Species Differences in the Response to Cholecystokinin (original) (raw)

CCK-58 elicits both satiety and satiation in rats while CCK-8 elicits only satiation

Peptides, 2014

Reduction of food intake by exogenous cholecystokinin (CCK) has been demonstrated primarily for its short molecular form, CCK-8. Mounting evidence, however, implicates CCK-58 as a major physiologically active CCK form, with different neural and exocrine response profiles than CCK-8. In three studies, we compared meal-pattern effects of intraperitoneal injections CCK-8 vs. CCK-58 in undeprived male Sprague-Dawley rats consuming sweetened condensed milk. In study one, rats (N=10) received CCK-8, CCK-58 (0.45, 0.9, 1.8 and 3.6 nmole/kg) or vehicle before a 4hour test-food presentation. At most doses, both CCK-8 and CCK-58 reduced meal size relative to vehicle. Meal-size reduction prompted a compensatory shortening of the intermeal interval (IMI) after CCK-8, but not after CCK-58, which uniquely increased the satiety ratio (IMI/size of the preceding meal). In the second study, lick patterns were monitored after administration of 0.9nmole/kg CCK-58, CCK-8 or vehicle. Lick cluster size, lick efficiency and interlick-interval distribution remained unaltered compared to vehicle, implying natural satiation, rather than illness, following both CCK forms. In study 3, threshold satiating doses of the two CCK forms were given at 5 and 30 minutes after meal termination, respectively. CCK 58, but not CCK-8 increased the intermeal interval and satiety ratio compared to vehicle. In conclusion, while CCK 58 and CCK-8 both stimulate satiation, thereby reducing meal size, CCK-58 consistently exerts a satiety effect,

Cholecystokinin and satiety: current perspectives

Nutrition, 2000

In the almost 30 years since the ability of peripheral administration of the brain/gut peptide cholecystokinin (CCK) to inhibit food intake was first demonstrated, significant progress in our overall understanding of the role of CCK in ingestive behavior has been made. A physiologic role for endogenous CCK in the control of meal size has been demonstrated and sites and mechanisms of action for CCK in food intake have been investigated. Recent work has uncovered roles for the CCK satiety pathway in the mediation of the feeding modulatory actions of estradiol, insulin, and leptin. The availability of the Otsuka Long Evans Tokushima Fatty (OLETF) rat, a strain lacking CCK A receptors, provides a unique model for the study of how deficits in a within-meals satiety signaling pathway may result in long-term changes in food intake and body weight.

A-71623, a selective CCK-A receptor agonist, suppresses food intake in the mouse, dog, and monkey

Pharmacology Biochemistry and Behavior, 1992

The anorectic actions of cholecystokinin (CCK)-8 and of a selective CCK-A agonist, A-71623, were examined in CD1 mice, beagle dogs, and cynomolgous monkeys. A-71623 suppressed intakes in all species tested, and the effects were blocked by a selective CCK-A antagonist, A-70104. In the dog only, CCK-8 was more potent on a molar basis compared to A-71623, although the effects of both CCK agonists were more short-lived in the dog compared to the other species tested. Our results support other evidence suggesting that the anorectic actions of exogenous application of CCK-8 in these species are mediated via stimulation of the CCK-A receptor subtype.

Dose–response effects of PEGylated cholecystokinin on the behavioral satiety sequence

Physiology & Behavior, 2009

Cholecystokinin (CCK) is known to have a short biological half-life. In order to prolong the half-life and create a new investigative tool, we previously PEGylated the peptide, yielding PEG-CCK(9), and demonstrated that it had a dose-dependent prolonged anorectic effect. The aim of this study was to investigate whether PEG-CCK(9) reduces food intake by inducing satiation or by abnormal physiological effects, such as pain, malaise, or nausea. An observational study was performed to examine the effects of different doses of PEG-CCK(9) (1, 2, 4, 8, or 16 microg kg(-1)) on feeding and other behaviors. The behavioral sequence associated with satiety (BSS), i.e. the orderly progression from eating, through grooming and activity, to resting, was analyzed. From the lowest dose tested (1 microg kg(-1)), PEG-CCK(9) caused a dose-dependent reduction in food intake due to a dose-related reduction in both the duration and frequency of eating and a dose-dependent increase in duration of rest. A dose-dependent acceleration in the temporal profile of the BSS was observed, while the normal structure of feeding behaviors was well preserved, except at the dose of 16 microg kg(-1) of PEG-CCK(9), at which a decrease in eating rate and grooming behavior was observed, together with the occurrence of a significant number of abdominal cramps. These findings suggest that the hypophagic response to PEG-CCK(9) is mainly induced by natural mechanisms of satiety, although abnormal physiological effects, such as abdominal cramps, might reinforce the food inhibitory effect, especially at high doses of PEG-CCK(9) (>8 microg kg(-1)).

Abdominal vagal mediation of the satiety effects of CCK in rats

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2004

CCK type 1 (CCK1) receptor antagonists differing in blood-brain barrier permeability were used to test the hypothesis that satiety is mediated in part by CCK action at CCK1 receptors on vagal sensory nerves innervating the small intestine. Devazepide penetrates the blood-brain barrier; A-70104, the dicyclohexylammonium salt of Nα-3-quinolinoyl-d-Glu- N,N-dipentylamide, does not. At dark onset, non-food-deprived control rats and rats with subdiaphragmatic vagotomies received a bolus injection of devazepide (2.5 μmol/kg iv) or a 3-h infusion of A-70104 (3 μmol·kg−1·h−1 iv) either alone or coadministered with a 2-h intragastric infusion of peptone (0.75 or 1 g/h). Food intake was determined from continuous computer recordings of changes in food bowl weight. In control rats both antagonists stimulated food intake and attenuated the anorexic response to intragastric infusion of peptone. In contrast, only devazepide was effective in stimulating food intake in vagotomized rats. Thus endoge...

