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1 Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California, Davis, Davis, California, United States; 2Center for Comparative Medicine, School of Veterinary Medicine, University of California, Davis, Davis, California, United States; 3Department of Medicine, GRASP Digestive Disease Center, Tupper Research Institute, Tufts-New England Medical Center, Tufts University, Boston, Massachusetts, United States
* To whom correspondence should be addressed. E-mail: heraybould{at}ucdavis.edu.
Cholecystokinin (CCK), acting at CCK1Rs on intestinal vagal afferent terminals, has been implicated in control of gastrointestinal function and food intake. Using CCK1R-/- mice, we tested the hypothesis that lipid-induced activation of the vagal afferent pathway and intestinal feedback of gastric function is CCK1R-dependent. In anesthetized CCK1R+/+ ("wildtype") mice, meal-stimulated gastric acid secretion was inhibited by intestinal lipid infusion; this was abolished in CCK1R-/- mice. Gastric emptying of whole egg, measured by nuclear scintigraphy in awake mice, was significantly faster in CCK1R-/- than CCK1R+/+ mice. Gastric emptying of chow was significantly slowed in response to administration of CCK-8 (22 pmol) in CCK1R+/+, but not CCK1R-/- mice. Activation of the vagal afferent pathway was measured by immunohistochemical localization of Fos protein in the nucleus of the solitary tract (NTS; region where vagal afferents terminate). CCK-8 (22 pmol IP) increased neuronal Fos expression in the NTS of fasted CCK1R+/+ mice; CCK-induced Fos expression was reduced by 97% in CCK1R-/- compared to CCK1R+/+ mice. Intralipid (0.2 ml of 20% Intralipid, 0.04 g lipid), but not saline, gavage increased Fos expression in the NTS of fasted CCK1R+/+ mice; lipid-induced Fos expression was decreased by 47% in CCK1R-/- compared to CCK1R+/+mice. We conclude that intestinal lipid activates the vagal afferent pathway, decreases gastric acid secretion, and delays gastric emptying via a CCK1R-dependent mechanism. Thus, despite a relatively normal phenotype, intestinal feedback in response to lipid is severely impaired in these mice.
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