Title: Gut-derived factors involved in the regulation of appetite and satiety

 

Key words: appetite, satiety, cognitive, sensory, mechanoreceptors, chemoreceptors, postprandial, olfactory, gustatory, taste, tastebuds, neuropeptides, gastrointestinal peptides, cholecystokinin, blood glucose, fat, protein, pancreatic enzymes, vagal nerve, glucagons-like peptide 1, gastric emptying, diabetes, obesity, peptide, intestine, stomach, food intake, appetite, anorexia, bulimia, leptin, lectin, obese, insulin,  

 

Date: Sept 2006

 

Category:

 

Nutrimed Module:

 

Type: Article

 

Author: Morgan, G

 

Gut-derived factors involved in the regulation of appetite and satiety

 

The regulation of appetite and satiety involves a complex interplay of neurological signals played out on many levels: from information originating in the cognitive plane to sensory information coming from peripheral sensory receptors. Peripheral receptors in the form of mechano- and chemo- receptors play a particularly important role in the control of appetite in the immediate postprandial phase of digestion. This review will look at the role played by gut-derived peptides in the relay of this information to the important satiety centre in the brain that helps to control appetite and maintain weight control.

 

Research over the last 50 years has confirmed the presence of multiple lines of communication between cortical, olfactory, taste, gastrointestinal, and other peripheral pathways involved in appetite control. Neuropeptides associated with these projections have been linked with both vagal- associated gut receptors and central receptors terminating in the ‘satiety centre’ located in the ventro-medial nucleus of the hypothalamus (Mantyh 1984). Four of the major gastrointestinal peptides involved in such pathways modulating appetite and food intake are described below.

 

Cholecystokinin

Of the major gut peptides modulating appetite and satiety, cholecystokinin has been the most researched in recent years. The close association of cholecystokinin release with food ingestion has been well documented. Whilst the initiation of feeding has been associated with changes in blood glucose levels and other factors, that of inhibition has been linked most closely to cholecystokinin release (Rayner 2000). The release of this peptide is predominantly determined by the entry of fat and protein into the gastrointestinal tract (Smith 1998). Release is associated with reduced gastric emptying, increased pyloric tone, the release of pancreatic enzymes and the suppression of appetite (Lieverse 1995). Mediation of satiety through cholecystokinin is through afferents of the vagal nerve and directly through receptors in the central nervous system.

 

Two types of cholecystokinin receptors have been described: CCK-A receptors found chiefly in the gastrointestinal tract, and CCK-B receptors found chiefly in the central nervous system (Wank 1995). A further division has been made between low-affinity vagal CCK-A receptors mediating satiety, and high- affinity CCK-A receptors that assist in evoking an increased pancreatic secretion (Owyang 2004). Although parenteral studies in humans have shown CCK levels to be inversely related to appetite and food intake, not all of the data, however, is consistent (Ballinger 1995). One study, for example, has shown no clear relationship between endogenous circulating levels of CCK, appetite and food intake, though the levels did appear higher in obese subjects following a fatty meal (French 1993).

 

Glucagon-like peptide-1

Glucagon-like peptide (GLP-1) has a similar effect to cholecystokinin in bringing about the suppression of appetite in the immediate postprandial period. Similar changes of delayed gastric emptying, increased pyloric tone, and satiety have been described following the ingestion of a meal. Responses to both fatty acid and glucose ingestion have been reported but most research has focused on GLP-1’s ability to increase insulin secretion and reduce appetite postprandially (Meier 2002, MacDonald 2002). A meta-analysis of such studies (Verdich 2001) has shown significant reductions in blood glucose levels, reduced gastric motility, and increased satiety, both in diabetic and non-diabetic subjects, following a meal. The changes in blood sugar levels are not thought to modulate satiety (Feinle 2002), its effect being thought to be mediated directly via central receptors in the paraventricular nucleus and the amygdale (Christophe 1998). An important role for GLP-1 in the modulation of both diabetes (Toft-Nielsen 1999, Gutzwiller 1999) and obesity (Naslund 1999, Meier 2002) has been postulated.

