04 Sep. Medical drug targets made visible in the body
Diabetes and obesity can now be treated with modern drugs. Semaglutide (Ozempic/Wegovy) and tirzepatide (Mounjaro/Zepbound) are well-known active ingredients in “weight loss injections”. In the case of tirzepatide, its mode of action is based on its effect on two receptors in the body: the GLP-1 receptor (glucagon-like peptide-1 receptor) and the GIPR receptor (glucose-dependent insulinotropic polypeptide receptor).
GLP1 and GIP receptors are found in both the pancreas and the brain. They ensure that enough insulin is released after a meal. While the mode of action of tirzepatide in the body has already been well researched, it was previously unclear exactly which specific cell and nerve types are targeted by the drug.
Fluorescence makes target cells visible
An international research team led by junior research group leader Johannes Broichhagen from the Leibniz Research Institute for Molecular Pharmacology (FMP) in Berlin, David Hodson from the Radcliffe Department of Medicine at the University of Oxford, and Anne de Bray from the University of Birmingham has succeeded in using new fluorescent markers to visualize the transport of drugs such as tirzepatide through the body and brain. “By describing the target cells for dual agonists, we can better understand how they exert their effects,” explains Hodson.
Junior research group leader Dr. Johannes Broichhagen from the Leibniz Research Institute for Molecular Pharmacology (FMP). Image: Matthias Rethmann
Broichhagen’s research team has now made some new and crucial discoveries in this area: after years of work, the researchers say they have succeeded in developing novel fluorescent markers using fluorophores (dual agonist LUXendins or daLUXendins). These enable the visualization and analysis of GLP1R and GIPR receptors simultaneously in living cells and tissues, and thus the visualization of the target cells of dual agonists such as tirzepatide.
Target cells in the brain and pancreas
Experiments with daLUXendins have shown that the markers bind most strongly to beta cells, but also to alpha and delta cells in the pancreas. In addition, it has been demonstrated that tirzepatide also reaches specific brain regions and nerve cells that are important for controlling appetite and metabolism. A particularly interesting discovery was the labeling of tanycytes, special cells in the brain that monitor metabolism and send signals to eating centers.
Limitations of the study and outlook
Limitations of the study include the fact that the markers and the drug tirzepatide are different molecules, and that the investigations have so far been carried out mainly on mouse models. According to the researchers, further research is needed to transfer the results to humans. In addition, only a limited selection of colors was used, but this is to be expanded in the future.
The study therefore provides important insights into why dual agonists are so successful. At the same time, it raises new questions: What would happen if the drugs‘ access to the brain were improved? And how do new triple agonists with additional glucagon content work? Based on these findings, it is possible to further improve the treatment of diabetes and obesity.
Original publication:
[A. de Bray et al.: Fluorescent GLP1R/GIPR dual agonist probes reveal cell targets in the pancreas and brain; Nat Metab 7, 1536–1549, 2025, https://doi.org/10.1038/s42255-025-01342-6
Source and image: leibniz-fmp.de