The roles of glucagon-like peptide-1 (GLP-1) in the mouse brain

grantor: University of TorontoGlucagon-like peptide-1 (GLP-1) is a gut-brain hormone synthesized by peptidergic cleavage of proglucagon in the pancreatic A cells and the L cells of the ileal mucosa. GLP-1 is involved in the regulation of pancreatic and gastric functions, stimulating insulin secretion and inhibiting gastric secretion, respectively. Although GLP-1 has been postulated to regulate food intake, mice with targeted disruption of the GLP-1 receptor (GLP-1R $-$/$-$ mice) exhibit normal body weights, suggesting that GLP-1 is not an exclusive determinant of the central mechanisms controlling appetite. The objective of this thesis was to further explore potential central sites of GLP-1 action by mapping the distribution of its receptors in the mouse brain as well as by studying the endocrine consequences of the loss of GLP-1 receptor mediated responses, in the GLP-1R $-$/$-$ mouse. Quantitative autoradiography demonstrates extensive distribution of GLP-1 receptors in the diencephalon and in the limbic system, suggesting that rather than specifically regulating appetite, GLP-1 may in fact play a role in a number of neuronal systems that influence neuroendocrine function and behavior. In studying GLP-1R $-$/$-$ mice from birth to adulthood, we found that while they appear phenotypically similar from the control wildtype mice (GLP-1R +/+), their reproductive development is subtly impaired. In addition, loss of GLP-1 signaling results in slight deficits in their stress responses. Responses to mild stress are subnormal, although responses to severe stress remain intact in GLP-1R $-$/$-$ animals. These data suggest that GLP-1 may play a subtle modulatory role in the CNS in regulating neuroendocrine mechanisms involved in regulating reproductive function and the control of adrenal function, in addition to its postulated involvement in the regulation of food intake.M.Sc