Cholecystokinin-induced satiety in weanling rats

Intraperitoneal injections fo the synthetic C-terminal octapeptide of cholecystokinin (CCK) into fasted 21-day-old weanling rats produced a significant suppression of intake of solid and liquid diets. Similar injections had no effect on water consumption of thirsty weanlings. The early appearance of CCK-induced satiety is consistent with the idea that this mechanism is responsible for the effectiveness of gastrointestinal factors in determining intake of very young rats.     

Cholecystokinin satiety and orosensory feedback

Cholecystokinin octapeptide (1.5 μg/kg CCK) was effective in reducing the number of bar-press responses for food reward. However, during the extinction session when a food pellet did not follow the bar-press, CCK was not effective in reducing the number of responses. Since the number of bar-presses during extinction is known to be positively related to the duration of food deprivation we concluded that CCK by itself did not reduce the hunger drive or the state of arousal related to food deprivation. The orosensory feedback from food intake was regarded to be a crucial element in the effect of CCK to promote satiety. It might be that food intake was needed to test the new state of satiety induced by CCK and thus without food intake during the extinction session the effect of CCK was not shown. We think that CCK may be characterized as a satiety inducer but probably not a hunger reducer. An attempt to introduce a limited amount of orosensory feedback during the extinction session was not successful in restoring the effect of CCK to suppress the food related operant response probably due to lack of proper temporal relationship between the CCK injection and the limited orosensory stimulation introduced.     

Effects of vagotomy on satiety induced by gastrointestinal hormones in the rat

Cholecystokinin, bombesin and pancreatic polypeptide are all reported to induce satiety in rodents. To test the hypothesis that cholecystokinin and bombesin induce satiety through release of pancreatic polypeptide, we compared the satiety inducing properties of each peptide in rats trained to eat a liquid diet (Magnacal). Studies were repeated after transabdominal truncal vagotomy (n = 8) or sham operation (n = 8). Peptides were given by intraperitoneal injection, and the volume of Magnacal ingested over a 2 hr period measured. After the injection of saline, unoperated rats (n = 16) ingested 30 +/- 2.3 ml of Magnacal. Caerulein (9 nmol/kg) and bombesin (27 nmol/kg) significantly inhibited food intake to 8 +/- 2.5 ml and 20 +/- 2.1 ml respectively. In contrast pancreatic polypeptide (27 nmol/kg) had no significant effect on food intake. Both caerulein and bombesin retained the ability to reduce food intake after vagotomy although the effects of caerulein were somewhat blunted. No significant changes in serum pancreatic poly peptide concentrations were observed after either the caerulein or bombesin injection. As both peptides release pancreatic polypeptide in higher mammals, species differences in release mechanisms appear to exist. We would conclude that caerulein and bombesin induced satiety is independent of pancreatic polypeptide release and that the weight loss induced by pancreatic polypeptide in obese rodents is unlikely to be due to induction of satiety.     

Consistency of cholecystokinin satiety effect across deprivation levels and motivational states

A gastrointestinal hormone, cholecystokinin (CCK), has recently been implicated in the regulation of meal size. The consistency of the CCK satiety effect was examined across deprivation levels and motivational states. In a series of experiments rats were food deprived for varying amounts of time and injected with various doses of the CCK octapeptide before consuming a test meal of a liquid diet. In Experiment 1, 20 rats were deprived for 5 or 19 hr and injected with 0, 15, and 40 Ivy dog units/kg (U/kg) of CCK and in Experiment 2, 18 rats were 48 hr deprived and were injected with 0, 40, or 80 U/kg of CCK. In Experiment 3, 12 rats were deprived for 92 hr and received 80 U/kg of CCK. In all experiments CCK produced a dose-related suppression in food intake. CCK did not appear to become less effective as deprivation increased: 15 U/kg suppressed intake by approximately 30% at 5 and 19 hr deprivation; 40 U/kg suppressed intake by approximately 50% at all three deprivation levels; 40 U/kg suppressed intake by approximately 72% at 48 hr deprivation and 66% at 92 hr deprivation. In Experiment 4, the effects of CCK on food consumed in absence of hunger (0 hr deprivation) were observed by administering hypertonic saline to food-sated rats before presentation of a liquid diet. Under these conditions 40 U/kg of CCK suppressed intake by 76%. An additional experiment indicated that the increased inhibitory effects observed in the latter experiment were not due to the added variable of thirst. Thus under a wide variety of deprivation conditions and under varying motivational states CCK is remarkably consistent in its inhibitory effects on food intake, which are best described by a constant percent of control intake.     

