GASTROINTESTINAL INTEGRATION AND FEEDING

Johns Hopkins University, Baltimore MD

Investigators

Linked publications & trials

Abstract

DESCRIPTION (applicant's abstract): This research is motivated by the fact that meals terminate when the majority of ingested nutrients are still in the gastrointestinal tract. Although a variety of pre-absorptive feedback signals arising from various sites in the GI tract have been identified, an assessment of their quantitative contribution to feeding control requires a consideration of the overall context in which these signals are produced. During feeding, multiple gastrointestinal sites are stimulated, provoking a variety of signals related to nutrient character, concentration, and quantity that exert major negative feedback influences on ongoing food intake. Food intake is also affected by the activity of hypothalamic signaling systems involved in overall energy balance. One way in which these hypothalamic signaling systems may exert their effects on food intake is by modulating responsivity to within-meal satiety signals to reduce meal size. The proposed experiments will address different aspects of the integration of signals involved in the control of meal size in different models and with diverse experimental approaches. Specifically, further studies are proposed on the satiety actions of the brain/gut peptide cholecystokinin (CCK). These are designed to evaluating the contribution of endogenous CCK to the vagal afferent and central neural representation of meals as expressed in vagal electrophysiological activity and patterns of c-Fos activation. Both pharmacological antagonism of CCK-A receptors and the OTELF rat, which lacks CCK-A receptors, will be used in these studies. In addition, interactions between hypothalamic and visceral afferent signaling systems in the control of meal size and meal-elicited patterns of neural activation will be studied. These experiments will examine whether and at what brain sites NPY, a melanocortin receptor agonist (MT11), a melanocortin antagonist (SHU9119), and CART modify the feeding inhibitory actions and patterns of neural activation produced by peripheral CCK and gastric and duodenal nutrient preloads. Experiments in rhesus monkeys will take advantage of the dynamics of nutrient gastric emptying to identify how factors of nutrient concentration and meal volume affect within-meal distribution of nutrients to influence meal size and daily food intake. Finally, as a first step to assessing potential interactions between ascending peripheral and central controls of food intake in rhesus monkeys, the potency and efficacy of 3rd ventricular administration of (a) the orexigenic compounds NPY, galanin, and the melanocortin receptor antagonist SHU9119 and (b) the anorexigenic compounds leptin and the melanocortin agonist MT11 to affect overall food intake and meal patterns will be evaluated.