Descripción del proyecto
Desentrañar el papel de los receptores del sistema nervioso en la obesidad y la diabetes
La incidencia global de la obesidad y la diabetes de tipo 2 va en aumento. Existe una relación clara entre la obesidad y la aparición de la diabetes y se carece de tratamientos farmacéuticos eficaces contra la obesidad. La regulación que el sistema nervioso ejerce sobre el glucagón, una hormona que aumenta el nivel de azúcar (glucosa) en sangre para evitar que descienda demasiado, y la insulina, una hormona que reduce el nivel de azúcar en sangre, desempeña un papel en ambas afecciones. El proyecto TRUSTED, financiado con fondos europeos, investigará el papel, actualmente desconocido, que desempeñan los agonistas y antagonistas del receptor de polipéptidos insulinotrópicos dependientes de la glucosa (GIPR, por sus siglas en inglés) en el metabolismo de la glucosa y la energía. Esto se complementará con estudios sobre el papel que desempeñan los coagonistas del receptor del péptido 1 similar al glucagón (GLP-1R)/GIPR en esta regulación esencial.
Objetivo
Obesity is a major health threat, but efficient pharmacotherapies are yet not available. First demonstrated by us to decrease body weight and hyperglycemia in obese mice, unimolecular co-agonists at the receptors for glucagon-like peptide-1 (GLP-1) and the glucose-dependent insulinotropic polypeptide (GIP) efficiently corrected obesity and type-2 diabetes in recent phase 3 clinical trials. While GLP-1R/GIPR co-agonists are safe and effective, GIP regulation of metabolism remains enigmatic, with GIPR agonists and antagonists both decreasing body weight and blood glucose.
My lab recently identified the CNS GIP receptor as a key regulator of energy metabolism, by showing that CNS loss of Gipr renders mice resistant to GIP-induced body weight loss. Emphasizing the relevance of this discovery, we showed that GLP-1R/GIPR co-agonism loses its superior body weight lowering potency over GLP-1R agonism in CNS-Gipr ko mice. My studies now finally enable assessment of how GIPR (ant)agonists and GLP-1R/GIPR co-agonists regulate energy and glucose metabolism. Whether GIPR (ant)agonists improve metabolism through central and peripheral mechanisms, which central regions/neurons/cells are targeted by GIPR (ant)agonists and by GLP-1R/GIPR co-agonists and the molecular mechanisms through which they control energy and glucose metabolism, remain unknown.
In this project I will solve the conundrum of how GIPR (ant)agonists and GLP-1R/GIPR co-agonists improve energy and glucose metabolism. I will map regional GIPR distribution (Aim 1), identify the central target regions of GIPR (ant)agonists and of GLP-1R/GIPR co-agonists (AIM 2), delineate their cellular and molecular signal mechanisms (AIM 3) and assess functional relevance of GIPR signal modification in key neuronal/cellular populations and the periphery (AIM 4). My studies will significantly advance the knowledge on how GIPR signaling regulates metabolism and will illuminate the paths for the development of future obesity drugs.
Ámbito científico
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
HORIZON-AG - HORIZON Action Grant Budget-BasedInstitución de acogida
85764 Neuherberg
Alemania