CCK satiety is differentially mediated by high- and low-affinity CCK receptors in mice and rats

Abstract

Cholecystokinin-JMV-180 (JMV-180) is an analogue of cholecystokinin C-terminal octapeptide (CCK-8), which has been shown to be an agonist at the proposed CCK pancreatic high-affinity site and a functional antagonist at the pancreatic low-affinity site in rats and to have agonist activity at both high- and low-affinity sites in the mouse. In this study we used JMV-180 to evaluate the potential participation of these two CCK-A sites in the satiety effect of CCK-8 in rats and mice. When tested at doses that ranged from 0.01 to 9.2 mumol/kg, JMV-180 did not reliably affect food intake of solid or liquid test diets in rats. When combined with CCK-8 (3.2 or 8.5 nmol/kg) JMV-180 dose dependently reversed the satiety effect of CCK-8. In contrast to these results in the rat, both JMV-180 (3.7-14.8 mumol/kg) and CCK-8 (1.7-6.8 nmol/kg) dose dependently reduced the intake of 20% sucrose in mice. Both CCK-8- and JMV-180-induced suppression of food intake were attenuated by the CCK-A antagonist MK-329 (24.8 nmol/kg). The results of these studies suggest that agonist activity at sites pharmacologically similar to the CCK pancreatic high-affinity site is not sufficient for expression of CCK satiety, whereas agonist activity at low-affinity-like sites is necessary to reduce food intake. Thus the anorexic activity of CCK appears to be mediated through an interaction with a receptor site pharmacologically similar to the pancreatic low-affinity CCK receptor site.

Low-affinity CCK-A receptors are coexpressed with leptin receptors in rat nodose ganglia: implications for leptin as a regulator of short-term satiety

“…The synergistic interaction with leptin was blocked by JMV-180, suggesting that these CCKAR are in the low-affinity state. These data provide a neurochemical basis to explain the observation that JMV-180 dose dependently reverses the effect of CCK-8 on satiety (38).…”

“…Currently, it is not known whether the CCK receptors at these two sites (i.e., pancreatic acini and vagus nerve) represent distinct proteins or different affinity states of the same receptor protein. Vagal high-affinity CCK receptors appear to be important in the mediation of postprandial pancreatic enzyme secretion (11), whereas low-affinity CCK receptors are involved in regulating short-term satiety (38). Using a rat model with a pancreatic-biliary cannula, Li et al (11) studied the effects of the CCK analog CCK-JMV-180 (JMV-180) on exocrine pancreatic secretion.…”

“…These observations indicate that both exogenous and endogenous CCK evoke pancreatic secretion by acting on high-affinity CCK receptors. On the other hand, Weatherford et al (38) demonstrated that JMV-180 dose dependently reversed the effect of CCK-8 on satiety, suggesting that the anorexic activity of CCK is mediated through an interaction with the low-affinity CCK receptor site. Hence, it appears that different affinity states of the vagal CCK-A receptors (CCKAR) mediate different digestive functions.…”

Cocaine- and amphetamine-regulated transcript is the neurotransmitter regulating the action of cholecystokinin and leptin on short-term satiety in rats

“…High-affinity vagal CCKARs mediate postprandial pancreatic enzyme secretion (15), whereas low-affinity CCKARs are involved in regulating short-term satiety (28). Electrophysiological recording and immunohistochemical studies have shown that predominantly low-affinity CCKARs are coexpressed with LRbs in the NG (15).…”

CCK-8 and CCK-58 differ in their effects on nocturnal solid meal pattern in undisturbed rats

“…The time needed to inject rats was ϳ30 s/rat. The dose of CCK was based on previous studies showing a robust reduction of food intake following injection of 2 nmol/kg CCK-8 (17,56). Experiments were repeated in a crossover design in the same batch of rats for each treatment.…”