Project description
Untangling the role of nervous system receptors in obesity and diabetes
Global incidences of obesity and type 2 diabetes are growing. There is a strong relationship between obesity and the onset of diabetes, and effective pharmaceutical therapies for obesity are lacking. Nervous system regulation of glucagon, a hormone that increases blood sugar (glucose) level to prevent it from dropping too low, and insulin, a hormone that decreases blood sugar level, plays a role in both. The EU-funded TRUSTED project will investigate the currently enigmatic role of glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists and antagonists in energy and glucose metabolism. This will be complemented by studies of the role of glucagon-like peptide-1 receptor (GLP-1R)/GIPR co-agonists in this critical regulation.
Objective
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.
Fields of science
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Funding Scheme
HORIZON-AG - HORIZON Action Grant Budget-BasedHost institution
85764 Neuherberg
Germany