the intake of 20% sucrose in mice. Both CCK-8- and JMV-180-induced suppression of food intake were attenuated by the CCK-A antagonist MK-329 (24.8 nmol/kg). The results of these studies suggest that agonist activity at sites pharmacologically similar to the CCK pancreatic high-affinity site is not sufficient for expression of CCK satiety, whereas agonist activity at low-affinity-like sites is necessary to reduce food intake. Thus the anorexic activity of CCK appears to be mediated through an interaction with a receptor site pharmacologically similar to the pancreatic low-affinity CCK receptor site.
Animals↗
Cholecystokinin octapeptide decreases food intake in white-crowned sparrows.
White-crowned sparrows maintained on short days (9:15-h light-dark cycle) were peripherally injected with 1.0, 4.0, and 16 micrograms/kg ip of cholecystokinin octapeptide (CCK-8). Meal size over the subsequent 30 min was significantly depressed in a dose-dependent fashion. Water intake was not affected. The anorexic effect caused by 4.0 micrograms/kg was attenuated by 100 micrograms/kg of the type-A CCK receptor antagonist MK-329 but not by 300 micrograms/kg of the type-B CCK receptor antagonist L 365,260, suggesting that CCK-induced suppression of food intake in this species is mediated by a CCK-A receptor. Administration of both CCK-A and CCK-B receptor antagonists alone resulted in no change in meal size. These experiments suggest that white-crowned sparrows, when weight stable, respond to CCK-8 in a manner comparable with several mammalian species.
Animals↗
Meal-induced c-fos expression in brain stem is not dependent on cholecystokinin release.
Sprague-Dawley rats injected with a "physiological" dose of cholecystokinin octapeptide (CCK-8; 6 micrograms/kg ip) expressed c-fos immunoreactivity in the nucleus of the tractus solitarius (NTS) and the area postrema (AP) of the brain stem. Injection of the CCK-A antagonist L-364,718 30 min before CCK-8 injection eliminated c-fos expression in these regions. These findings support the hypothesis that CCK-8 induced c-fos expression is mediated by CCK-A receptors. We then tested whether a meal (Isocal) could activate c-fos, and, if so, whether this response could be eliminated by L-364,718. Ingestion of Isocal induced c-fos immunoreactivity in the NTS and AP. Meal-induced c-fos expression was not blocked by the CCK-A antagonist L-364,718. These findings demonstrate for the first time that a purely physiological nonnoxious stimulus, a meal, induces c-fos in the rat brain stem and indicate that feeding induces c-fos expression by a pathway that is largely, if not entirely, independent of CCK release.
Animals↗
Cholecystokinin octapeptide analogues suppress food intake via central CCK-A receptors in mice.
To examine the mechanism of the satiety-producing effect of cholecystokinin (CCK) in the central nervous system, we compared the potency of intraperitoneally (ip) or intracerebroventricularly (icv) administered CCK-8 and its analogues on food intake in fasted mice. The icv administration of a small dose of CCK-8 (0.03 nmol/brain) or of Suc-(Thr28, Leu29, MePhe33)-CCK-7 (0.001 nmol/brain) suppressed food intake for 20 min, whereas CCK-8 (1 nmol/kg, which is equivalent to 0.03 nmol/brain) or Suc-(Thr28, Leu29, MePhe33)-CCK-7 (1 nmol/kg) had satiety effect after ip administration. Dose-response studies indicated the following rank order of potency: Suc-CCK-7 > or = Suc-(Thr28, Leu29, MePhe33)-CCK-7 > or = CCK-8 > or = (Nle28,31)-CCK-8 >> desulfated CCK-8 = CCK-4 = 0 in the case of ip administration and Suc-(Thr28, Leu29, MePhe33)-CCK-7 >> Suc-CCK-7 > or = CCK-8 > or = (Nle28,31)-CCK-8 >> desulfated CCK-8 = CCK-4 = 0 in the case of icv administration. The selective CCK-A receptor antagonist MK-329 reversed the inhibitory effect of the centrally as well as peripherally administered CCK-8, or of Suc-(Thr28, Leu29, MePhe33)-CCK-7, whereas the selective CCK-B receptor antagonist L-365260 did not. The icv administered CCK-8 did not appear in the peripheral circulation. These findings suggest the participation of CCK-A receptors in the brain in mediating the satiety effect of CCK and the difference in CCK-A receptors in the brain and peripheral tissues.
