The goal of this application is to determine the physiological role of gastrin releasing peptide (GRP), released by the enteric neurons of the gastrointestinal tract, in the regulation of meal size in rats. Despite accumulating evidence that support such role, two fundamental questions remain unanswered: (1) Is GRP a physiological signal that regulates meal size? (2) If indeed GRP is a physiological signal that regulates meal size, then how does it do that? This application attacks these questions by providing a decisive test of the hypothesis at risk: Gastrin releasing peptide, released in response to nutrients, regulates meal size by first activating the enteric nerves of the gut, which in turn activates the extrinsic innervation of the gastrointestinal tract and then the feeding control areas of the dorsal vagal complex of the hindbrain.
Four Specific Aims will test this hypothesis systematically. (1) Determine the physiological role of endogenous GRP in regulating meal size. (2) Determine the gastrointestinal site of action of endogenous GRP responsible for regulating meal size. (3) Determine the role of enteric neuronal GRP in regulating meal size. (4) Determine the afferent pathway that GRP utilizes to regulate meal size. First, to determine the physiological role of GRP in regulating a normal meal size, we will use the spontaneously feeding undisturbed rat preparation to characterize individual meals by recording second-by-second intakes of liquid diets using lickometers and a reliable and valid behavioral observation scale. Following that, we will employ potent, and highly selective, receptor antagonists and antibodies to reverse the effect. Second, to determine the gastrointestinal site of action of endogenous GRP on meal size we will deliver GRP to organ-selective abdominal sites by close-arterial infusions and measure meal size. Our preliminary results have shown that one site of action of GRP lies in the vascular bed of the left gastric artery. Third, to determine the role of the enteric neurons in GRP-regulation of meal size we will employ chemical and surgical ablations of these neurons combined with detection of Fos-like immunoreactivity (Fos-LI;a marker for neuronal activation) while measuring the effect on meal size. Forth, to determine the afferent pathway that GRP utilizes to regulate meal size we will perform selective ablations of extrinsic abdominal nerves (vagotomy, sympathectomy and both) and measure meal size and Fos-LI in response to exogenous and endogenous GRP. In this application we propose that: (1) GRP makes an important physiological contribution to the regulation of meal size. (2) The myenteric neurons of the gastrointestinal tract comprise the site of action of GRP to regulate meal size. (3) The enteric nervous system of the gastrointestinal tract has a role in the regulation of meal size by GRP. (4) The vagus and / or the sympathetic nerves have a role in transmitting the GRP-satiation signal from the enteric neurons to the hindbrain.

Public Health Relevance

Obesity is a common clinical problem especially in the African American community. This disease results from poor control of food intake and poor understanding of the processes that regulate it. The proposed research will investigate the role of the hormone gastrin releasing peptide in the regulation of food intake.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Enhancement Award (SC1)
Project #
5SC1DK094972-02
Application #
8326054
Study Section
Special Emphasis Panel (ZGM1-MBRS-0 (NP))
Program Officer
Agodoa, Lawrence Y
Project Start
2011-09-01
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$298,602
Indirect Cost
$73,602
Name
Tuskegee University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
128214178
City
Tuskegee
State
AL
Country
United States
Zip Code
36088
Washington, Martha C; Salyer, Sarah; Aglan, Amnah H et al. (2014) Intravenous infusion of gastrin-releasing peptide-27 and bombesin in rats reveals differential effects on meal size and intermeal interval length. Peptides 51:145-9
Washington, Martha C; Park, Karen H; Sayegh, Ayman I (2014) Obese and lean Zucker rats respond similarly to intraperitoneal administration of gastrin-releasing peptides. Peptides 58:36-41
Reeve Jr, Joseph R; Washington, Martha C; Park, Karen H et al. (2014) Sequence analysis and feeding responses evoked by the large molecular form of gastrin releasing peptide (GRP) in the rat GRP-29. Peptides 59:1-8
Sayegh, Ayman I; Washington, Martha C; Raboin, Shannon J et al. (2014) CCK-58 prolongs the intermeal interval, whereas CCK-8 reduces this interval: not all forms of cholecystokinin have equal bioactivity. Peptides 55:120-5
Washington, Martha C; Aglan, Amnah H; Sayegh, Ayman I (2014) The stomach and/or upper duodenum contain sites of action that control meal size and intermeal interval length by exogenous rat gastrin releasing peptide. Peptides 55:41-6
Sayegh, Ayman I (2013) The role of cholecystokinin receptors in the short-term control of food intake. Prog Mol Biol Transl Sci 114:277-316
Sayegh, Ayman I (2013) The role of bombesin and bombesin-related peptides in the short-term control of food intake. Prog Mol Biol Transl Sci 114:343-70
Lateef, Dalya M; Washington, Martha C; Raboin, Shannon J et al. (2012) Duodenal myotomy blocks reduction of meal size and prolongation of intermeal interval by cholecystokinin. Physiol Behav 105:829-34
Wright, Susan A; Washington, Martha C; Garcia, Carlos et al. (2012) Gastrin releasing peptide-29 requires vagal and splanchnic neurons to evoke satiation and satiety. Peptides 33:125-31
Brown, Thelma A L; Washington, Martha C; Metcalf, Shannon A et al. (2011) The feeding responses evoked by cholecystokinin are mediated by vagus and splanchnic nerves. Peptides 32:1581-6

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