The satiety effect of cholecystokinin: A progress report

Peptides, Vol. 2, Suppl. 2, pp. 57-59, 1981. Printed in the U.S.A.

The Satiety Effect of Cholecystokinin: A Progress Report G. P. SMITH, 2 J. GIBBS, 3 C. JEROME, F. X. P I - S U N Y E R H . R. K I S S I L E F F

A N D J. T H O R N T O N

Department of Psychiatry, Cornell University Medical College and E. W. Bourne Behavioral Research Laboratory, New York Hospital Department of Medicine and Obesity Research Center, St. Luke's-Roosevelt Hospital Center Columbia University College of Physicians and Surgeons and Department of Biostatistics, Mt. Sinai School of Medicine, New York, N Y

SMITH, G. P., J. GIBBS, C. JEROME, F. X. PI-SUNYER, H. R. KISSILEFF AND J. THORNTON. The satiety effect ofcholecystokinin: A progress report. PEPTIDES 2: Suppl. 2, 57-59, 1981.--The satiety effect of cholecystokinin (CCK) that was first observed in rats has now been extended to chickens, rabbits, pigs, sheep, rhesus monkeys, lean mice, genetically obese mice and rats, neurologically obese rats, lean men and women, and obese men. The effect is specific and can be obtained in animals and humans without reports or signs of sickness. The mechanism of the effect is unknown, but the gastric vagal fibers are necessary for the effect. This has led to the hypothesis that the satiety effect is due to activation of vagal afferent fibers that inhibit the central control system of feeding by CCK acting directly on recently described vagal CCK receptors and/or indirectly through a gastric smooth muscle effect that vagal receptors are sensitive to. Cholecystokinin Vagus Cholecystokinin receptors

Vagal afferents Genetic obesity

Satiety Gastric emptying Obesity Food intake Vagal receptors

N I N E years ago, we reported that cholecystokinin (CCK) inhibited food intake in rats [13]. The inhibition was doserelated. The inhibition was also behaviorally specific for feeding because doses of CCK that inhibited the intake of food in food-deprived rats did not inhibit the intake of water in water-deprived rats [13,29]. The range of doses that inhibited feeding did not produce signs of acute toxicity, such as increased body temperature. There were also no signs of chronic toxicity: Rats remained apparently healthy when CCK was administered three times a week for 6 months. In the next two years we demonstrated that C C K mimicked the satiety effect of ingested food. We did this by administering C C K to 17 hr food deprived rats while they were sham feeding a liquid diet. We had discovered that under these conditions rats sham feed almost continuously for hours [50]. When C C K was administered intraperitoneally, however, sham feeding stopped [14] and rats displayed a sequence of behaviors that characterized postprandial satiety [3]. Since C C K mimicked ingested food by inhibiting sham feeding and by eliciting the behavioral sequence of satiety, we proposed the hypothesis that endogenous C C K released by ingested food in the small intestine was one of the physiological mechanisms for postprandial satiety. These results and the hypothesis generated from them

Feeding behavior

have been scrutinized and investigated in a number of ways in subsequent years. Although most of our work has been done with the synthetic octapeptide (CCK-8), there is no reason to suspect that other forms of CCK, such as CCK-33, will have qualitatively different effects on food intake. Thus, the various forms o f CCK are not specified in this paper. In this paper we summarize the important aspects of recent work and indicate the growing edges of the problem. The satiety effect has been confirmed in the rat [1,4] and extended to other species including chickens [39], rabbits [19], pigs [2], sheep [17], rhesus monkeys [12,15], lean mice [27, 34, 47], genetically obese mice [27, 34, 47], genetically obese rats [25,26], neurologically obese rats [23,41], lean men and women [22, 43, 44, 48], and obese men [36]. It is remarkable that the initial results in the lean rat were representative of the effects in other species. This suggests that the satiety effect of CCK is the result of activating a fundamental, physiological mechanism. Our recent results in men are particularly important for three reasons. First, the main effect of CCK is that men stop eating sooner [22,36]. This is what our hypothesis predicts. If CCK is one of the endogenous mechanisms for satiety, then administration of exogenous C C K at the beginning of a meal should produce a concentration of circulating CCK that is

1Supported by grants from NIH (AM 26687, AM 17240), from NIMH (MH 15455) and from Squibb & Co. zSupported by NIMH Research Development Award MH 00149. Send reprint requests to G.P.S. at E.W. Bourne Behavioral Research Laboratory, New York Hospital, 21 Bloomingdale Road, White Plains, NY 10605. aSupported by a fellowship from Irma T. Hirschl Foundation.

