Involvement of apolipoprotein A-IV and cholecystokinin1 receptors in exogenous peptide YY3 36-induced stimulation of intestinal feedback.

Peptide YY (PYY)(3-36), released by intestinal lipid elicits functional effects that comprise the intestinal feedback response to luminal nutrients, but the pathway of action is not fully characterized. The aim of the present study was to determine the role of the apolipoprotein (apo) A-IV-cholecystokinin (CCK)(1) receptor (CCK(1)R) pathway in exogenous PYY(3-36)-induced activation of the gut-brain axis and inhibition of gastric emptying and food intake. PYY(3-36) (5 microg/100 g ip) significantly inhibited gastric emptying of a chow meal in wild-type but not A-IV(-/-) mice andCCK(1)R receptor blockade with devazepide (10 microg/100 g), abolished PYY(3-36)-induced inhibition of gastric emptying. PYY(3-36)-induced inhibition of food intake in both ad libitum-fed and 16-h fasted mice was unaltered in A-IV(-/-) mice, compared with wild-type controls, or by CCK(1)R receptor blockade with devazepide. PYY(3-36) activated neurons in the midregion of the nucleus of the solitary tract (bregma -7.32 to -7.76 mm) in A-IV(+/+) mice; this was measured by immunohistochemical localization of Fos protein. PYY(3-36)-induced Fos expression was significantly reduced by 65% in A-IV(+/+) mice pretreated systemically with the sensory neurotoxin capsaicin (5 mg/100 g), 78% by the CCK(1)R antagonist, devazepide (10 microg/100 g), and 39% by the Y2R antagonist, BIIE0246 (200 and 600 microg/100 g) and decreased by 67% in apo A-IV(-/-) mice, compared with A-IV(+/+) controls. The data suggest a role for apo A-IV and the CCK(1)R in PYY(3-36)-induced activation of the vagal afferent pathway and inhibition of gastric emptying, but this is likely not the pathway mediating the effects of PYY(3-36) on food intake.

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.

Apolipoprotein A-IV is involved in detection of lipid in the rat intestine.

Long chain triglyceride (>C12) in the intestinal lumen potently inhibits gastric emptying and acid secretion via the vagal afferent pathway. While the mechanism of inhibition involves the formation of chylomicrons, the essential role of the apolipoprotein apo A-IV is unclear. Using apo A-IV(-/-) mice, we tested the hypothesis that inhibition of gastric emptying and gastric acid secretion in response to dietary lipid is dependent upon apo A-IV. As measured by nuclear scintigraphy in awake mice, gastric emptying of an ingested whole-egg meal was significantly faster in apo A-IV(-/-) knockout versus A-IV(+/+) controls (34 +/- 1 versus 54 +/- 3 min, P < 0.0001). In anaesthetized A-IV(+/+) mice, meal-stimulated gastric acid secretion was 59% inhibited by intestinal lipid infusion; this was abolished in apo A-IV(-/-) mice. Oral gavage of lipid in awake mice activated neurones throughout the nucleus of the solitary tract (NTS) in A-IV(+/+) mice, measured by immunohistochemical localization of Fos protein expression. However, in the mid region of the NTS (bregma -7.32 to -7.76 mm), Fos expression in response to intestinal lipid was significantly decreased by 50% in apo A-IV(-/-) mice compared to A-IV(+/+) controls. We conclude that activation of the vagal afferent pathway and inhibition of gastric function in response to dietary lipid is partly dependent upon apo A-IV.

A non-invasive method for measurement of gastric emptying in mice: effects of altering fat content and CCK A receptor blockade.

The ability to make repetitive non-invasive measurements of gastric emptying of nutritive solids in awake, unstressed mice is highly desirable. The aim of the present study was to develop such a technique using nuclear scintigraphy and diets differing in triglyceride content. Awake mice were accustomed to light restraint and to feeding cooked, egg white (0.00 g fat g(-1)), whole egg (0.10 g fat g(-1)), or egg yolk (0.31 g fat g(-1)). Gastric emptying of each diet was measured by labelling the test meals with Technetium(99m) Mebrofenin and using a conventional gamma camera equipped with a high resolution, parallel hole collimator. Gastric emptying of cooked whole egg was also determined following administration of either vehicle or CCK A receptor antagonist, devazepide. The half-emptying time (t(1/2)) significantly increased with increasing triglyceride content from 14 +/- 5 min to 51 +/- 6 min and 82 +/- 4 min for egg white, whole egg and egg yolk, respectively. Administration of devazepide significantly decreased t(1/2) of whole egg to 28 +/- 2 min. These results demonstrate the sensitivity and predictability of this technique in mice and importantly, provide an opportunity to alter the macronutrient or caloric content of the meal to determine effects on gastric emptying.