Cholecystokinin has been around a long time, initially described as a hormone with cholecystokinetic (modulating gall bladder contractility) and pancreozymic (release of pancreatic enzymes) properties. Recognition of additional functions  as a growth factor and neurotransmitter has  increased the importance of this hormone. With newer assays and purification methods improving sensitivity and specificity, better characterisation of its physiological role has become possible. CCK is in fact the first gut hormone to have been implicated in the control of appetite. 

In 1928, Ivy and Oldberg suggested the possibility of a hormone in the small intestine that stimulated contraction of the gall bladder. American Journal of Physiology 1928; 86: 559-613   In 1943, Harper and Raper discovered Pancreozymin  Journal of Physiology 1943; 102: 115-125   which was later identified as the above cholecystokinetic and named Cholecystokinin.  Isolation of CCK mRNA from a thyroid medullary carcinoma  led on to cDNA sequencing followed by characterisation of the CCK gene on chromosome 3 in humans. Hum Genet. 1986 May;73(1):77-80 Reliable CCK assays were developed in the early 1980s. CCK-33 was described initially , with varying sizes of the peptide being identified since, in the gut and brain.  CCK-22 and CCK-33 predominate in human plasma but CCK-8 and CCK-58 are also present in the plasma. J Clin Endocrinol Metab. 2001 Jan;86(1):251-8. The molecular pattern of secreted CCK varies between regions of the intestine with a predominance of CCK-8 in the duodenum compared to the distal gut,   Regul Pept. 1984 Jan;8(1):9-19. probably accounting for the changing patterns of circulating CCK in relation to time after meals. Also, CCK-8 is cleared more slowly from the blood than CCK-33 and CCK-22.

pro-CCK is produced from pre-pro-CCK. pro-CCK undergoes cell specific processing resulting in differing functions in various sites of the body. J Biol Chem. 1986 May 5;261(13):5832-40  CCK is synthesised in endocrine l cells of the small intestine Gastroenterology. 1976 Apr;70(4):528-32   as well as in pituitary corticotrophs and melanotrophs Proc Natl Acad Sci U S A. 1987 May;84(9):3019-23 and adrenal medullary cells. CCK nerve fibres are numerous in the colon, Brain Res. 1979 Apr 13;165(2):201-18   in the myenteric Auerbach plexus and submucous Meissner plexus, and around the pancreatic islets. Nature. 1980 Mar 6;284(5751):33-8  Outside of the gut, CCK nerve fibres are abundant in cortical areas and hypothalamus Brain Res. 1979 Apr 13;165(2):201-18  and to a lesser extent in the genitourinary tract and peripheral somatic nerves as well as afferent vagal nerve fibres. J Physiol. 1981 May;314:501-11  CCK fibres are absent in the stomach. CCK mRNA has been found to be in similar concentrations in the cerebral cortical tissues and the duodenal mucosa.

Fat rich food is the main stimulus for CCK release. While proteins and l-amino acids also effect significant CCK release, carbohydrates have  only minimal effect . J Clin Invest. 1985 Apr;75(4):1144-52     Fasting levels of CCK are as low as 1 pmol/L in the basal state and rise to 3-5 pmol/L within 80 minutes of food ingestion.  Exogenous CCK infusion produces gall bladder contraction and enzyme release similar to meal induced patterns. CCK actions are mediated through two receptors- CCK-A (A for alimentary) receptor in the gut mediating gall bladder contraction, relaxation of sphincter of Oddi, pancreatic enzyme secretion, delay of gastric emptying and inhibition of gastric acid secretion; Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3125-9  while CCK-B receptors [B for brain] , which are identical to gastrin receptors in the parietal cells, predominate in the brain with abundant expression in the pancreas as well. Biochem Biophys Res Commun. 1992 Nov 30;189(1):296-303.

CCK stimulates the synthesis and release of exocrine pancreatic enzymes (amylase, chymotrypsinogen, trypsinogen) as well as fluid and bicarbonate secretion, the latter partly mediated through potentiation of secretin action. This ability has been utilised in the CCK-secretin test to measure stimulated duodenal secretions.  CCK releases small intestinal enzymes as alkaline phosphatase, disaccharidase and enterokinase. Digestion. 1973;9(6):469-81.CCK-33 has a weak action in stimulating insulin and glucagon  Nature. 1980 Mar 6;284(5751):33-8 via the islet expressed CCK-B receptors. CCK has pancreatotrophic actions (facilitates pancreatic growth).  It can also increase intestinal blood flow. CCK inhibits gastric acid secretion from the parietal cells via somatostatin release from the fundic D-cells. Gastroenterology. 2004 Feb;126(2):476-87.

 Exogenous CCK induces  satiety with inhibition of food intake. Nature. 1973 Oct 12;245(5424):323-5     Administration of CCK agonist  in rats have been shown to decrease food intake  J Pharmacol Exp Ther. 1999 May;289(2):752-61.   This effect may well be mediated via vagal fibres as suggested by the abolition of CCK induced satiety in vagotomised rats. Science. 1981 Aug 28;213(4511):1036-7   Human infusion of CCK-8 resulted in reduction of food intake acutely. Clin Sci (Lond). 1995 Oct;89(4):375-81.  CCK-A and CCK-B receptor antagonists in rats decrease food induced satiety. Science. 1989 Sep 29;245(4925):1509-11  CCK-A receptor antagonist administration in healthy humans produced increased calorie intake. Am J Physiol Regul Integr Comp Physiol. 2001 Apr;280(4):R1149-54   .   But all assumptions are not straightforward with regard to CCK receptors and appetite regulation. CCK-A receptor deficient Otsuka Long Evans Tokushima Fatty rats eat more and are obese, Nutrition. 2000 Oct;16(10):858-65  but CCK-A receptor knock out rats are not obese and demonstrate normal food intake. Although acute infusion of CCK induces satiety, repeated administration resulted in tolerance to its effect with increased frequency of meal intake, such that no significant weight loss was induced with CCK in rats. Am J Physiol. 1984 May;246(5 Pt 2):R776-87

Apart from short term meal satiety, CCK may also have a role in long term signalling through interaction with leptin and insulin. Co-administration of low doses of Leptin with CCK increases the anorectic effects of CCK.  Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10455-60.   Insulin injection at low doses centrally increases the satiating effect of CCK. Physiol Behav. 1995 Oct;58(4):755-60    Development of chronic obesity with insulin and leptin resistance would have implications on the satiety facilitating effects of these hormones. CCK activates mouse brainstem NTS POMC neurons. CCK actions seem to be medicated through neuronal melanocortin-4 receptor (MC4-R) receptors.   Nat Neurosci. 2004 Apr;7(4):335-6

  While CCK has already been in use in the assessment of exocrine function of the pancreas through the  secretin-CCK testing, for the diagnosis of cystic duct syndrome and cholecystoadenomas, therapeutic uses are evolving including treatment of paralytic ileus and pancreatic insufficiency. CCK administration can produce panic attack like state (panicogenic) Fundam Clin Pharmacol. 1996;10(2):116-26. which needs to be investigated further to elucidate the neural role of CCK in this condition.  Decreased CCK secretion in pathological states including Coeliac disease J Clin Invest. 1982 Jan;69(1):218-25. and bulimia nervosa as well as the decreased neural CCK demonstrated in Parkinson's, Huntington's disease and Schizophrenia Fundam Clin Pharmacol. 1996;10(2):116-26. might offer further modalities for therapeutic interventions. CCK agonists might have a role in obesity treatment,  J Med Chem. 1996 Jul 5;39(14):2655-8.  although studies have not yet been encouraging.

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