Cholecystokinin's Role in Homeostasis

Cholecystokinin (CCK) is a lipophilic peptide hormone (Rehfeld & Agersnap 2011). The precursor to CCK is the biologically inactive preprocholecystokinin, consisting of 115 amino acids (Rehfeld & Agersnap 2011; Grider 1994). Preprocholecystokinin is altered post-translationally to form CCK of various lengths between 5 and 83 amino acid residues (Wu et al. 2007; Rehfeld 2004). Depending on their length, different CCK peptides bind to various receptors throughout the body, inducing different physiological effects (Grider 1994). All forms of CCK have a chain of seven identical peptides, including alpha-amidated and sulphated amino acids, which act as the biologically active C-terminus (Figure 1) (Rehfeld 2004).
                                                               Figure 1. The amino acid sequence of CCK-33, ending in the C-terminal sequence (Danho et al. 1988).

Synthesis and Secretion
‘Alimentary’ CCK is synthesised in I cells of the proximal small intestine, and stored in granulated form in secretory vesicles near the basement membrane of the I cell. The granule then travels to the apical surface of the I cell, where upon stimulation it is secreted in its active form into the duodenal lumen (Rehfeld 2004; Rehfeld & Agersnap 2011). CCK must be secreted in granules, as the active form of the protein would auto-digest I cells. The strongest stimulus for CCK release is the presence of undigested fats and proteins in the duodenal lumen. Carbohydrates and hydrochloric acid (HCl) in the duodenum are weak stimulators of CCK release (Rehfeld & Agersnap 2011).

CCK Receptors
There are two receptors to which cholecystokinin will bind (Figure 2). CCK-A receptors are highly selective and will bind only sulphated CCK with high affinity. These receptors are implicated in aiding digestion as they are present in the gallbladder, pancreas, pyloric sphincter and stomach (Wu et al. 2007).  CCK-B is less selective receptor, present mostly in the central nervous system where CCK acts as a neuropeptide (Oikonomou et al. 2008; Rehfeld & Agersnap 2011).
CCK binds to an extracellular cell-surface receptor, due to the hydrophilic nature of the hormone. The mode of action for CCK-A and B receptors is a receptor-coupled G protein pathway (Oikonomou et al. 2008). When the C-terminus binds to its target receptor, the G-protein pathway is activated, bringing about various physiological effects (Rehfeld 2004).

 
Figure 2. CCK A and B receptors (Wank 1998).

CCK ACTIONS AT TARGET TISSUES
Cholecystokinin has synchronistic effects on different digestive organs in order to enhance and facilitate digestion. From a physiological perspective, it is logical that secretions of the gallbladder and pancreas are coupled with an inhibition of gastric motility and secretions. This ensures a similar ratio of chyme to digestive juices, maintaining optimal digestive homeostasis (Dockray 2009).

A. The Gallbladder
Stimulated by fats in the duodenum, CCK binds to CCK-A receptors on the gallbladder and liver and induces bile secretion from both organs (Rehfeld 2004) (Figure 3). With the smooth muscle of the gallbladder rhythmically contracting under CCK influence, bile enters the common bile duct via the cystic duct (Rehfeld 2004). CCK also causes a relaxation of the sphincter of Oddi, allowing bile to be secreted into the duodenal lumen (Rehfeld 2004). Bile acts to emulsify fat globules, so that pancreatic lipase can swiftly digest smaller fat droplets (Rehfeld 2004).

B. The Stomach
CCK binds to CCK-A receptors present on D cells in the stomach’s pyloric glands. CCK causes D cells to release somatostatin, reducing gastrin secretion from G cells (Figure 3). The result is reduced HCl secretion from parietal cells, reducing the rate of secretions and digestion in the stomach (Rehfeld 2004; Wank 1998). CCK-A receptors are also present on chief cells in the gastric glands, where CCK binding decreases pepsinogen release, reducing protein digestion (Wank 1998).  CCK also inhibits gastric motility by binding to CCK-A receptors on the pyloric sphincter, causing a contraction of the sphincter which decreases the secretion of chyme into the duodenum (Wank 1998). These are all important homeostatic mechanisms that allow food already in the duodenum to be digested, before an influx of undigested food enters.

C. The Pancreas
CCK stimulates the secretion of digestive enzymes from the acinar cells of the pancreas, into the duodenal lumen (Figure 3). These enzymes include pancreatic amylase, which digests carbohydrates, lipase, proteases and peptidases (Rehfeld 2004). Proteases and peptidases, including trypsinogen and chymotrypsinogen, are secreted in inactive forms, to avoid auto-digestion. Once activated by entero-peptidase and trypsin in the duodenal lumen, they digest proteins and peptides present in the lumen (Rehfeld 2004).  CCK binding to CCK-A receptors on the pancreas induces the G-protein pathway, activating phospholipase C, which in turn increases intracellular stores of calcium. This increased calcium then activates protein kinases; this mechanism is responsible for the secretion of pancreatic enzymes (Rehfeld 2004).

Figure 3. The actions of CCK on various digestive organs (Menlo School n.d.).


CCK Degradation
CCK is degraded by enzymes that break the peptide bonds of the hormone, at either the liver, kidney, or in the gastrointestinal tract (Ohlsson et al. 2004).

