Comment by Gerard P. Smith and James Gibbs (May, 2014)

It was 1972 and we were stuck. We had just completed an experiment that provided strong evidence against Mayer’s (1953) hypothesis that decreased glucose utilization was a physiological signal for the initiation of eating under normal laboratory conditions (Smith et al., 1972). With the loss of Mayer’s hypothesis and dwindling support for the gastric-contraction theory of hunger (Penick et al., 1963; Stunkard and Fox, 1971), there was no good candidate mechanism for the initiation of eating and the ingestion of a meal.

On the other hand, we were impressed that our monkeys and rats stopped eating within 30 minutes after they began. It was clear that ingested food was the adequate stimulus for this apparent inhibitory reflex. The site of this inhibitory action of food must be along the preabsorptive path that ingested food or its digestive products took from the mouth, through the stomach, and into the small intestine or by the absorbed nutrient molecules acting postabsorptively.

At the time two mechanisms for terminating a meal had been proposed. One was increased glucose utilization in the brain (Mayer, 1953). But if decreased glucose utilization was not the mechanism for the control of initiating and eating meals under usual conditions (Smith et al., 1972), then increased glucose utilization was not a mechanism for the termination of eating.

Gastric distention was the other current mechanism for terminating eating. That this volumetric effect in the stomach was the only endogenous mechanism for such an important biological event as terminating a meal seemed unlikely to us.

So we decided to test the effect of gut hormones on food intake. We had four reasons: First, a number of hormones were released by the mechanical and chemical stimuli of ingested food contacting the luminal surface of the stomach and small intestine (Makhlouf 1974). Second, the hormones could stop eating because they were released before eating stopped. Third, a number of the hormones were available in pure or partially pure form. Fourth, there was considerable knowledge concerning their structure-functions relationships for visceral motor and secretory effects.

We began with cholecystokinin (CCK). The first experiments worked — intraperitoneal injections of impure extracts of CCK and synthetic CCK-8 stopped eating and decreased meal size in a dose-related manner in male Sprague Dawley rats. The inhibitory effect was specific in two ways: First, CCK decreased intake of liquid and solid food, but did not change water intake. Second, doses of CCK that inhibited food intake were not sufficient to serve as an unconditioned stimulus for the formation of a conditioned taste aversion to saccharin. This made it likely that CCK was not inhibiting food intake by causing subclinical sickness. We presented a preliminary report of this research at the Federation meeting in 1972 (Gibbs, et al., 1972) and published a complete paper in 1973 (Gibbs et al., 1973a).

The 1973a paper reported the effects of exogenous CCK. A second paper in 1973 (Gibbs et al., 1973b) reported the relative importance of endogenous CCK for terminating food intake. We reasoned that if CCK were a significant mechanism for terminating eating, preventing ingested food from stimulating its release from the duodenal mucosa should produce a larger meal. We used the chronic gastric-fistula rat to produce sham feeding (SF). When the rat ingested a liquid diet with the cannula open, the ingested food drained out of the stomach and did not enter the small intestine. This prevented gastric distention and the release of CCK from the duodenum. Rats that were food deprived for 17 hours did not terminate eating during a two-hour test (Gibbs and Smith, 1977, Figure 1; Gibbs, et al., 1973b; Young, et al., 1974). The relevance of the lack of CCK release to the sustained eating was not clear, however, because other intestinal hormones were also not released.

To clarify the situation, we did two experiments. In the first, we infused liquid diet into the duodenum during SF (Gibbs and Smith, 1977, Figure 2; Liebling et al., 1975). In the second, we injected CCK intraperitoneally prior to SF (Gibbs and Smith, 1977, Figure 3; Gibbs et al., 1973b). Both procedures terminated SF and produced the behavioral sequence of satiety, the signature of the onset of postprandial satiety (Antin et al., 1975), despite the absence of gastric distention. These results convinced us and many others to pursue the hypothesis. In 1992 the accumulated evidence was sufficient for us to conclude that the satiety effect of CCK was a physiological function of the endogenous hormone (Smith and Gibbs, 1992).

In addition to the question of the physiological status of the satiety effect of CCK, our 1977 paper shows that we were aware of the therapeutic implications of a hormonal signal that decreased food intake. The last two pages summarize experiments in rhesus monkeys that confirmed the results in rats (Gibbs and Smith, 1977, Figure 4; Gibbs et al., 1976) and extended them by showing decreased caloric intake in the first 3 hours after gastric preloads of l-phenylalanine that released CCK, but not after isovolumetric gastric preloads of d-phenylalanine that did not release CCK (Gibbs and Smith, 1977, Figure 5). In contrast to the physiological satiating function of CCK, however, the efficacy of CCK for the treatment of obesity remains uncertain.

References

Antin, J., J. Gibbs, J. Holt, R.C. Young, and G.P. Smith. Cholecystokinin elicits the complete behavioral sequence of satiety in rats. J. Comp. Physiol. Psychol. 89: 784-790, 1975.

Gibbs, J., J.D. Falasco, and P.R. McHugh. Cholecystokinin decreased food intake in rhesus monkeys. Am. J. Physiol. 230: 15-18, 1976.

Gibbs, J., and G.P. Smith. Cholecystokinin and satiety in rats and rhesus monkeys. Am. J. Clin. Nutr. 30: 758-761, 1977.

Gibbs, J., R.C. Young, and G.P. Smith. Federation Proc. 31: 397, 1972.

Gibbs J., R.C. Young, and G.P. Smith. Cholecystokinin decreases food intake in rats. J. Comp. Physiol. Psychol. 84: 488-495, 1973a. (This paper was selected as a Citation Classic by Current Contents 20 years later (Gibbs, Young, and Smith,1993). We considered using it here, but the publisher refused permission to post it on the Society’s website.)

Gibbs, J., R.C. Young, and G.P. Smith. Cholecystokinin elicits satiety in rats with open gastric fistulas. Nature 245: 323-325, 1973b.

Gibbs, J., R.C. Young, and G.P. Smith. Current Contents, Number 25, June 28, 1993.

Liebling, D.S., J.D. Eisner, J. Gibbs, and G.P. Smith. Intestinal satiety in rats. J. Comp. Physiol. Psychol. 89: 955-965, 1975.

Makhlouf, G.M. The neuroendocrine design of the gut. The play of chemicals in a chemical playground. Gastroenterol. 67: 159-184, 1974.br>
Mayer, J. Glucostatic mechanism of regulation of food intake. N. Engl. J. Med. 249:13-16,1953.

Penick, S.B., G.P. Smith, K. Weineke,Jr., and L.E. Hinkle, Jr. An experimental evaluation of the relationship between hunger and gastric motility. Am. J. Physiol. 205: 421-426,1963.

Smith, G.P. and J. Gibbs. The development and proof of the cholecystokinin hypothesis of satiety. In Dourish, C.T., S.J. Cooper, S.D. Iversen, and L.L. Iversen (eds.) Multiple cholecystokinin receptors in the CNS. Oxford, England: Oxford University Press, 1992, p 166-182.

Smith, G.P., J. Gibbs, A.J. Strohmayer, and P.E. Stokes. Threshold doses of 2-deoxy-D-glucose for hyperglycemia and feeding in rats and monkeys. Am. J. Physiol. 222:77-81, 1972.

Stunkard, A.J. and S. Fox. The relationship of gastric motility and hunger. A summary of the evidence. Psychosom. Med. 33: 123-134, 1971.

Young, R.C., J. Gibbs, J. Antin, J.Holt, and G.P. Smith. Absence of satiety during sham feeding in the rat. J. Comp. Physiol. Psychol. 87: 795-800, 1974.