Cholecystokinin effects on feeding, glucose, and pancreatic hormones in rhesus monkeys☆

Physiology & Behavior, 1983

effects on feeding, glucose, and pancreatic hormones in rhesus monkeys. PHYSIOL BEHAV 30(4) [509][510][511][512][513][514][515][516][517][518] 1983.--The effects of cholecystokinin on feeding, and on plasma glucose and pancreatic hormone responses to a mixed-meal were determined in lean rhesus monkeys. Following an overnight fast the octapeptide of cholecystokinin (CCK-8) was administered intravenously over a 6 minute period coincident with the initiation of free feeding or an intragastric infusion of a mixed liquid diet. CCK-8 inhibited feeding and delayed the plasma glucose and insulin response to a mixed-meal. The threshold for the feeding effect ranged from 30 to 120 ng/kg/min across monkeys and did not extend beyond 15 minutes of the start of the CCK infusion. The delays in plasma glucose and insulin were not dependent on rate or amount of food entering the stomach. Further, there were no alterations from basal levels in plasma glucose or insulin prior to the onset of CCK-induced feeding inhibition. There was no evidence that CCK-8 stimulated insulin release, nor was the usual close relationship between plasma glucose and insulin levels in response to a mixed-meal changed by CCK-8. Cholecystokinin (CCK-8) Feeding behavior Meal size Meal length Plasma glucose Plasma insulin Plasma glucagon Plasma pancreatic polypeptide Mixed-meal challenge Rhesus monkeys (Macaca mulatta)

Brain regions where cholecystokinin suppresses feeding in rats

Brain Research, 2000

The gut-brain peptide, cholecystokinin CCK , inhibits food intake when injected either systemically or within the brain. To determine Ž. whether CCK's effect in the brain is anatomically specific, CCK-8 0.8, 4, 20, 100, 500 pmol was microinjected into one of 14 different brain sites of rats, and its impact on subsequent food intake was measured. CCK-8 at 500 pmol significantly suppressed intake during the Ž first hour post-injection following administration into six hypothalamic sites anterior hypothalamus, dorsomedial hypothalamus, lateral. Ž hypothalamus, paraventricular nucleus, supraoptic nucleus, ventromedial hypothalamus and two hindbrain sites nucleus tractus. Ž solitarius, fourth ventricle. Although lower doses were sometimes effective anterior hypothalamus, dorsomedial hypothalamus, nucleus. tractus solitarius , there appeared to be no significant difference in potency among sites. Injections into the medial amygdala, nucleus accumbens, posterior hypothalamus, dorsal raphe, and ventral tegmental area were either ineffective or produced a delayed response. The higher doses required for most sites, as well as the widespread effectiveness of CCK-8 within the hypothalamus, suggest that spread of Ž. CCK-8 to adjacent brain sites, and or to the periphery, may have been required for anorexia to occur. Findings reported in an Ž. accompanying paper provide strong evidence that paraventricular nucleus injection of CCK-8 500 pmol did not increase plasma CCK-levels sufficiently to suppress feeding by a peripheral mechanism. Together, these results suggest that CCK may be acting as a neurotransmitter or neuromodulator within two different brain regions to produce satiety-one region which includes the nucleus tractus solitarius in the hindbrain, and another more distributed region within the medial-basal hypothalamus.

Attenuated satiation response to intestinal nutrients in rats that do not express CCK-A receptors

Peptides, 2001

Pharmacological experiments suggest that satiation associated with intestinal infusion of several nutrients is mediated by CCK-A receptors. Otsuka Long-Evans Tokushima Fatty, (OLETF), rats do not express CCK-A receptors and are insensitive to the satiationproducing effects of exogenous CCK. To further evaluate the role of CCK-A receptors in satiation by intestinal nutrient infusion, we examined intake of solid (pelleted rat chow) or liquid (12.5% glucose) food intake, following intestinal infusions of fats (oleic acid or fat emulsion), sugars (maltotriose or glucose), or peptone in OLETF rats and Long Evans Tokushima Otsuka control rats (LETO). Intestinal infusion of glucose or maltotriose reduced solid food intake more in LETO than in OLETF rats from 30 min through 4 h post infusion. Reduction of solid food intake by intestinal infusions of fat or peptone did not differ between OLETF and LETO rats during the first 30 min post infusion, but reduction of intake by these infusates was attenuated in OLETF rats over the ensuing 4h post infusion. Intestinal infusion of glucose, oleate, fat emulsion and peptone reduced 30-min intake of 12.5% glucose more in LETO than OLETF rats. Furthermore, pretreatment with the CCK-A receptor antagonist, devazepide, attenuated intestinal nutrient-induced reduction of food intake only in LETO, but not OLETF rats. Our results confirm pharmacological results, indicating that CCK-A receptors participate in satiation by nutrients that elevate plasma CCK concentrations, as well as by nutrients that do not stimulate secretion of endocrine CCK. In addition, our results indicate: 1) that OLETF rats have deficits in the satiation response to a variety of intestinal nutrient infusions; 2) that the temporal pattern for CCK-A receptor participation in satiation by intestinal nutrients is different during ingestion of liquid and solid foods and 3) that intestinal nutrients provide some satiation signals that are CCK-A receptor mediated and some that are not.