Universally, researchers agree that peripheral sensory systems play a critical role in the control of meal size. However, they sustain a lively controversy as to the origin of satiety-relevant feedback. Some tend to focus on discrete sources (e.g., the stomach) of potentially-relevant feedback and, as a result, do not address the important issue of integration of intake-inhibitory signals when feedback from disparate sources is concurrently available. This is a serious omission for clinical approaches (both behavioral and pharmacological) to feeding disorders, as well as for nervous system-oriented research into substrates that modulate ingestive behavior as a function of physiological and metabolic variables. In this project the Investigator and his colleagues will undertake a comprehensive analysis of the relative contributions of oral, gastric, and post-gastric signals to the control of nutritive fluid ingestion in the rat. They will provide the first extensive study of the mechanisms that control gastric emptying during ingestion. For this purpose, they will evaluate the effects of: (a) quality and concentration of nutritive fluids ingested, (b) route (oral versus intragastric), rate, and duration of fluid delivery, and (c) complete and selective transections of the subdiaphragmatic vagus nerve, and (d) pharmacological treatment. For the intake studies, the researchers will develop and exploit specialized testing paradigms (intra-oral infusion; drop-size-controlled lickometry) that allow the experimenter to control the parameters of fluid delivery, and the rat to decide when to stop ingesting. This ability to manipulated fluid stimulus delivery facilitates the analysis of gastric emptying during ingestion, and permits the researchers to bring gastric emptying and behavioral results (meal size and duration) into explicit register. To evaluate the relative weightings of feedback from gastric and postgastric sources in the satiation process, the researchers will (a) measure the gastric and postgastric distribution of nutrient at meal's end, and (b) evaluate the effects on meal size and duration of manipulations that systematically bias the rate of gastric fill relative to the rate at which nutrient empties from the stomach. The Investigator expects these experiments to lead to a model for the integrative mechanisms that underlie short-term satiety under normal conditions where oral, gastric, and postgastric receptors are stimulated concurrently.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK042284-05
Application #
2444039
Study Section
Special Emphasis Panel (ZRG2-BPO (01))
Project Start
1993-01-01
Project End
2000-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
5
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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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