Amino Acid Sequence↗
Modulation of food intake by peripherally administered amylin.
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.
Amyloid↗
Identification of gastrin as a growth peptide in human pancreatic cancer.
The present study reports the first evidence that the gastrointestinal peptide gastrin stimulates the growth of several human pancreatic cancer cells in culture and in tumors transplanted to nude mice. Gastrin promoted growth of all cell lines tested at a dose comparable to the binding affinity, providing evidence for a physiologically relevant receptor. The stimulatory effects of gastrin were blocked by the CCK-B/gastrin receptor antagonist L-365,260 and not by the CCK-A receptor antagonist L-364,718. Growth of PANC-1 cells in culture were inhibited by L-365,260, suggesting that gastrin is tonically produced by PANC-1 cells for regulation of growth. Athymic nude mice bearing PANC-1 xenografts were treated for 24 days subcutaneously with either 1% bovine serum albumin (diluent), pentagastrin (1 mg/kg), or L-365,260 (1 mg/kg) twice daily. Tumors from the pentagastrin-treated mice were found to weigh more and have greater protein and DNA content than controls, whereas these values were all decreased in tumors of L-365,260-treated mice. Receptor binding capacity changed in tumors of animals treated with the peptide or antagonist, suggesting a regulatory process. Gastrin immunoreactivity was detected in a transplanted PANC-1 human tumor. These results identify gastrin as a potent trophic peptide that actively stimulates growth of human pancreatic cancer and does so through a CCK-B/gastrin-like receptor.
Animals↗
Diet-independent suppression of ingestive behavior by cholecystokinin octapeptide and amino acids.
Male rats consumed much more of an intraorally administered mixed protein, fat and carbohydrate solution than of a carbohydrate solution. Injection of cholecystokinin octapeptide (CCK-8, 0.6-5.0 microgram) suppressed intake of both solutions, but the CCK-A receptor antagonist L-364, 718 (20-40 micrograms) facilitated only carbohydrate intake. Blood levels of CCK-8 were higher after intake of the carbohydrate than the mixed solution. Blood levels of isoleucine, leucine, lysine, threonine, valine, and tryptophan increased only after intake of the mixed solution. Injection of these amino acids suppressed intake of both solutions. Blood levels of amino acids were also less after the seventh than after the first session ingesting the mixed solution. Treatment with CCK-8 or amino acids inhibits intake of any diet, but when secreted endogenously, these signals may terminate the meal in a diet-dependent manner.
Amino Acids↗
CCK is involved in both peripheral and central mechanisms controlling food intake in chickens.
The aim of this work was to study the involvement of cholecystokinin (CCK) in the control of food intake in chickens. The following aspects were studied: 1) the effects of intravenous and intracerebroventricular sulfated octapeptide of CCK (CCK-8s) on voluntary food intake; 2) the effects of two CCK-receptor antagonists. L-365,260 and L-364,718, on food intake; and 3) the ability of such drugs to block the effects of CCK-8s on food intake in the chicken. Intravenous and intracerebroventricular CCK-8s caused a decrease in food intake. Intraperitoneal L-365,260, a CCK-receptor antagonist with low affinity for the two CCK receptors described in the chicken, increases food intake. Intracerebroventricular L-364,718, a drug that has high affinity for the chicken central CCK-receptor type, increased food intake. The effect of intravenous CCK-8s on food intake was not blocked by L-364,718 or L-365,260, whereas that of intracerebroventricular CCK-8s was blocked by intracerebroventricular L-364,718. It is concluded that central endogenous CCK plays a role in the control of food intake, which is dependent on central CCK-receptor type; nevertheless, peripheral CCK also decreases food intake acting on the peripheral CCK-receptor type. The fact that intracerebroventricular L-364,718 is able to increase food intake is related to its high affinity for the central CCK-receptor type of this species. Finally, three different speculations that might explain the fact that intraperitoneal L-365,260 increases food intake are discussed.
Animals↗