CCK-58 elicits both satiety and satiation in rats while CCK-8 elicits only satiation

Abstract

Reduction of food intake by exogenous cholecystokinin (CCK) has been demonstrated primarily for its short molecular form, CCK-8. Mounting evidence, however, implicates CCK-58 as a major physiologically active CCK form, with different neural and exocrine response profiles than CCK-8. In three studies, we compared meal-pattern effects of intraperitoneal injections CCK-8 vs. CCK-58 in undeprived male Sprague-Dawley rats consuming sweetened condensed milk. In study one, rats (N=10) received CCK-8, CCK-58 (0.45, 0.9, 1.8 and 3.6 nmole/kg) or vehicle before a 4-hour test-food presentation. At most doses, both CCK-8 and CCK-58 reduced meal size relative to vehicle. Meal-size reduction prompted a compensatory shortening of the intermeal interval (IMI) after CCK-8, but not after CCK-58, which uniquely increased the satiety ratio (IMI/size of the preceding meal). In the second study, lick patterns were monitored after administration of 0.9nmole/kg CCK-58, CCK-8 or vehicle. Lick cluster size, lick efficiency and interlick-interval distribution remained unaltered compared to vehicle, implying natural satiation, rather than illness, following both CCK forms. In study 3, threshold satiating doses of the two CCK forms were given at 5 and 30 minutes after meal termination, respectively. CCK 58, but not CCK-8 increased the intermeal interval and satiety ratio compared to vehicle. In conclusion, while CCK 58 and CCK-8 both stimulate satiation, thereby reducing meal size, CCK-58 consistently exerts a satiety effect, prolonging IMI. Given the physiological prominence of CCK-58, these results suggest that CCK’s role in food intake regulation may require reexamination.

Central and peripheral control of food intake

“…Th ere are various forms of CCK with various eff ects on the meal size and the intervals between meals. While CCK 58 and CCK-8 both stimulate satiation, thereby reducing meal size, CCK-58 consistently exerts a satiety eff ect (Overduin et al 2014). Similar results have been reported with CCK-33, which has been found to reduce the food intake by prolonging the inter-meal interval (Washington et al 2011;Lateef et al 2012).…”

Role of gastrointestinal hormones in feeding behavior and obesity treatment

“…The major circulating forms are CCK-8, CCK-22, CCK-33, and CCK-58, all having the same attribute, a C-terminal heptapeptide amide sequence for binding [42][43][44]. Although they have the same attribute, not all forms of CCK show equal bioactivity; for example, both CCK-8 and CCK-58 can reduce meal size after administration, but only CCK-58 increases the intermeal interval time, while CCK-8 reduces this interval, as shown in previous studies [45,46]. CCK performs its action through cholecystokinin-1 (CCK1) receptors and/or cholecystokinin-2 (CCK2) receptors [47].…”

Metabolic Actions of the Type 1 Cholecystokinin Receptor: Its Potential as a Therapeutic Target

“…While the earliest studies utilized natural porcine CCK-33, all more recent studies used synthetic CCK, specifically CCK-8, due to ease of synthesis and inclusion of the minimal fragment with full activity and potency at CCK1R, the carboxyl-terminal heptapeptide-amide. In feeding studies, this peptide has been shown to reproducibly reduce meal size [6], however, its impact on inter-meal interval has been variable, with some studies demonstrating more frequent meals (shortening of inter-meal interval), capable of offsetting the beneficial impact of reduced meal size [23, 24]. It is now appreciated that the dominant form of CCK released into the circulation is a longer form of this hormone with an amino-terminal extension, CCK-58 [25].…”

“…It is now appreciated that the dominant form of CCK released into the circulation is a longer form of this hormone with an amino-terminal extension, CCK-58 [25]. CCK-58 has been consistently shown to not only reduce meal size, but also extend the inter-meal interval [23, 24]. This provides important reassurance that the “ satiation ” effect of CCK (reduced meal size) is not offset by reduced “satiety” (increased meal frequency).…”