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.

Subsidie
€ 1.999.928
2022

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:

  1. Map regional GIPR distribution (Aim 1).
  2. Identify the central target regions of GIPR (ant)agonists and of GLP-1R/GIPR co-agonists (Aim 2).
  3. Delineate their cellular and molecular signal mechanisms (Aim 3).
  4. 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

Startdatum1-9-2022
Einddatum31-8-2027
Subsidiejaar2022

Partners & Locaties

Projectpartners

  • HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBHpenvoerder

Land(en)

Germany

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