CenTral and PeRipheral NervoUs SyStem acTion of GIPR in ObEsity and Diabetes
This project aims to elucidate the mechanisms of GIPR (ant)agonists and GLP-1R/GIPR co-agonists in regulating energy and glucose metabolism to inform future obesity drug development.
Projectdetails
Introduction
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.
Current Understanding
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.
Significance of Discovery
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 knockout mice. My studies now finally enable assessment of how GIPR (ant)agonists and GLP-1R/GIPR co-agonists regulate energy and glucose metabolism.
Research Questions
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.
Project Aims
In this project, I will solve the conundrum of how GIPR (ant)agonists and GLP-1R/GIPR co-agonists improve energy and glucose metabolism. The specific aims are:
- 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).
- Assess functional relevance of GIPR signal modification in key neuronal/cellular populations and the periphery (Aim 4).
Expected Outcomes
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.
Financiële details & Tijdlijn
Financiële details
Subsidiebedrag | € 1.999.928 |
Totale projectbegroting | € 1.999.928 |
Tijdlijn
Startdatum | 1-9-2022 |
Einddatum | 31-8-2027 |
Subsidiejaar | 2022 |
Partners & Locaties
Projectpartners
- HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBHpenvoerder
Land(en)
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