ThemesGastrointestinal Satiety SignalsI. An overview of gastrointestinal signals that influence food intakeStephen C. Woods Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio 45267Woods, Stephen C. Gastrointestinal Satiety Signals. I. An over-view of gastrointestinal signals that influence food intake. Am J Physiol Gastrointest Liver Physiol 286: G7G13, 2004; 10.1152/ ajpgi.00448.2003.An overview is presented of those signals gener- ated by the gastrointestinal (GI) tract during meals that interact with the central nervous system to create a sensation of fullness and satiety. Although dozens of enzymes, hormones, and other factors are se- creted by the GI tract in response to food in the lumen, only a handfulare able to influence food intake directly. Most of these cause meals to terminate and hence are called satiety signals, with CCK being the most investigated. Only one GI signal, ghrelin, that increases mealsize has been identified. The administration of exogenous CCK or other satiety signals causes smaller meals to be consumed, whereas blocking the action of endogenous CCK or other satiety signals causes larger meals to be consumed. Satiety signals are relayed to the hindbrain, either indirectly via nerves such as the vagus from the GItract or else directly via the blood. Most factors that influence how much food is eaten during individual meals act by changing the sensitivity to satiety signals. This includes adiposity signals as well as habits and learning, the social situation, and stressors.cholecystokinin; adiposity signals; ghrelin; bombesinTHE GASTROINTESTINAL(GI) tract accepts ingested food and processes it mechanically and chemically to render what has been eaten into small, absorbable units. Hence, carbohydrates are processed in the stomach and intestine to monosaccharides such as glucose and fructose, most lipids are digested to fatty acids and monoacylglycerols, and proteins are digested to amino acids. These monosaccharides, fatty acids, and mono- acylglycerols (resynthesized to form triacylglycerols in the intestinal epithelial cells), amino acids, plus micronutrients, such as vitamins and minerals, are subsequently absorbed into the body. The overall process of digestion is coordinated by interactions of the enteric nervous system, which innervates the walls of the GI tract, plus numerous hormonal and other chemical signals generated by cells embedded in the wall of the gastrointestinal tract. The object of this theme article is toreview the role of some of these chemical signals in influencing food intake. As a group, these are called satiety signals, because most of them create a sensation of fullness in humans and cause food intake to be reduced when administered to humans or animals. At least one of the GI signals, ghrelin, appears to have the opposite effect, stimulating enhanced food intake. Satiety signals are so named because when they are admin- istered to animals before a meal, a decrease in the size of that meal is observed. Several other criteria must be met, however, before a hormone, neurotransmitter, or other internal signal isconsidered a satiety signal. For one, if the signal influences thesize of normal meals, it should be the case that blocking or compromising its endogenous activity leads to increased meal size. That is, the administration of an antagonist to the signal or the generation of an animal lacking a receptor for the signal should be associated with consumption of greater than normal amounts of food. Another criterion is that the reduction of food intake caused by administration of the “satiety” signal should not be the consequence of illness or malaise, or of some sort of incapacitation, and the animal (or person) receiving the com- pound should engage in behaviors that occur when meals end naturally. That is, there are many reasons why the administra- tion of an exogenous compound might cause an animal to eat less food, reasons that have little or nothing to do with normal satiety. Finally, the secretion of an endogenous satiety signalmust be elicited by ingested food with a temporal profile consistent with contributing to the normal cessation of eating. These criteria are well accepted (26, 70, 71, 82).MEALSFood intake occurs in distinct bouts or meals, with the frequency and size of individual meals over the course of a day comprising an individuals meal pattern. Most animals, includ- ing humans, have habitual meal patterns, consuming approxi- mately the same number of meals and at the same times of day each day. Within a given species, however, there is consider- able variation among individuals in terms of the number of meals as well as the spacing and size of each meal. The factors that control when meals occur are distinct from those that control when they end; i.e., different factors control meal onset and meal size. Until the last 25 years, meal onset was thought to be under the control of factors related to immediately availab