Effects of peripheral CCK receptor blockade on feeding responses to duodenal nutrient infusions in rats

Abstract

A cholecystokinin receptor (CCKAR) antagonists differing in blood-brain barrier permeability were used to test the hypothesis that duodenal delivery of protein, carbohydrate, and fat produces satiety in part by an essential CCK action at CCKARs located peripheral to the blood-brain barrier. Fasted rats with open gastric fistulas received devazepide (1 mg/kg iv) or A-70104 (700 nmol ⅐ kg Ϫ1 ⅐ h Ϫ1 iv) and either a 30-min intravenous infusion of CCK-8 (10 nmol ⅐ kg Ϫ1 ⅐ h Ϫ1 ) or duodenal infusion of peptone, maltose, or Intralipid beginning 10 min before 30-min access to 15% sucrose. Devazepide penetrates the blood-brain barrier; A-70104, the dicyclohexylammonium salt of N␣-3-quinolinoyl-D-Glu-N,N-dipentylamide, does not. CCK-8 inhibited sham feeding by ϳ50%, and both A-70104 and devazepide abolished this response. Duodenal infusion of each of the macronutrients dose dependently inhibited sham feeding. A-70104 and devazepide attenuated inhibitory responses to each macronutrient. Thus endogenous CCK appears to act in part at CCKARs peripheral to the blood-brain barrier to inhibit food intake. receptor antagonist; devazepide; A-70104; satiety CCK is a peptide that is found throughout the brain and in neurons and endocrine cells of the gastrointestinal tract. Studies demonstrating that type A CCK receptor (CCKAR) antagonists stimulate food intake in a variety of species provide compelling evidence that CCK plays an essential role in producing the satiation that occurs with ingestion of a meal (6,13,14,23,39,48). The popular hypothesis is that CCK, secreted from enteroendocrine cells in the upper small intestine in response to duodenal delivery of nutrients, acts through paracrine stimulation of intestinal vagal sensory neurons to inhibit food intake. This hypothesis is supported by studies demonstrating the existence of CCK-secreting endocrine cells in the epithelium of the upper small intestine (7, 60), CCKARs within vagal afferent nerves (40, 66), activation of intestinal vagal afferent neurons by exogenous and endogenous CCK (17,20,31), and similar attenuation by CCKAR antagonists and vagal neural lesions of anorexic responses to exogenous CCK and nutrient administration (51).Several lines of evidence suggest that this mechanism is not the only one by which CCK produces satiety. For example, we and others have demonstrated that systemic administration of the CCKAR antagonist devazepide can increase food intake in rats whether or not they are vagotomized (45) or pretreated with capsaicin to lesion visceral sensory nerves (52). CCKAR antagonists reported not to cross the bloodbrain barrier [2-naphthalenesulfonyl-L-aspartyl-2-(phenethyl)-amide (25) and A-70104 (64)] have also been reported to have no effect on food intake in rats (22) or pigs (4, 24) when administered systemically under the same conditions in which devazepide stimulates food intake (22, 23). Because CCK does not readily penetrate the blood-brain barrier (41), these results suggest that endogenous CCK may also be acting as a neurotransmitter or neuro...

Role of peptide YY(3–36) in the satiety produced by gastric delivery of macronutrients in rats

“…We observed a similar inverse relationship between orexigenic responses to CCK receptor blockade and rate of macronutrient delivery to the gastrointestinal tract (35,(45)(46)(47). Together, these results suggest that gut peptides PYY and CCK each play an essential role in mediating the satiety response to lower rates of nutrient delivery to the gastrointestinal tract and that higher delivery rates stimulate redundant satiety mechanisms.…”

“…Our results suggest that the nutrient infusions may have reduced a "ceiling effect" that limited the expression of an orexigenic response to Y2 receptor blockade in the hungry rats. We previously provided evidence using this approach that the gut peptide cholecystokinin and the pancreatic peptide amylin play essential roles in mediating nutrient-induced satiety (34,35,(45)(46)(47).…”

“…A second set was used for the 3 kcal/h dose of Tryptone, 4 kcal/h dose of Liposyn II, and 2 kcal/h dose of Polycose. Based on our similar studies using duodenal nutrient infusions (34,35), these macronutrient doses were predicted to produce a 25-50% reduction in food intake during the first few hours of the dark period. Yiin et al (49) have provided evidence that, in rats, similar gastric rates of infusion of Polycose, corn oil, and casein produce learned flavor preferences rather than aversions, suggesting that they do not reduce food intake by producing malaise.…”

Pork Peptone Stimulates Cholecystokinin Secretion from Enteroendocrine Cells and Suppresses Appetite in Rats

“…2,3) The role of peripheral CCK in satiety is evident from studies with CCK receptor antagonists and vagotomized subjects, which have been shown to abolish anorexia produced by gastric or duodenal delivery of nutrients. 4,5) In rats, dietary proteins have been reported to be more satiating than carbohydrate or fat, 6) and to be a major stimulus of intestinal CCK release. 7,8) Endogenous CCK has been shown to induce anorexia after gastric or duodenal delivery of peptones.…”

“…7,8) Endogenous CCK has been shown to induce anorexia after gastric or duodenal delivery of peptones. 4,5) It is believed that CCK release by dietary protein is regulated by endogenous, trypsin-sensitive CCK-releasing peptides, 9) but some studies both in vivo and in vitro have found that dietary protein and its peptide react on CCK-producing cells directly to stimulate CCK release. [10][11][12] Previously we found that intraduodenal infusion of a peptic hydrolysate of soybean -conglycinin, -conglycinin peptone (BconP), suppresses food intake through this CCK release.…”