Following its release, CCK elicits multiple effects on the gastrointestinal system, including the regulation of gut motility, contraction of the gallbladder, pancreatic enzyme secretion, gastric emptying, and gastric acid secretion.60,61 Most of these are thought to be due to endocrine actions of circulating CCK that has entered the bloodstream. Over 30 years ago, Gibbs et al first demonstrated that exogenous administration of either purified CCK or synthetic CCK-8 into the peritoneal cavity (ip) of rats reduced meal size.62 The response is dose dependent, with larger doses causing a greater reduction of food intake, and they observed that the CCK must be administered near the start of a meal to be effective. If CCK is administered more than 15 minutes before animals begin eating, it has no effect on meal size. The same group also observed that exogenous CCK elicited the same sequence of behaviors that noninjected rats display when they terminate meals.14 Centrally administered CCK also causes animals to consume smaller meals.63,64 The finding that exogenous CCK reduces meal size in rats has been replicated in many labs and extended to numerous species, including nonhuman primates and humans.19,20,65–70
The observation that the administration of exogenous CCK reduces meal size, although consistent with the hypothesis that CCK is a natural satiety factor, is insufficient in and of itself to draw conclusions. Stronger evidence would be the demonstration that endogenous CCK, acting during normal meals, acts to limit caloric intake. Consistent with this, the administration of specific CCK-1 antagonists increases meal size in experimental animals and humans.71–74
Behavioral experiments indicate that CCK is truly a short-term, meal-reducing signal. This is illustrated by the fact that repeated or long-term chronic75 or intermittent76 administration of CCK to rats has no effect on weight loss. When the size of every meal is reduced by CCK, animals compensate by increasing meal frequency.76,77 Although the effects of exogenous CCK are brief, acting within the time of an ongoing meal, CCK also appears to interact with long-term signals of energy balance such as leptin and insulin.78 The anorectic effects of CCK can be augmented by the coadministration of subthreshold concentrations of leptin.79–82 Analogously, administering low doses of insulin directly into the brain also increases the satiating effect of CCK.83,84 Because leptin and insulin are important signals indicating the level of body fat to the brain,1,3,4,85 the implication is that body fat is regulated, at least in part, by changes in the sensitivity to meal-generated satiety signals such as those given by CCK. That is, if an individual loses body weight, the consequently reduced leptin and insulin signals in the brain would render the individual less sensitive to CCK, and there would be a tendency to eat larger meals; the opposite would occur if an individual were to gain body weight. When individuals are chronically obese, however, they are characterized with insulin and leptin resistance; hence, rats with hypothalamic obesity have hyperinsulinemia but a normal sensitivity to CCK’s satiating action,86 and fatty Zucker rats with genetic obesity have slightly reduced sensitivity to CCK.87 Although these forms of obesity are characterized with a blunted response to adiposity hormones, others are characterized by an absent response to CCK. Rats with a spontaneous mutation of the CCK-1 receptor (called OLETF rats88) eat slightly enlarged meals and gradually develop mild obesity over their lifetime.89,90