C o p y r i g h t © 1981 A N K H O

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SMITH E T A L .

suprathreshold for satiety sooner than when circulating levels of CCK are dependent upon the release of CCK from the small intestine by ingested food. Second, humans treat CCK as if it were food. When they eat less as a result of CCK treatment, they report and appear as if they were normally satisfied [22,36]. This is also consistent with our hypothesis that CCK from the intestine encodes food stimuli in the small intestine for the central neural control system for feeding behavior. This is a very important point in considering the therapeutic potential of CCK for obese patients. These initial experiments suggest that humans react to CCK as if it were food. Previous anorectic agents have attempted to inhibit food intake without providing the equivalent pleasures of feeding. This is probably why they have been so ineffective. Third, the lack of reports or signs of significant discomfort or toxicity in these human studies [22, 36, 43, 44] is a decisive demonstration that CCK can inhibit food intake without making people sick. This settles the sterile controversy [9, 16, 18] concerning this point in animals. The controversy was sterile because unambiguous evidence of nausea is not attainable in animals at the present time [40]. Although considerable progress has been made concerning the characteristics and generality of the satiety effect of CCK, the mechanism(s) remains unknown. Given that satiety is a behavioral effect, it is plausible to assume that circulating CCK acts directly on the brain to produce it. DellaFera and Baile obtained apparently convincing evidence for this assumption when they demonstrated that infusion of CCK into the C S F decreased food intake [6,7] and that injection of antibodies to CCK increased food intake in sheep [8]. Parrott and Baldwin [33] confirmed the inhibitory effect on food intake of centrally administered CCK in pigs. Attempts to produce this phenomenon in rats have failed [6,31]. The reason for the species difference in response in not known. The results of Della-Fera and Baile are compelling, but they are probably not relevant to the site of action of circulating CCK released by ingested food in the small intestine because circulating CCK does not gain access to the C S F [5] and does not penetrate the blood-brain barrier [32]. The inhibition of food intake after central administration of CCK is probably mimicking an action of brain C C K [10, 20, 24, 30, 35: 37, 45, 46] on central CCK receptors [21, 38, 42]. The lack of evidence that circulating CCK from the small intestine has significant access to central CCK receptors led

us to search for a peripheral site of action. Since CCK produces numerous smooth muscle effects in abdominal viscera, we hypothesized that one or more of these effects activated visceral afferents that traveled in the vagus nerve to the brain to inhibit the central neural control system of feeding. We tested this hypothesis by measuring the effect of CCK-8 on food intake in rats that had undergone total vagotomy or selective vagotomy of the hepatic, gastric or coeliac branches. We found that total and gastric vagotomy markedly reduced or abolished the satiety effect of CCK-8, but hepatic, coeliac and combined hepatic-coeliac vagotomies did not [41]. Thus, among the branches of the abdominal vagus, the gastric branches are necessary and sufficient for the satiety effect of CCK. This result suggests that the critical effect of CCK monitored by the gastric vagal fibers is in the stomach or possibly in another part of the terminal field of the gastric branches, such as the first part of the duodenum. In fact, Moran and McHugh have specified the critical event as the inhibition of gastric emptying [28]. The fact that the inhibition of gastric emptying by CCK-8 is also abolished by abdominal vagotomy in the dog [49] is consistent with their suggestion and our vagotomy results. Another possible mechanism has emerged from the work of Zarbin et al [51]. They demonstrated CCK receptors traveling distally in vagal fibers. If circulating CCK had access to these receptors, and if farther work demonstrates that the receptors are in afferent fibers, then CCK could activate vagal afferents directly by binding to these receptors. Since C C K is present in vagal afferent fibers [11], it is possible that the vagal receptors serve intravagal C C K rather than circulating CCK from the small intestine. We wish to emphasize the speculative nature of current ideas about the mechanism of the satiety effect. The importance of the gastric vagal fibers is established in the rat, but the critical event that is monitored and the relative importance of vagal afferent and efferent fibers is not. Our working hypothesis is that the critical event is a smooth muscle effect of CCK that activates vagal afferent fibers. In summary, the satiety effect of CCK is established, but the physiological mechanism of this effect in unknown.

ACKNOWLEDGEMENT We thank Mrs. Ellen Andrews for typing the manuscript.

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