CCK, originally isolated from the intestine, has been extensively investigated and reviewed with regard to its role as a regulator of food intake (60,61). Multiple forms of CCK, varying in length from 8 to 83 amino acids, have been isolated from the intestine, blood, and brain (60). Though they differ in size, they originate from a single gene resulting in the formation of different molecular forms by post-translational processing (60,62). CCK is produced primarily by the I-cells in the duodenum and jejunum and, to a lesser extent, in the ilial mucosa (60). CCK-58, -33, -22, and -8 are the main forms that are released from I-cells into the plasma. However, CCK is also produced in the brain, in which it is one of the most abundant peptides, and by the enteric nerve endings, where they act as neurotransmitters. The biologically active form of CCK shares a sequence (carboxy terminus) homology with gastrin (60). Two receptors have been identified for CCK: CCKa (CCK 1) receptor in the GI tract and CCKB (CCK 2) receptor in the brain, through which the peptide exerts its biological actions (63,64) (see "Mechanism of Action" below).

CCK is a known satiety peptide; it slows gastric emptying and inhibits gastric acid secretion, but stimulates intestinal motility and gallbladder contraction, and increases pancreatic exocrine secretion. All these help the digestion process. CCK is known to inhibit food intake in humans and rodents (65,66). The food inhibitory actions of CCK are enhanced by gastric distension, which implies that chemoreceptors are involved. However, the duration of its action is short, with a half-life of only 1 to 2 min. Therefore, no anorectic effect is observed if CCK is administered more than 15 min before meal intake (62). In addition, chronic administration of CCK, although it reduces food intake, increases meal frequency. Consequently, long-term administration does not appear to have any effects on body weight (60). This suggests that CCK is a short-term inhibitor of food intake.

Mechanism of Action

CCK exerts its effect via the CCK A and B receptors. Both are seven-domain transmembrane receptors from the G protein-coupled receptor superfamily. The CCK A receptor, primarily alimentary, mediates gallbladder contraction, relaxation of the sphincter of Oddi, pancreatic growth, and enzyme secretion. It delays gastric emptying, and inhibits gastric acid secretion by binding to sulfated CCK peptides. CCK A receptors have also been found in the pituitary, myenteric plexus, and areas of the midbrain. CCK B is the predominant receptor in the brain, but is also found in the stomach and pancreas. It is less restrictive, with a structure identical to the gastrin receptor, and binds nonsulfated CCK peptides (67).

In addition, circulating CCK sends satiety signals to the ARC via the vagal stimuli through the NTS and area postrema, and/or directly by crossing the blood-brain barrier. Peripheral administration of CCK, at doses sufficient to inhibit food intake, has been shown to induce synthesis of c-fos in brainstem, NTS and the dorsal vagal nucleus (68).

Fig. 2. Preproglucagon products. GRPP, glicentin-related pancreatic polypeptide; GLP-1, glu-cagon-like peptide -1 (7-36); GLP-2, glucagon-like peptide-2; SP-1, spacer peptide-1; SP-2, spacer peptide-2; SP, signal peptide.

Vagotomy blocks the effect of CCK on food intake indicating neuronal requirement for the mediation of CCK action to the CNS. Rats lacking functional CCK A receptors are diabetic, hyperphagic, and obese (69,70), whereas receptor-deficient mice have been shown to have normal body weight.

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