There is universal agreement that peripheral sensory systems play a critical role in the control of meal size and patterning. However, the origin of satiety-relevant feedback is a matter of some controversy. Researchers tend to focus on discrete sources (e.g., the stomach) or potentially relevant feedback and, as a result have not addressed the important issue of the integration of intake-inhibitory signals when feedback from disparate sources is concurrently available. This leaves important open issues for clinical approaches (both behavioral and pharmacological) to feeding disorders, and for neural investigation into substrates that modulate ingestive behavior as a function of physiological and metabolic variables. The proposed experiments will provide an analysis, in the rat, of the relative contributions of oral, gastric and post-gastric sources to the termination of individual test meals, and the size and spacing of meals ingested throughout the day. Analysis of gastric emptying is central to this research program insofar as emptying determines the proportion of the ingested load that contacts gastric and post-gastric receptors. Thus, several experiments address the distinction between mechanisms that control gastric emptying within versus between meals as functions of : quality, volume and concentration of nutrients ingested; oral versus gastric stimulus delivery; time of day/night; deprivation state; and CNS administration of pharmacological agents that affect peptide receptor systems of great contemporary interest for the control of ingestion (corticotropin releasing factor, melanocortin, and neuropeptide Y). For food intake studies, we develop and exploit specialized testing paradigms (intra-oral infusion, drop-size-controlled lickometry, automated meal pattern analysis with access-restriction capability). The ability to manipulate aspects of stimulus delivery facilitates the analysis of gastric emptying, and allows us to bring emptying and behavioral results/meal size, duration and spacing, into explicit register. To evaluate the relative emptying and behavioral results(meal size, duration and spacing) into explicit register, to evaluate the relative weightings of gastric and post-gastric sources to satiation and satiety, we will characterize ingestive responses to manipulation that systematically bias the accumulation of nutrients within and beyond the stomach (e.g., reversible pyloric occlusion, intra-gastric and intra-intestinal infusion, and pharmacological treatments).

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-1 (01))
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Yanovski, Susan Z
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University of Pennsylvania
Schools of Arts and Sciences
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Faulconbridge, Lucy F; Grill, Harvey J; Kaplan, Joel M et al. (2008) Caudal brainstem delivery of ghrelin induces fos expression in the nucleus of the solitary tract, but not in the arcuate or paraventricular nuclei of the hypothalamus. Brain Res 1218:151-7
Williams, D L; Grill, H J; Cummings, D E et al. (2006) Overfeeding-induced weight gain suppresses plasma ghrelin levels in rats. J Endocrinol Invest 29:863-8
Faulconbridge, Lucy F; Grill, Harvey J; Kaplan, Joel M (2005) Distinct forebrain and caudal brainstem contributions to the neuropeptide Y mediation of ghrelin hyperphagia. Diabetes 54:1985-93
Grill, Harvey J; Carmody, Jill S; Amanda Sadacca, L et al. (2004) Attenuation of lipopolysaccharide anorexia by antagonism of caudal brain stem but not forebrain GLP-1-R. Am J Physiol Regul Integr Comp Physiol 287:R1190-3
Daniels, Derek; Markison, Stacy; Grill, Harvey J et al. (2004) Central structures necessary and sufficient for ingestive and glycemic responses to Urocortin I administration. J Neurosci 24:11457-62
Williams, Diana L; Cummings, David E; Grill, Harvey J et al. (2003) Meal-related ghrelin suppression requires postgastric feedback. Endocrinology 144:2765-7
Faulconbridge, Lucy F; Cummings, David E; Kaplan, Joel M et al. (2003) Hyperphagic effects of brainstem ghrelin administration. Diabetes 52:2260-5
Williams, Diana L; Grill, Harvey J; Cummings, David E et al. (2003) Vagotomy dissociates short- and long-term controls of circulating ghrelin. Endocrinology 144:5184-7
Williams, D L; Bowers, R R; Bartness, T J et al. (2003) Brainstem melanocortin 3/4 receptor stimulation increases uncoupling protein gene expression in brown fat. Endocrinology 144:4692-7
Grill, Harvey J; Schwartz, Michael W; Kaplan, Joel M et al. (2002) Evidence that the caudal brainstem is a target for the inhibitory effect of leptin on food intake. Endocrinology 143:239-46

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