A3 - Role of Y-Receptors in the Regulation of Food Intake
At present, the modulation of satiety and hunger hormone activity is a promising approach in the development of new anti-obesity pharmaceuticals. Members of the Neuropeptide Y hormone family (Neuropeptide Y, Pancreatic Polypeptide and Peptide YY) are key player in the central and peripheral regulation of food intake, mediated by Gi protein coupled receptors Y1, Y2, Y4, und Y5. Since agonists are needed for all satiety hormones, receptor internalization has to be taken into account, as it may contribute to cell surface receptor desensitization and activation of alternative signaling pathways. Consequently, to understand the mechanisms and therapeutic potential of agonistic ligands, receptor internalization has to be studied in detail.
Aim of the project is the in vitro characterization of cellular effects influenced by Y-receptor subtype specific internalization, we could previously demonstrate, as well as the analysis of its contribution to physiological functions in vivo. We hypothesize that tissue and subtype specific Y-receptor signaling and internalization contribute to the central and peripheral regulation of food intake, thereby influencing the therapeutic potential of agonistic peptides. We will compare agonistic peptide ligands, which provoke altered receptor internalization and recycling as compared to the endogenous ligand NPY, with respect to cell specific internalization and signaling. Following the characterization of internalization patterns in hypothalamic cell lines, we will compare ligand induced expression profiles. Furthermore, we will evaluate the physiological effects induced in vivo after intracerebroventricular injection of these peptides, to understand the significance of receptor internalization in vivo zu verstehen.
Abbildung 1: Characterization of the ligands NPY, [F7,P34] NPY and [Gly34] NPY . Left: All peptides show comparable induction of G-protein signalling. Right: HEK293 cells stably expressing Y1-YFP fusionproteins (Yellow). Incubation with the respective TAM labelled peptides (red) for 60 min induces different receptor internalization. Nuclei are stained in blue.
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