Gut Peptides in the Control of Food Intake

TH Moran

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Multiple gut peptides are involved in the overall control of food intake. Plasma levels of gut peptides are differentially affected by food intake, and the different patterns of release around meals provides an indication of a peptide’s specific role in feeding control. Ghrelin is a gastric peptide whose plasma levels are high before meals and are suppressed in response to food intake. Consistent with this pattern, ghrelin has been shown to stimulate food intake by hastening meal initiations. Cholecystokinin (CCK) is released from upper intestinal sites in response to food intake. CCK inhibits eating in a manner consistent with a role in satiety. Pancreatic glucagon and amylin play similar roles in meal termination. In contrast, the lower gut peptides, peptide YY (3–36) and glucagon-like peptide 1, are released more slowly in response to food intake and levels remain elevated for hours after a meal. This pattern of release suggests effects across multiple meals, and these peptides have been shown to inhibit food intake by both decreasing meal size and increasing the satiating potency of consumed nutrients. Together, these actions indicate multiple roles for gut peptides in feeding control. International Journal of Obesity (2009) 33, S7–S10; doi:10.1038/ijo.2009.9

Keywords: ghrelin; cholecystokinin; amylin; pancreatic glucagon; PYY(3–36) and GLP-1

During a meal, ingested nutrients contact multiple sites with physiological signals playing a relatively minor role. along the alimentary tract that have the potential to monitor Exceptions have been identified, with most of these arising the character and amounts of food ingested and signal this from a state of nutrient deprivation or the blockade of information to the brain, informing decisions about current central or peripheral metabolic fuel utilization, with sub- and future food intake. Among these potential signals, gut stances such as 2-deoxyglucose preventing brain glucose peptides derived from the enteroendocrine cells are attrac- utilization or mercaptoacetate preventing hepatic fatty-acid tive candidates for two reasons: first, they are localized in the oxidation.1 However, recent data have suggested a role for epithelium of the gastrointestinal tract in an ideal location the gastric peptide ghrelin in the normal patterning of food to respond to luminal nutrients and second, their patterns of intake in experimental animals and humans. Ghrelin is a release are altered in response to nutrient ingestion in ways peptide produced by enteroendocrine cells in the oxyntic that could affect both short- and longer-term food intake. glands of the stomach and upper intestine, which is the Recent research has identified roles for multiple gut peptides endogenous ligand for the growth hormone stimulatory in feeding control. These roles can be best appreciated as receptor (GHS-R). In humans, its pattern of release is such contributing to meal initiation, within-meal satiety that plasma ghrelin levels rise before meals and rapidly and across-meal satiety influences. Available data regarding decline when food is consumed.2 In rats, plasma ghrelin the patterns of release, effects of exogenous administration levels are elevated before the dark cycle, the time of greatest and actions of the endogenous peptides lead to these food consumption, and in response to food deprivation.3 differentiations. Exogenously administered ghrelin stimulates food intake and does so whether administered peripherally or into the brain ventricular system.4 Ghrelin stimulates food intake at Meal initiation times when feeding would not normally occur and increases the amount consumed when administered at the beginning Most decisions about when to eat are dictated by food of the dark cycle. Consistent with a role in meal initiation, availability, social conventions and learned associations, central ghrelin administration results in increases in meal number without significant changes in meal size.5 The site of action for ghrelin to affect food intake has been Correspondence: Dr TH Moran, Department of Psychiatry and Behavioral extensively investigated. GHS-Rs are widely distributed in Sciences, Johns Hopkins University School of Medicine, Ross 618, 720 Rutland Ave., Baltimore, MD 21205, USA. the brain and GHS-R mRNA has been localized to the 6 E-mail: [email protected] nodose ganglion, the site of vagal afferent cell bodies. Gut peptides TH Moran S8 Ghrelin-producing neurons have also been identified in the endogenous peptide. Administration of CCK antagonists brain, including hypothalamic sites. Recent work has clearly increases overall food intake by increasing meal size.15 shown that vagal afferent fibers are not necessary for the Cholecystokinin exerts its satiety action primarily through stimulation of food intake.7 Neither chemical nor surgical the activation of subdiaphragmatic vagal afferent neurons. vagal deafferentation affected the ability of peripheral Vagal afferent cell bodies in the