Role of gastric distention in cholecystokinin's satiety effect in golden hamsters

Cholecystokinin (CCK) inhibits gastric emptying in a number of species. Since gastric distention is facilitated by reduced gastric emptying, and since gastric distention is a long-known satiety stimulus, it is possible that CCK suppresses feeding by facilitating gastric distention satiety mechanisms. In the first experiment peripheral injections of CCK-octapeptide (CCK-8) inhibited gastric emptying in hamsters. The effective dose range corresponded to the dose range previously shown to be effective at inhibiting feeding in hungry hamsters. In a second experiment the sham-feeding paradigm, in which orally ingested liquid diet passes out of a gastric fistula (thereby eliminating gastric distention), was used to determine whether CCK-8 would reduce hamster feeding in the absence of gastric distention. An intraperitoneal dose of CCK-8 produced a slight and statistically unreliable suppression of sham-feeding. In contrast, the same dose produced a robust and reliable inhibition of feeding during a real-feeding trial (the gastric fistula was closed and the stomach was thus able to distend). These data therefore suggest that enhanced gastric distention may contribute to or magnify the satiety effect of peripherally administered CCK in this species. A third experiment examined the mechanism of CCK action on gastric emptying and feeding. Since (in other species) CCK appears to reduce the rate of gastric emptying primarily by constricting the pyloric sphincter, it was predicted that destroying pyloric control of gastric emptying by pyloroplasty would attenuate CCK's effect on both gastric clearance and feeding. However, pyloroplasty did not alter the normal inhibition of gastric emptying nor the usual feeding inhibitory response after a given dose of CCK-8.(ABSTRACT TRUNCATED AT 250 WORDS)     

CCK,endogenous insulin condition and satiety in free-fed rats

Cholecystokinin (CCK) has been shown to elicit insulin secretion and increased insulin availability has been shown to correlate with increased satiety attributed to reduced size of spontaneously occurring meals. The present experiment, however, clearly showed that CCK was effective in suppressing food ingestion in free-fed rats independent of the animal's level of insulin. Rats were tested with 1, 2 and 4 μg/kg of CCK-octapeptide (Sincalide, Squibb) during a baseline (pancreatic-normal) period, an insulin-poor state (streptozotocin diabetic) and an insulin clamped condition (diabetic treated by a minipump). CCK produced a highly significant (p<0.01) reduction of food intake compared to saline, control injections regardless of the insulin conditions of the animals. Higher doses of CCK were more effective than lower doses during all three periods of study. CCK and hyperinsulinemia function independently if they produce satiety or reductions in food intake.     

Role of oropharyngeal stimulation in cholecystokinin-induced satiety in the sham feeding rat

The belief that oropharyngeal stimulation potentiates the satiety produced by cholecystokinin (CCK) is based on the demonstration that the ability of 20% pure CCK to suppress feeding is enhanced the closer it is injected to a meal. The increase efficacy of CCK with closer temporal proximity to a meal might simply reflect increased peptide levels at the time of feeding. Further, since oropharyngeal synergy has never been demonstrated with pure CCK, studies were performed to evaluate the role of oropharyngeal stimulation in CCK-induced satiety. Rats equipped with gastric fistulae were injected IP with CCK-8 15 min before a test sham feed. In one condition, rats sham fed for 15 min prior to CCK injection; in the other, they did not. CCK-8 suppressed eating in only those cases when its administration was accompanied by oropharyngeal stimulation. Thus, oropharyngeal cues enhance the satiety action of exogenous CCK. A second experiment examined whether oropharyngeal synergy requires oropharyngeal stimulation prior to peptide delivery. CCK-8 was injected into rats coincident with the initation of a test sham feed. Rats had either sham fed, or not sham fed, for 15 min prior to CCK administration. Both conditions produced similar and significant suppressions of eating during the test sham feed. Thus, oropharyngeal cues enhance the action of CCK and oropharyngeal amplification needs only contiguous pairings of oropharyngeal stimulation and feeding.     

