Intracerebroventricular administration of glucagon-like peptide-1 (7-36) amide (GLP-1) reduces food intake and produces symptoms of visceral illness, such as a conditioned taste aversion (CTA). The central hypothesis of the present work is that separate populations of GLP-1 receptors mediate the anorexia and taste aversion associated with GLP-1 administration. To test this hypothesis, we first compared the ability of various doses of GLP-1 to induce anorexia or CTA when administered into either the lateral or fourth ventricle. Lateral and fourth ventricular GLP-1 resulted in reduction of food intake at similar doses, whereas only lateral ventricular GLP-1 resulted in a CTA. Such data indicate that both hypothalamic and caudal brainstem GLP-1 receptors are likely to participate in the ability of GLP-1 to reduce food intake. We also hypothesized that the site that must mediate the ability of GLP-1 to induce visceral illness is in the central nucleus of the amygdala (CeA). Administration of 0.2 or 1.0 g of GLP-1 (7-36) but not the inactive GLP-1 (9-36) resulted in a strong CTA with no accompanying anorexia. In addition, bilateral CeA administration of 2.5 g of a GLP-1 receptor antagonist before intraperitoneal administration of the toxin lithium chloride resulted in a diminished CTA. Together, these data indicate that separate GLP-1 receptor populations mediate the multiple responses to GLP-1. These results indicate that GLP-1 is a flexible system that can be activated under various circumstances to alter the ingestion of nutrients and/or produce other visceral illness responses, depending on the ascending pathways of the GLP-1 system that are recruited. Key words: conditioned taste aversion; GLP-1; food intake; visceral illness; central nucleus of the amygdala; hypothalamusGlucagon-like peptide-1 (7-36) amide (GLP-1) is a posttranslational product of preproglucagon that is produced in the brainstem (Han et al., 1986;Jin et al., 1988). GLP-1-producing neurons project to a number of brain areas, including the central nucleus of the amygdala (CeA) and the paraventricular nucleus of the hypothalamus (PVN) (Goke et al., 1995), and the GLP-1 receptor (GLP-1r) is located in these regions (Han et al., 1986;Merchenthaler et al., 1999). Intracerebroventricular administration of GLP-1 (Tang-Christensen et al., 1996;Turton et al., 1996;van Dijk et al., 1997) or injection directly into the PVN (McMahon and Wellman, 1997) potently inhibits food intake. Therefore, it has been proposed that GLP-1 has a physiological role in the suppression of food intake.Although the effect of GLP-1 to cause anorexia is unquestioned, the regulatory system served by GLP-1 is unclear. Some investigators have proposed that GLP-1 has a role in energy balance Turton et al., 1996;Goldstone et al., 1997;Meeran et al., 1999), possibly through interactions with leptin signaling (Goldstone et al., 1997(Goldstone et al., , 2000. However, some evidence indicates that GLP-1 is involved in suppression of food intake through mediating the response to visceral i...
During a meal, ingested nutrients accumulate in the stomach, with a significant portion passing on to the small intestine. The gastrointestinal presence of ingested nutrients initiates a range of physiological responses that serve to facilitate the overall digestive process. Thus peptides and transmitters are released, and various neural elements are activated that coordinate gastrointestinal secretion and motility and can eventually lead to meal termination or satiety. Among the range of gastrointestinal peptides released by ingested nutrients is the brain/gut peptide CCK. CCK plays a variety of roles in coordinating gastrointestinal activity and has been demonstrated to be an important mediator for the control of meal size.
Responses to stressors serve to adjust physiology and behavior to increase short-term survival at the potential expense of increasing susceptibility to disease over the long term. We show that glucagon-like peptide-1 (7-36) amide (GLP-1) increases levels of the stress-activated hormones ACTH and corticosterone when administered directly into the rat brain and increases levels of anxiety as measured by the elevated plus maze. The endocrine response is preferentially activated by GLP-1 administration in the paraventricular nucleus of the hypothalamus, whereas the anxiety response is preferentially activated by administration in the central nucleus of the amygdala. Furthermore, GLP-1 antagonists block increases in stress hormones associated with the toxin LiCl and both the endocrine and anxiety responses to vertical heights. Although diverse neural circuits must necessarily process disparate stressors, the current data implicate a role for the GLP-1 system as a critical mediator of multiple stress responses.
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