 

Peptide YY3-36

Peptide YY3-36 (PYY) is another appetite modulating peptide secreted in the gastrointestinal tract. It is mostly secreted by L-cells in the mucosa of the large intestine in response to feeding. Its concentration rises in both lean and obese subjects in response to feeding (Batterham 2003). Both in mice (Challis 2003), and humans (Batterham 2003), parenteral infusions of this peptide during the prandial period have been associated with satiety and reductions in food intake. Its effect has been shown to be modulated by receptors in the hypothalamus (Challis 2003). Mutations of both the PYY gene and its receptor may be linked to some cases of early onset obesity (Hung 2004). Low PYY levels may well contribute to obesity (Batterham 2003), and replacement therapy with this peptide has been proposed as one form of treatment for this condition (Druce 2004).

 

Ghrelin (or gherelin)

Ghrelin, a growth hormone-releasing peptide secreted by the stomach, is the only peptide secreted in the gastrointestinal tract that has a promoting rather that an inhibitory effect on appetite and eating. Both in rats (Wren 2001) and in humans (English 2002), parenteral administration of ghrelin has been associated with overeating and obesity. Its modulation of appetite is mediated by vagal afferents and central receptors (Andrews 2002). Although levels of ghrelin appear paradoxically low in the obese, the normal drop in blood concentrations during a meal appears to be considerably blunted in the obese, suggesting a role of this peptide in the pathophysiology of obesity (English 2002).

 

The modulation of gut-derived peptides in the control of appetite and food intake

Gut-derived modulators of appetite and satiety are important cofactors in the coordination of afferent stimuli to the ‘satiety centre’ in the central nervous system. Mechano- and other chemical modulators provide other signals that interact and modify information associated with the gut-derived peptide receptors already described. Interactions with fluctuating glucose levels in the pre- and post-prandial phase play an important role in the regulation of short-term food intake and satiety (Feinle 2002). In the long-term, interaction of these gut-derived peptides with other modulators play an important role in appetite and weight control over time.

 

The peripheral modulators insulin and leptin appear to be the most important determinants in the long-term regulation of appetite and weight control. Both affect the sensitivity of central receptors to peripheral signals associated with such peptides as cholecystokinin and ghrelin. Thus, CCK-modulated satiety is blunted in the presence of lectin deficiency (McMinn 2004), and an induced ghrelin response is downregulated in the presence of a fast-induced lectin deficiency (Hewson 2002). Whilst insulin and lectin themselves are not thought to affect short-term appetite control, their, and possibly ghrelin’s, interaction with the gut-derived peptides is thought to be an important factor in long-term weight management (Havel 2001). Dysregulation of these factors is now considered to be a major factor in obesity and eating disorders. Thus, in the obese, leptin responses appear to be blunted and unable to respond appropriately to continuing weight gain (Jequier 2002). Ghrelin levels have been found to be abnormal in cases of binge eating (Hellstrom 2004), bulimia (Monteleone 2003), and anorexia nervosa (Jimerson 2004). Both binge eating and bulimia nervosa (Jimerson 2004) have been linked to a blunting of the normal satiating response of cholecystokinin to a meal. Signal modulation in the hypothalamus to peripheral receptor information is, likewise, complex. Serotonin receptors, both centrally and peripherally, for example, interact with cholecystokinin, thus modifying the satiety response (Hayes 2004). Information carried by gut-derived peptides interact at the hypothalamic level with a variety of peripheral and central signals and help to determine the overall response to food ingestion. Food palatability, cognitive variables, and associated endorphin release are examples of sensory information impinging on the satiety centre in the hypothalamus and modifying its response (Melchior 2002).

 

Summary

The four gut-derived peptides described play an important role in the regulation of food intake and satiety. In particular they play a pivotal role in the control of food intake in the immediate postprandial period. Their effect is modified both in the short- and long-term by other modulators, peripherally and centrally. Although less important in long-term weight control, they have still been shown to react with certain long-term modulating factors. Therapeutically, their role in obesity management appears to be limited at present but recent lines of research are developing at a rapid pace and this may result in the development of peptide derivatives with greater therapeutic scope in the near future.        

 

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