Regulation of energy homeostasis by GLP-1 receptive neuronal networks
Glucagon-like peptide-1 (GLP-1) is an incretin hormone. It is derived from the posttranslational processing of proglucagon. This prohormone is synthesized by three cell populations, the neuroendocrine L cells of the intestinal mucosa, the ß cells of the pancreatic Langerhans islands and in a neuronal population located in the nucleus tractus solitarii (NTS) and intermediate reticular nucleus of the medulla oblongata.
GLP-1 is produced, however, only in the gut and the brain as its production requires PC1/3 catalyzed posttranslational processing of proglucagon. GLP-1 has a critical role in the regulation of energy and glucose homeostasis, and exerts its effects via the GLP-1 receptor (GLP-1R). It decreases circulating glucose levels by slowing down the gastric emptying, and by stimulating insulin production and inhibiting glucagon secretion. Furthermore, GLP-1 has potent inhibitory effect on food intake, and can decrease the hedonic value of food and the motivation to eat. These properties have made GLP-1R an important drug target in the field of type 2 diabetes and obesity. Long acting GLP-1 agonists, liraglutide, semaglutide and dulaglutide have been marketed for the treatment of type two diabetes, while liraglutide is approved for the treatment of obesity. Despite of the widespread use of these GLP-1 analogues, it is not clear, how their effects are mediated on the energy homeostasis via the brain.
To uncover the neuronal elements that mediate the effects of GLP-1 signaling on the energy expenditure, we map the GLP-1R-containing elements in the brain and spinal cord, identify the chemotype and connectivity of these neuronal groups and using cell type specific GLP-1R KO animals, we determine the role of these neuronal groups in the regulation of energy homeostasis and in the mediation of the effects of GLP-1 signaling on the energy homeostasis.