Current Research into Cholecystokinin
Kohnke et al. 2009(a) investigated the long-term effects of thylakoid supplementation on appetite, body mass, and food consumption in mice (Kohnke et al. 2009a).  Thylakoids are plant proteins that delay fat digestion and absorption by binding to fat globules in the duodenum, a mechanism that retards fat digestion by lipase, and thus increases satiety (Kohnke et al. 2009a). Fifteen apolipoprotein deficient mice were placed in a test group that were fed a high-fat diet supplemented with thylakoid power. Another fifteen apolipoprotein deficient mice were placed in a control group, fed a high-fat diet (Kohnke et al. 2009a). After 100 days, the mice were humanely killed and blood serum was collected and stored, and body fat was analysed using a dual energy x-ray analysis. Serum free fatty acids, triglycerides, glucose, leptin, CCK, PYY and cholesterol were measured using highly specific kits. The pancreas was harvested and lipase concentrations were measured (Kohnke et al. 2009a). Mice that were fed the thylakoid-supplemented diet had a reduced food intake, body weight, body fat mass, serum glucose, triglycerides, PYY, leptin and FFA levels compared to controls. Serum CCK levels were increased, which was posited to be due to retarded fat digestion because of thylakoid adherence, increasing the stimulus for CCK release (Figure 4). Increased CCK levels caused the mice to experience satiety and consume less food. Increased lipase levels were attributed to the increased CCK levels, stimulating the acinar cells in the pancreas to secrete pancreatic lipase (Kohnke et al. 2009a).
In the same year, Kohnke et al. 2009(b) conducted another experiment, investigating the effects of thylakoid supplementation on human satiety. Eleven healthy participants were fed one test meal per week, containing either 0, 5, 10, 25, or 50 grams of thylakoid powder added to a standard pesto sandwich (Kohnke et al. 2009b). Samples of plasma were taken at regular intervals following ingestion of the meal until 360 minutes postprandially. Plasma CCK, ghrelin, leptin, insulin, and free fatty acid (FFA), all implicated in hunger and satiety signals, were measured (Kohnke et al. 2009b). As in their previous experiment, they saw increased levels of CCK around 6 hours postprandially, as well as leptin, in those who consumed the meals that contained thylakoids. Plasma concentrations of the hunger hormone, ghrelin, were reduced with thylakoid supplementation (Kohnke et al. 2009b). This research adds another set of data which illustrates that thylakoids act to increase satiety through increasing CCK levels while synergistically decreasing ghrelin levels, maintaining digestive homeostasis.
This research is pertinent as it is especially relevant to the dietetics discipline, in which obesity is currently a major issue, causing many negative health outcomes. Thylakoid supplements don’t inhibit fat digestion, unlike other pharmacological agents currently promoted for weight loss. Thylakoids prolong fat digestion and absorption, by adherence to fat globules, leading to increased satiety and thus decreased food intake (Kohnke et al. 2009b).

References

Danho, W, Madison VS, Triscari J (1988). Cholecystokinin analogs for controlling appetite [ONLINE]. Viewed 19 September 2013,
< http://www.google.com/patents/EP0296574A2?cl=en>.

Dockray, G (2009). Cholecystokinin and gut-brain signalling. Regulatory Peptides, vol. 155, p. 6-10.

Grider, 1994. Role of Cholecystokinin in the Regulation of Gastrointestinal Motility. Journal of Nutrition vol. 124, no. 8, p. 1334S-1339S.

Kohne, R, Lindbo, A, Larsson, T, Lindquist, M.R., Emek, S, Albertsson, P, Rehfeld, J, Landin-Olsson, M, & Erlanson-Albertsson, C (2009)b. Thylakoids promote release of the satiety hormone cholecystokinin while reducing insulin in healthy humans. Scandinavian Journal of Gastroenterology, vol 44, no 6, p. 712-9.

Kohnke, R, Lindqvist, A, Goransson, N, Emek, S, Albertsson, P, Rehfeld, J, Hultgardh-Nilsson, A & Erlansson-Albertsson, C (2009)a. Thylakoids Suppress Appetite by Increasing Cholecystokinin Resulting in Lower Food Intake and Body Weight in High-fat Fed Mice. Phytotherapy Research, vol. 23, no. 12, p. 1778-83.

Menlo School, (n.d.). Hormones and Digestion [ONLINE]. Viewed 21 September 2013, <http://sun.menloschool.org/~dspence/biology/chapter29/chapt29_6.html>.

Ohlsson, B, Rehfeld, J & Forsling, M (2004). Oxytocin and cholecystokinin secretion in woman with colectomy. BMC Gastroenterology, vol 4, no. 25.

Oikonomou, E, Buchfelder, M & Adams, EF (2008). Cholecystokinin (CCK) and CCK receptor expression by human gliomas: Evidence for an autocrine/paracrine stimulatory loop. Neuropeptides, vol. 42, no. 3, p. 255-265.

Rehfeld, J & Agersnap, M (2011). Unsulphated cholecystokinin: An overlooked hormone? Regulatory Peptides, vol.173, p. 1-3.

Rehfeld, J (2004). Cholecystokinin. Best Practise and Research Clinical Endocrinology and Metabolism, vol. 18, no. 4, p. 569-86.

Wank, S (1998). CCK Receptors: an exemplary family. American Journal of Physiology - Gastrointestinal and Liver Physiology, vol. 274, p. G607-G613.

Wank, S (1998). Schematic models of rat CCK-AR (A) and CCK-BR (B) [ONLINE]. American Journal of Physiology - Gastrointestinal and Liver Physiology, viewed 24^th September 2013,
<http://ajpgi.physiology.org/content/274/4/G607>.

Wu, C., Doong, M, Wang, P (2007). Involvement of cholecystokinin receptor in the inhibition of gastrointestinal motility by oxytocin in ovariectomised rats.  European Journal of Pharmacology, vol. 580, p. 407-415.