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.
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.
|Mhalhal, Thaer R; Washington, Martha C; Newman, Kayla et al. (2017) Infusion of exogenous cholecystokinin-8, gastrin releasing peptide-29 and their combination reduce body weight in diet-induced obese male rats. Appetite 109:172-181|
|Williams, Kasey E; Washington, Martha C; Johnson-Rouse, Tanisha et al. (2016) Exogenous glucagon-like peptide-1 acts in sites supplied by the cranial mesenteric artery to reduce meal size and prolong the intermeal interval in rats. Appetite 96:254-259|
|Washington, Martha C; Mhalhal, Thaer R; Sayegh, Ayman I (2016) Cholecystokinin-33, but not cholecystokinin-8 shows gastrointestinal site specificity in regulating feeding behaviors in male rats. Horm Behav 85:36-42|
|Washington, Martha C; Mhalhal, Thaer R; Johnson-Rouse, Tanisha et al. (2016) Roux-en-Y gastric bypass augments the feeding responses evoked by gastrin-releasing peptides. J Surg Res 206:517-524|
|Washington, Martha C; Williams, Kasey; Sayegh, Ayman I (2016) The feeding responses evoked by endogenous cholecystokinin are regulated by different gastrointestinal sites. Horm Behav 78:79-85|
|Washington, Martha C; Mhalhal, Thaer R; Sayegh, Ayman I (2016) The BB2 receptor antagonist BW2258U89 attenuates the feeding responses evoked by exogenous gastrin releasing peptide-29. Horm Behav 85:1-4|
|Sayegh, Ayman I; Washington, Martha C; Johnson, Ruth E et al. (2015) Celiac and the cranial mesenteric arteries supply gastrointestinal sites that regulate meal size and intermeal interval length via cholecystokinin-58 in male rats. Horm Behav 67:48-53|
|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; 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|
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