nodose ganglion express ghrelin to affect food intake. Central sites of action have CCK1 receptors, which are axonally transported to the also been suggested. Both peripheral and central ghrelin subdiaphragmatic vagal branches.16 CCK activates vagal administration induce neural activation and NPY mRNA afferent fibers innervating both the stomach and the upper expression in the hypothalamic arcuate nucleus, suggesting intestine,17,18 and surgical or chemical lesion of vagal a role for arcuate NPY in mediating the feeding stimulatory afferent fibers essentially eliminates the ability of peripheral actions of ghrelin.8 Whether this is the site of action for CCK to inhibit food intake.19–21 plasma ghrelin or represents the site of a final mediating The pancreatic peptides, glucagon and amylin, share a mechanism is unclear. Ghrelin has been shown to cross the number of properties with CCK. They show similar patterns blood–brain barrier9 providing a potential mediation for of release in response to food intake in that plasma levels rise such an action, but the ability of both third and fourth rapidly with feeding and return to near-baseline levels with cerebroventricular ghrelin to stimulate food intake and meal termination. Meal contingent amylin or glucagon increase arcuate NPY mRNA expression suggests a distributed administration dose-dependently reduces meal size without system with a final common output involving the arcuate affecting intake at subsequent meals.22,23 Meal termination nucleus.8 has been shown to be an action of endogenous amylin and The ability of ghrelin antagonists to reduce food glucagon as receptor antagonists or specific antibodies intake supports a role for endogenous ghrelin in feeding increase food intake.24,25 activation. Ghrelin antagonist administration reduces The feeding-inhibitory actions of glucagon are peripher- food intake, suggesting a role for the peptide in overall ally mediated and dependent on intact hepatic vagal energy balance,10 a role also supported by data showing the signaling.26 In contrast to the other peptides with a ability of ghrelin administration to decrease energy expen- role in meal termination, the actions of amylin are diture.11 Results with ghrelin knockout mice have been centrally mediated. Chemical or surgical vagotomy inconsistent. However, some knockouts show a lean does not affect the ability of peripheral amylin to inhibit phenotype and are resistant to the obesogenic actions of food intake. Amylin’s actions are mediated by the area high-fat diets.12 postrema, a circumventricular organ with a porous blood– brain barrier. The area postrema expresses amylin receptors and area postrema lesions block the satiety actions of amylin.27 Within-meal satiety signaling

A number of gut peptides are rapidly released with the initiation of feeding and some of these have been shown to Across-meal satiety signaling inhibit food intake after their exogenous administration. The patterns of release of some of the peptides and actions Other gut peptides have patterns of release and actions that limited to single meals after exogenous administration are consistent with effects beyond the meal that stimulated suggest roles for these peptides in meal termination. Three their release. Both peptide YY (PYY) and glucagon-like examples will be discussed: cholecystokinin (CCK), pancrea- peptide 1 (GLP-1) are synthesized and released from L cells tic glucagons and amylin, with the major focus on CCK. located primarily in the distal intestine. In contrast to the Cholecystokinin is synthesized and released from I cells of pattern of release of within meal satiety peptides, elevations the upper intestine. It plays a variety of roles in the digestive in plasma PYY and GLP-1 occur more slowly, not peaking process, slowing gastric emptying mediating intestinal until after meal termination and remaining high for several motility and stimulating pancreatic and gall bladder secre- hours after a meal.28,29 tions. In response to the intraluminal intestinal presence of PYY circulates in two molecular forms, PYY(1–36) and nutrient digestive products, plasma CCK levels rise rapidly, PYY(3–36), and peripheral administration of PYY(3–36) has peaking within a few minutes of meal initiation, remaining been shown to inhibit food intake in a variety of test elevated through the meal and declining to baseline levels situations.30 The effects of meal contingent PYY(3–36) have with meal termination.13 yet to be investigated, but individual peripheral doses can Exogenously administered CCK inhibits food intake by affect intake for many hours, suggesting actions beyond a reducing meal size and duration. Meal contingent CCK single meal. Bolus doses or slow intravenous infusions have administration reduces the size of that meal without been shown to affect food intake by reducing the size of affecting the subsequent intermeal interval or the size of multiple meals and increasing the satiety ratio (length of the the following meal.14 Meal termination is also a role of the post-meal interval/amount consumed).31,32

