Targeted disruption of the murine CCK1 receptor gene reduces intestinal lipid-induced feedback inhibition of gastric function.
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.
Department of Anatomy, Physiology, and Cell Biology, School of Vetinary Medicine, University of California, Davis School of Veterinary Medicine, Davis, CA 95616, USA.
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Whited
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Thao
K C Kent
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Lloyd
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Kopin
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Raybould
D000818:Animals; D005246:Feedback / Q000187:drug effects / Q000502:physiology; D005746:Gastric Emptying / Q000187:drug effects / Q000502:physiology*; D020868:Gene Silencing; D008055:Lipids / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D043887:Receptor, Cholecystokinin B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013270:Stomach / Q000187:drug effects / Q000294:innervation* / Q000502:physiology*; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology*
D008055:Lipids; D043887:Receptor, Cholecystokinin B