Obese mice and the satiety effects of cholecystokinin, bombesin and pancreatic polypeptide

Cholecystokinin (CCK-8), bombesin (BBS) and pancreatic polypeptide (PP) are gastrointestinal hormones which are released during a meal and which decrease food intake when administered exogenously. The satiety effects of CCK-8, BBS and PP were measured in weanling and adult Bar Harbor obese and lean mice. Weanling mice fasted 5.5 hr were less sensitive to both CCK-8 and BBS at 5–6 weeks of age, when body weights of the obese were 20% greater than lean. The obese were equally sensitive as lean mice to CCK-8 and BBS at 7–8 weeks of age when the obese were 50% heavier. After a 3.0 hr fast adult obese mice, weighing 100% more than lean mice, were less sensitive to satiety effects of lower doses of CCK-8 (1.0 μg/kg) and PP (8 μg/kg) but equally sensitive to higher doses of CCK-8 (2.0 μg/kg), PP (16 μg/kg) and all doses of BBS (2.0, 4.0 and 8.0 μg/kg). After a 6-hr fast, 16 μg/kg PP did not affect food intake in obese or lean mice, whereas 32 μg/kg PP decreased food intake more in obese than lean mice. Thus both weanling and adult obese mice, as obese rats, are less sensitive to the putative satiety agent CCK-8.     

Vagal mediation of the cholecystokinin satiety effect in rats

Central (intracerebroventricular) and peripheral (intraperitoneal) injections of the octapeptide of cholecystokinin (CCK-8) were compared to determine the most effective route of administration to elicit satiety for food intake in the rat. Subdiaphragmatic bilateral vagotomy and spinal cordotomy (T2-T3) were also performed to investigate the importance of visceral nerves for the satiety effect. CCK-8 suppressed feeding and elicited satiety resting behavior when injected peripherally but it was less effective when injected centrally. The satiety effect of CCK-8 or CCK-33 following peripheral injections was blocked by vagotomy whereas spinal cordotomy had no effect. The results indicate that some component of the vagus is required to mediate the peripherally induced cholecystokinin satiety effect, but the splanchnic nerves are not necessary. The weak effect of CCK-8 following ventricular administration is additional evidence suggesting that cholecystokinin of intestinal origin acts in the periphery rather than directly on the brain to elicit its typically rapid satiety effect in rats.     

Cholecystokinin-induced satiety is mediated through interdependent cooperation of CCK-A and 5-HT3 receptors

Recent evidence supports a role for the serotonin-3 (5-HT3) receptors in the modulation of cholecystokinin (CCK)-induced satiation. Likewise, 5-HT's anorectic response has been linked to recruitment of peripheral CCK-A receptors. Evidence to date, however, does not elucidate whether there is a concomitant interaction between CCK-A and 5-HT3 receptors or whether each receptor functions independently in the negative feedback control of food intake elicited by CCK. In the present study, we used selective receptor antagonists to investigate the roles of CCK-A and 5-HT3 receptors in CCK-induced satiation. Intraperitoneal administration of CCK-8 reduced 30-min 15% sucrose intake in a dose-responsive manner. Prior treatment with ondansetron (1.0 mg/kg ip), a highly selective 5-HT3 receptor antagonist, attenuated CCK-induced suppression of food intake in a dose-responsive manner. Pretreatment with lorglumide (1.0 mg/kg ip), a selective CCK-A receptor antagonist, reversed CCK-induced inhibition of sucrose intake. Finally, simultaneous blockade of CCK-A and 5-HT3 receptors by lorglumide and ondansetron, as well as concomitant administration of the two antagonists with CCK, produced a significant synergistic increase in sucrose intake compared with intakes after administration of saline, CCK, or either antagonist alone. These findings support evidence that CCK-A and 5-HT3 receptors cooperate interdependently in control of short-term food intake. Most likely, this interconnection exists through a feed-forward parallel model arising from CCK-A and 5-HT3 receptors, where activation of one system engages the other to intensify the overall satiety signal.     

Cholecystokinin-8 increases the satiety ratio in diabetic rats more than cholecystokinin-33

Cholecystokinin (CCK) is a satiety peptide and a potential anti-diabetic agent, which exists in different forms (e.g. CCK-8 and CCK-33). In normal rats, CCK-8 and 33 stimulate insulin secretion similarly but their satiety effects vary. In diabetic rats, those effects require testing. Here, we compared size of the first meal (10% sucrose test diet), intermeal interval (IMI, time between first and second meal) and satiety ratio (SR, amount of satiation produced by every unit of food consumed in the first meal) by CCK-8 or 33 (0, 1, 3, 5 nmol/kg) intraperitoneally in streptozotocin-injected (diabetic) and citrate buffer-injected (control) rats. We found that both peptides reduce meal size in diabetic and control rats with no difference between groups, CCK-33 (5 nmol) prolonged IMI in diabetic rats and CCK-8 and CCK-33 increased satiety ratio in control rats, but only CCK-8 increased it in the diabetic group. Therefore, CCK-8 increases the satiety ratio in diabetic rats more than CCK-33.     

