Descrizione del progetto
Chiarire il ruolo dei recettori del sistema nervoso nell’obesità e nel diabete
L’incidenza globale dell’obesità e del diabete di tipo 2 è in aumento. I due disturbi sono fortemente correlati e per l’obesità mancano ancora terapie farmaceutiche efficaci. In entrambi i casi è coinvolta la regolazione da parte del sistema nervoso del glucagone, un ormone che aumenta il livello di zucchero (glucosio) nel sangue per evitare che si abbassi troppo, e dell’insulina, un ormone che riduce il livello di zucchero nel sangue. Il progetto TRUSTED, finanziato dall’UE, studierà il ruolo ancora misterioso degli agonisti e degli antagonisti del recettore del polipeptide insulinotropico glucosio-dipendente (GIPR) nel metabolismo energetico e del glucosio. A ciò si aggiungeranno studi sul ruolo dei co-agonisti del recettore del peptide-1 del glucagone (GLP-1R)/GIPR in questa regolazione fondamentale.
Obiettivo
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.
Campo scientifico
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-AG - HORIZON Action Grant Budget-BasedIstituzione ospitante
85764 Neuherberg
Germania