Forebrain but not hindbrain glucagon-like peptide-1 receptors participated in specific circuitry for reduction of food intake by illness

Glucagon-like peptide I (GLP-I) is a post-translational product of the preproglucagon gene. GLP-I is secreted from endocrine cells in the small intestine but also is synthesized by a small population of neurons in the brain. Brain neurons that synthesize GLP-I are located in the nucleus of the solitary tract (NTS), the brain area in which primary vagal sensory neurons synapse. Binding sites for GLP-I are found throughout the brain and are especially dense in the NTS and the hypothalamus. Other researchers have reported that microinjections of GLP-I into the forebrain ventricles reduce meal size (short-term food intake). Since forebrain areas containing GLP-I binding sites are associated with the control of feeding, we hypothesized that hindbrain GLP-I would also have an effect on food intake. To assess the merit of this hypothesis, we made microinjections ofGLP-1 into either the fourth cerebral ventricle or lateral cerebral ventricle and then measured intake of a liquid meal (15 % sucrose) over thirty minutes. We found that compared to control injections, fourth ventricular injection ofGLP-1 in volumes that do not reach the forebrain ventricles, reduced 30 min liquid food intake by 49 %. Lateral ventricular GLPI infusions reduced liquid food intake by 33%. In addition, reduction of food intake by fourth ventricle GLP-I was abolished by preinjection of exendin (9-39), a GLP-I receptor antagonist. We then conducted a dose response experiment to determine the effect of varying the dose of intracranioventricular (i.c.v.) GLP-I on solid food intake. Doses of I j.lg, 3j.lg, and 5j.lg GLP-I were infused into the fourth or lateral ventricle. We found that 3j.lg was the lowest dose of GLP-I that significantly reduced food intake when infused into either ventricle. GLP-I has been reported to evoke behavioral responses that are associated with feelings of illness when infused into the lateral ventricle. Such effects include reduction in short-term food intake and conditioning of taste aversions. Some investigators have postulated that GLP-I may mediate the effects of other illness producing stimuli such as lithium chloride (LiCI) injection. We conducted an experiment in which we infused a GLP-I receptor antagonist (exendin 9-39) into the lateral ventricle prior to intraperitoneal (i.p.) injection of LiCI. As a supplemental procedure, we conducted the same experiment with i.p. cholecystokinin (CCK), because CCK has been shown to reduce food intake without inducing signs of illness. We found that the GLP-I antagonist partially attenuated the reduction of food intake caused by lithium. In addition, we found that lateral ventricle injection of the GLP-I antagonist did not attenuate reduction of food intake by CCK. These results suggest that, at least in the forebrain, GLP-I is involved in mediating the reduction in food intake caused by LiCI, and that CCK acts through a GLPI-independent pathway to reduce food intake. Our next set of experiments will be to investigate the effects of fourth ventricle GLP-I receptor antagonist on reduction of food intake by LiCI and CCK. In summary, GLP-I reduces food intake by acting in both the forebrain and the hindbrain. However, only forebrain GLP-I receptors appear to participate in reduction of food intake by illness-producing stimuli. Furthermore, my results suggest that there are distinct neurochemical circuits for reduction of food intake by illness-producing and satiation-producing stimuli. GLP-I participates in responses to illness, but not to satiation stimuli, like CCK.Honors College, Washington State UniversityBilles, Sonja K. and Ritter, Robert C. Forebrain but not hindbrain glucagon-like peptide-1 receptors participated in specific circuitry for reduction of food intake by illness, Washington State University Honors College thesis, Spring 2003, 27 p