Decreased sensitivity of Zucker obese rats to the putative satiety agent cholecystokinin

In obese rodents increased daily food intake leading to accumulation of adipose tissue is frequently accompanied by increased meal size and loss of the normal diurnal variations in feeding pattern. Increased meal size of obese rats may be due to decreased sensitivity to factors which elicit satiety. We compared Zucker obese and lean rat feeding behavior responses to octapeptide of cholecystokinin (OP-CCK), a peptide shown to decrease meal size in several species. Obese rats were less sensitive than lean rats to OP-CCK (.06, .25 and 1.0 μg/kg/meal) injected before each of four consecutive scheduled meals in the light portion of the diurnal cycle, when obese meal size was larger than lean. However, neither obese nor lean rats responded to injection of the same doses of OP-CCK during meals in the dark, when average meal size was larger than during the light and when average meal size of the obese rats was similar to that of lean rats. In both obese and lean rats injection of OP-CCK affected daily feeding pattern. Obese and lean Zucker rats are less sensitive to OP-CCK when meal size is larger, whether this is due to phase of the diurnal cycle (dark vs. light in both obese and lean rats) or phenotype (obese vs. lean rats in the light).     

Fat in the intestine as a regulator of appetite--role of CCK

The present review summarizes the appetite-suppressing effects of intestinal fat in the regulation of food intake in humans, with a special focus on the role of cholecystokinin (CCK). Current evidence supports a role for intestinal fat (especially long-chain free fatty acids) acting via the peptide CCK as a physiological satiety pathway. The regulation of satiety is, however, complex and it is not surprising that multiple control systems exist. It is interesting to note that nutrients, such as hydrolysis products of fat in the small intestine, stimulate the release of satiety peptides, such as CCK or PYY, that serve as satiety signals. CCK, released from the gastrointestinal tract by the local action of digested food, exerts various functions: stimulation of gallbladder contraction and exocrine pancreatic secretion, inhibition of gastric emptying, and inhibition of appetite. CCK functions therefore (1) as a positive feedback signal to stimulate digestive processes and (2) as negative feedback signal to limit the amount of food consumed during an individual meal.     

Protein-induced satiety: effects and mechanisms of different proteins

Relatively high protein diets, i.e. diets that maintain the absolute number of grams of protein ingested as compared to before dieting, are a popular strategy for weight loss and weight maintenance. Research into multiple mechanisms regulating body weight has focused on the effects of different quantities and types of dietary protein. Satiety and energy expenditure are important in protein-enhanced weight loss and weight maintenance. Protein-induced satiety has been shown acutely, with single meals, with contents of 25% to 81% of energy from protein in general or from specific proteins, while subsequent energy intake reduction was significant.

Protein-induced satiety has been shown with high protein ad libitum diets, lasting from 1 to 6 days, up to 6 months. Also significantly greater weight loss has been observed in comparison with control.

Mechanisms explaining protein-induced satiety are nutrient-specific, and consist mainly of synchronization with elevated amino acid concentrations.

Different proteins cause different nutrient related responses of (an)orexigenic hormones. Protein-induced satiety coincides with a relatively high GLP-1 release, stimulated by the carbohydrate content of the diet, PYY release, while ghrelin does not seem to be especially affected, and little information is available on CCK. Protein-induced satiety is related to protein-induced energy expenditure. Finally, protein-induced satiety appears to be of vital importance for weight loss and weight maintenance.

With respect to possible adverse events, chronic ingestion of large amounts of sulphur-containing amino acids may have an indirect effect on blood pressure by induction of renal subtle structural damage, ultimately leading to loss of nephron mass, and a secondary increase in blood pressure. The established synergy between obesity and low nephron number on induction of high blood pressure and further decline of renal function identifies subjects with obesity, metabolic syndrome and diabetes mellitus II as particularly susceptible groups.     