International Journal of Obesity Gut peptides TH Moran S9 Both peripheral and central sites of action for PYY(3–36) in regulating CB-1 and MCH receptor abundance. Am J Physiol for inhibiting food intake have been proposed. Subdiaphrag- Gastrointest Liver Physiol 2006; 290: G1289–G1297. matic vagotomy significantly reduced the feeding inhibition 7 Arnold M, Mura A, Langhans W, Geary N. Gut vagal afferents are 33 not necessary for the eating-stimulatory effect of intraperitone- produced by a relatively small dose of PYY(3–36). Actions ally injected ghrelin in the rat. J Neurosci 2006; 26: 11052–11060. of PYY(3–36) at Y2 receptors in the hypothalamus have also 8 Kinzig KP, Scott KA, Hyun J, Bi S, Moran TH. Lateral ventricular been shown and direct effects of circulating PYY(3–36) at ghrelin and fourth ventricular ghrelin induce similar increases in such central sites have been proposed.30 food intake and patterns of hypothalamic gene expression. Am J Physiol Regul Integr Comp Physiol 2006; 290: R1565–R1569. Glucagon-like peptide 1 inhibits food intake following its 9 Cowley MA, Smart J, Rubinstein M, Cerdan M, Diano S, peripheral administration. The actions of GLP-1 on food Horvath T et al. Leptin activates anorexigenic POMC neurons intake are brief because of its rapid degradation by dipeptyl- through a neural network in the arcuate nucleus. Nature 2001; peptidase IV (DPP-IV), resulting in small transient suppres- 411: 480–484. 10 Asakawa A, Inui A, Kaga T, Katsuura G, Fujimiya M, Fujino MA sions in food intake after bolus administration. However, et al. Antagonism of ghrelin receptor reduces food intake and prolonged intravenous infusions or bolus administration of body weight gain in mice. Gut 2003; 52: 947–952. GLP-1 analogs that are resistant to DPP-IV degradation result 11 Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in in significant food intake suppressions.34,35 Similar to the rodents. 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Modulation or mimick- Blockade of type A, but not type B, CCK receptors postpones ing of this peptide signaling may provide powerful tools satiety in rhesus monkeys. Am J Physiol 1993; 265: R620–R624. 16 Moran TH, Norgren R, Crosby RJ, McHugh PR. Central and for affecting the overall energy balance and producing peripheral vagal transport of cholecystokinin binding sites occurs weight loss. in afferent fibers. Brain Res 1990; 526: 95–102. 17 Schwartz GJ, McHugh PR, Moran TH. Gastric loads and cholecystokinin synergistically stimulate rat gastric vagal afferents. Am J Physiol 1993; 265: R872–R876. Conflict of interest 18 Schwartz GJ, Tougas G, Moran TH. Integration of vagal afferent responses to duodenal loads and exogenous CCK in rats. Peptides The author has declared no financial interests. 1995; 16: 707–711. 19 Moran TH, Baldessarini AR, Salorio CF, Lowery T, Schwartz GJ. Vagal afferent and efferent contributions to the inhibition of food intake by cholecystokinin. 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