Central infusion of glucagon-like peptide-1-(7-36) amide (GLP-1) and intraperitoneal (i.p.) injection of lithium chloride (LiCl) produce similar patterns of c-Fos induction in the rat brain. These similarities led us to assess the hypothesis that neuronal activity caused by i.p. injection of LiCl involves activation of central GLP-1 pathways. We therefore determined if third-ventricular (i3vt) infusion of a GLP-1 receptor antagonist would block LiCl-induced c-Fos expression in the brainstem. Relative to rats pretreated with i3vt infusion of vehicle, pretreatment with the potent GLP-1 receptor antagonist, des His1 Glu9 exendin-4 (10.0 microgram), significantly attenuated LiCl-induced (76 mg/kg; i.p.) c-Fos expression in several brainstem regions, including the area postrema, the nucleus of the solitary tract, and the lateral parabrachial nucleus. While central infusion of des His1 Glu9 exendin-4 also blocked GLP-1-induced (10.0 microgram) anorexia and c-Fos expression, the antagonist produced no independent effects on food intake or c-Fos expression. These results suggest that LiCl-induced c-Fos expression in the rat brainstem is mediated, at least in part, by GLP-1 receptor signaling.

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INTRODUCTIONIngestion of food is a necessary and pleasant occupation that allows humans and other species to maintain caloric homeostasis and a certain level of body weight. Ironically, in doing so, one's 'milieu interieur' is put at risk because meal-induced fuel excursions can have deleterious effects on metabolic (e.g. glycosylation causing loss of enzymatic efficacy) and cardiovascular (e.g. triglyceride accumulation, increased blood pressure, etc.) processes. 1,2 To reduce these perturbations to a minimum, evolution has provided many species (including humans and rodents) with a fine-tuned system enabling ingested nutrients to be anticipated, efficiently digested, and stored. 3 One of these mechanisms includes passage of nutrients through the digestive tract, triggering the release of a number of peptides from endocrine cells located in the wall of various parts of the gastrointestinal tract. These peptides serve important functions in facilitating the process of nutrient digestion/storage. Among these, the truncated (i.e. 7-36) amidated form of glucagon-like peptide-1 (GLP-1) has attracted considerable attention over the last several years. Firstly, because of its remarkable peripheral insulinotropic effects that could be useful for clinical purposes. Secondly, because more recent data suggest an important role of this peptide in the central nervous system (CNS) control of ingestive behavior. Although the present paper mainly focusses on the latter issue, a short review of peripheral GLP mechanisms is necessary for a better understanding of the processes that relate GLP-1 to food intake. GLP-1 FROM THE GASTROINTESTINAL TRACTGLP-1 is processed from proglucagon in mucosal L cells of the distal portion of the ileum and in the A cells of the pancreas. Ingested food, particularly when rich in carbohydrates, causes the level of circulating GLP-1 (mainly of ileal origin) to increase, and in turn, GLP-1 potently stimulates the secretion of insulin from pancreatic B cells via receptor-mediated processes (for reviews, see refs 4 and 5). In contrast, it reduces the secretion of glucagon, at least under ad libitum feeding conditions. 6 While GLP-1 may have some direct stimulatory effects on glucose clearance in peripheral tissue 7,8 (presumably via activation of specific GLP-1 receptors in liver, muscle, kidney Summary Glucagon-like peptide-1 (7-36) amide (GLP-1) is processed from proglucagon in the distal ileum as well as in the CNS. In the periphery, GLP-1 acts as an incretin factor and profoundly inhibits upper gastrointestinal motility ('ileal brake'), the latter presumably involving the CNS. Within the CNS, GLP-1 has a satiating effect, since administration of GLP-1 into the third cerebral ventricle reduces short-term food intake (and meal size), while administration of GLP-1 antagonists have the opposite effect. In addition, activation of GLP-1 receptors in certain brain regions elicits strong taste aversions. Similarities between toxin-and GLP-1-induced neuronal activity in the CNS (brain stem) suggest a role f...