Soup and satiety

Energy-yielding fluids generally have lower satiety value than solid foods. However, despite high water content, soups reportedly are satiating. The mechanisms contributing to this property have not been identified and were the focus of this study. A within-subject design, preload study was administered to 13 male and 18 female adults (23.7+/-0.9 years old) with a mean body mass index (BMI) of 23.0+/-0.7 kg/m2. At approximately weekly intervals, participants reported to the lab after an overnight fast and completed questionnaires on mood, appetite, psychological state, strength, and fine motor skills. After administration of motor tasks, participants consumed a 300-kcal preload in its entirety within 10 min. The test foods included isocaloric, solid, and liquefied versions of identical foods high in protein, fat, or carbohydrate. Single beverage and no-load responses were also tested. The same questionnaires and motor skills tests were completed at 15-min intervals for 1 h and at 30-min intervals for an additional 3 h after loading. Diet records were kept for the balance of the day. The soups led to reductions of hunger and increases of fullness that were comparable to the solid foods. The beverage had the weakest satiety effect. Daily energy intake tended to be lower on days of soup ingestion compared to the solid foods or no-load days and was highest with beverage consumption. Thus, these data support the high satiety value of soups. It is proposed that cognitive factors are likely responsible.     

Studying ingestive behavior with Gerry Smith

During the approximately 15 years that Gerry and I collaborated on studying the ingestive behavior of the rat, we showed (1) using a microstructural analysis of the licking behavior of that animal, that the volume ingested during 30-min intake tests was controlled by an interaction between oropharyngeal and postingestional stimulation; (2) that the inhibiting effect of dopamine blockade on intake acts through sensory rather than motor systems; (3) that CCK-8 acts on licking behavior the same way that gastric filling does. We also discovered (4) that learning altered the effectiveness of oropharyngeal stimulation to control the intake of concentrated carbohydrate and sodium chloride solutions; and (5) that the stomach is remarkably insensitive to the volume of its contents.     

Eating provides important physiological signals for satiety and drinking

Eating has important physiological consequences. Experiments in which food and components of food are manipulated in ways to activate various food-contingent physiological signals have revealed mechanisms for eating-elicited satiety and thirst. This kind of approach also has revealed that eating can activate physiological signals for drinking to prevent challenges to fluid homeostasis.     

Adiposity signaling and meal size control

Signaling from energy stores provides feedback on overall nutrient availability to influence food intake. Beginning with seminal studies by Woods and colleagues identifying insulin as an adiposity signal, it has become clear that such factors affect food intake by modulating the efficacy of within meal feedback satiety signals. More recent work with leptin has revealed actions of the hormone in modulating the efficacy of multiple gut feedback signals, identified the dorsal hindbrain as a site of signal integration and suggested both local and descending hypothalamic to hindbrain actions in mediating these effects. The original work by Woods and colleagues provided the necessary experimental paradigms for these advances.     

Triggering of habituation: reconsidered

Habituation of the flexor withdrawal reflex was studied in conscious rats. In control experiments in which 300 stimuli were applied (interstimulus interval 10 sec) there was found to be a linear begative correlation between log response and the number of stimuli. In other experiments stimuli were given in two trains separated by a 15 min pause. The first train contained 20, 40, 60, or 80 stimuli. The initial responses to the second train were significantly greater than the control responses recorded an identical period of time after the first stimulus in the experiment. In experiments in which the first train contained 40, 60, or 80 stimuli, a significant degree of recovery occurred during the 15 min pause. The initial rates of habituation to the second train in these experiments was greater than rates observed to the corresponding stimuli in the control series. The rates of decrement to subsequent stimuli however, were not different from control values. The data were discussed with reference to the hypothesis that habituation could be triggered by initial experience.     

Olfactory influences on appetite and satiety in humans

Odor stimuli play a major role in perception of food flavor. Food-related odors have also been shown to increase rated appetite, and induce salivation and release of gastric acid and insulin. However, our ability to identify an odor as food-related, and our liking for food-related odors, are both learned responses. In conditioning studies, repeated experience of odors with sweet and sour tastes result in enhanced ratings of sensory quality of the paired taste for the odor on its own. More recent studies also report increased pleasantness ratings for odors paired with sucrose for participants who like sweet tastes, and conversely decreased liking and increased bitterness for quinine-paired odors. When odors were experienced in combination with sucrose when hungry, liking was not increased if tested sated, suggesting that expression of acquired liking for odors depends on current motivational state. Other studies report sensory-specific satiety is seen with food-related odors. Overall, these studies suggest that once an odor is experienced in a food-related context, that odor acquires the ability to modify both preparatory and satiety-related components of ingestion.