Gut peptides in the control of food intake

International Journal of Obesity (2009) 33, S7–S10 & 2009 Macmillan Publishers Limited All rights reserved 0307-0565/09 $32.00 www.nature.com/ijo REVIEW 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 along the alimentary tract that have the potential to monitor the character and amounts of food ingested and signal this information to the brain, informing decisions about current and future food intake. Among these potential signals, gut peptides derived from the enteroendocrine cells are attractive candidates for two reasons: first, they are localized in the epithelium of the gastrointestinal tract in an ideal location to respond to luminal nutrients and second, their patterns of release are altered in response to nutrient ingestion in ways that could affect both short- and longer-term food intake. Recent research has identified roles for multiple gut peptides in feeding control. These roles can be best appreciated as contributing to meal initiation, within-meal satiety and across-meal satiety influences. Available data regarding the patterns of release, effects of exogenous administration and actions of the endogenous peptides lead to these differentiations. Meal initiation Most decisions about when to eat are dictated by food availability, social conventions and learned associations, Correspondence: Dr TH Moran, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Ross 618, 720 Rutland Ave., Baltimore, MD 21205, USA. E-mail: with physiological signals playing a relatively minor role. Exceptions have been identified, with most of these arising from a state of nutrient deprivation or the blockade of central or peripheral metabolic fuel utilization, with substances such as 2-deoxyglucose preventing brain glucose utilization or mercaptoacetate preventing hepatic fatty-acid oxidation.1 However, recent data have suggested a role for the gastric peptide ghrelin in the normal patterning of food intake in experimental animals and humans. Ghrelin is a peptide produced by enteroendocrine cells in the oxyntic glands of the stomach and upper intestine, which is the endogenous ligand for the growth hormone stimulatory receptor (GHS-R). In humans, its pattern of release is such that plasma ghrelin levels rise before meals and rapidly decline when food is consumed.2 In rats, plasma ghrelin levels are elevated before the dark cycle, the time of greatest food consumption, and in response to food deprivation.3 Exogenously administered ghrelin stimulates food intake and does so whether administered peripherally or into the brain ventricular system.4 Ghrelin stimulates food intake at times when feeding would not normally occur and increases the amount consumed when administered at the beginning of the dark cycle. Consistent with a role in meal initiation, 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 extensively investigated. GHS-Rs are widely distributed in the brain and GHS-R mRNA has been localized to the nodose ganglion, the site of vagal afferent cell bodies.6 Gut peptides TH Moran S8 Ghrelin-producing neurons have also been identified in the brain, including hypothalamic sites. Recent work has clearly shown that vagal afferent fibers are not necessary for the stimulation of food intake.7 Neither chemical nor surgical vagal deafferentation affected the ability of peripheral ghrelin to affect food intake. Central sites of action have also been suggested. Both peripheral and central ghrelin administration induce neural activation and NPY mRNA expression in the hypothalamic arcuate nucleus, suggesting a role for arcuate NPY in mediating the feeding stimulatory actions of ghrelin.8 Whether this is the site of action for plasma ghrelin or represents the site of a final mediating mechanism is unclear. Ghrelin has been shown to cross the blood–brain barrier9 providing a potential mediation for such an action, but the ability of both third and fourth cerebroventricular ghrelin to stimulate food intake and increase arcuate NPY mRNA expression suggests a distributed system with a final common output involving the arcuate nucleus.8 The ability of ghrelin antagonists to reduce food intake supports a role for endogenous ghrelin in feeding activation. Ghrelin antagonist administration reduces food intake, suggesting a role for the peptide in overall energy balance,10 a role also supported by data showing the ability of ghrelin administration to decrease energy expenditure.11 Results with ghrelin knockout mice have been inconsistent. However, some knockouts show a lean phenotype and are resistant to the obesogenic actions of high-fat diets.12 endogenous peptide. Administration of CCK antagonists increases overall food intake by increasing meal size.15 Cholecystokinin exerts its satiety action primarily through the activation of subdiaphragmatic vagal afferent neurons. Vagal afferent cell bodies in the nodose ganglion express CCK1 receptors, which are axonally transported to the subdiaphragmatic vagal branches.16 CCK activates vagal afferent fibers innervating both the stomach and the upper intestine,17,18 and surgical or chemical lesion of vagal afferent fibers essentially eliminates the ability of peripheral CCK to inhibit food intake.19–21 The pancreatic peptides, glucagon and amylin, share a number of prop (...truncated)