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NEUROREGULATION AND MOTILITY

Targeted disruption of the murine CCK₁ receptor gene reduces intestinal lipid-induced feedback inhibition of gastric function

¹Department of Anatomy, Physiology, and Cell Biology and ²Center for Comparative Medicine, School of Veterinary Medicine, University of California, Davis, California; and ³Department of Medicine, Center for Gastroenterology Research on Absorptive and Secretory Processes, Tupper Research Institute, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts

Submitted 19 December 2005 ; accepted in final form 21 March 2006

Cholecystokinin (CCK), acting at CCK₁ receptors (CCK₁Rs) on intestinal vagal afferent terminals, has been implicated in the 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^+/+ ("wild type") 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; a 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 with CCK₁R^+/+ mice. Intralipid (0.2 ml of 20% Intralipid and 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 with 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.

gastric emptying; gastric acid secretion; cholecystokinin; vagal afferent; nucleus of the solitary tract

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