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Drugs that bind to and activate the receptors for the hormones GLP-1 and GIP are effective in the treatment of obesity and diabetes. Surprisingly, active substances are currently being developed that not only activate the GIP receptor (agonists) but also block it (antagonists). They also have a positive effect on body weight. A team from Helmholtz Munich, the German Center for Diabetes Research (DZD) and Ludwig-Maximilians-Universität München (LMU) has now discovered that GIPR agonism and antagonism engage different mechanisms to decrease body weight and food intake. These new findings could pave the way for more targeted medication against obesity.
Agonists and antagonists of the GIP receptor influence body weight and food intake through various mechanisms in the brain. This is shown by studies led by DZD scientist Prof. Dr. Timo Müller from Helmholtz Munich. Researchers from Helmholtz Munich, the DZD, the Walther Straub Institute of Pharmacology and Toxicology, the LMU and Eli Lilly have now published their latest findings in Nature Metabolism.
Incretins also Act on the Central Nervous System
Background: Intestinal hormones (incretins) such as GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) play a significant role in the regulation of blood glucose levels and energy metabolism. After ingestion, they are released in the intestine and have a variety of effects. Depending on the blood sugar level, they promote the release of insulin from the pancreas – a mechanism known as the incretin effect. At the same time, GLP-1 inhibits the release of glucagon, a hormone that increases blood sugar levels.
In addition, GLP-1 slows down gastric emptying, and this reduces the rise in blood sugar after eating. Both hormones also have an effect on the central nervous system – GLP-1 reduces the feeling of hunger via specific satiety centers in the brain. GIP also appears to influence appetite and food intake via other neuronal pathways.
Agonists and Co-Agonists Help you Lose Weight
The fact that GLP-1 agonists such as semaglutide help to lose weight has been well studied scientifically. Even stronger effects can be achieved if the GIP receptor is additionally stimulated – for example with tirzepatide, which activates both receptors simultaneously (polyagonist). The surprising thing is: Drugs that block the GIP receptor, i.e., GIPR antagonists, can also reduce weight in combination with GLP-1 agonists.
Previous studies have shown that GIPR agonists act in the brain independently of the GLP-1 receptor. To achieve this, they use neurons that release the inhibitory neurotransmitter gamma aminobutyric acid (GABA) (GABAergic neurons). However, it was previously unclear how GIPR antagonists exert their effect.
How GIPR Agonists and Antagonists Reduce Body Weight
In their study, the researchers used transgenic mice in which the GIP receptor in GABAergic neurons was specifically deactivated. In addition, they carried out single-cell RNA sequencing (scRNA-seq) in wild-type mice. They wanted to find out how and where in the brain GIPR agonists and antagonists influence energy metabolism.
“Our study shows that although GIPR agonists and antagonists both lead to weight loss and reduced food intake, they do this via completely different and independent mechanisms. Our work explains how GIPR agonists and antagonists act in the brain to regulate energy metabolism,” says last author of the study Timo Müller, who is also Director of the Institute for Diabetes and Obesity. The effect of GIPR agonists is only possible if the GIPR signal in GABAergic neurons in the brain is intact. “As regards GIPR antagonists, however, this signal plays no role,” adds the co-corresponding author, Prof. Matthias Tschöp, CEO and Scientific Director of Helmholtz Munich. “Conversely, the following applies: The effect of GIPR antagonists depends essentially on a functioning transmission of the GLP-1R signal, while the effect of GIPR agonists does not,” says Robert Gutgesell, who is first author of the publication together with Ahmed Khalil.
Single cell analyses provide additional information: Only GIPR antagonists – but not agonists – activate similar signaling pathways in the hindbrain as the GLP-1 receptor. The hindbrain is considered an important control center for controlling appetite and energy balance.
“Our data has finally solved a mystery in biomedical research,” summarizes Müller. “Although both classes of active agents achieve similar effects, they act at completely different sites in the brain – with a key role of the GLP-1 receptor specifically for the effect of GIPR antagonists.” The new findings may pave the way for a more focused development of drugs that target the GIP system in the brain.
Helmholtz Munich is a top biomedical research center. Its mission is to develop pioneering solutions for a healthier society in a rapidly changing world. Interdisciplinary research teams focus on environmental diseases, in particular the treatment and prevention of diabetes, obesity, allergies and chronic lung diseases. www.helmholtz-munich.de
The German Center for Diabetes Research (DZD) e.V. is one of the eight German Centers for Health Research. It unites experts in the field of diabetes research and combines basic research, epidemiology and clinical application. The aim of the DZD is to make a significant contribution to the successful, customized prevention, diagnosis and treatment of diabetes mellitus through a novel, integrative research approach. www.dzd-ev.de
Prof. Dr. rer. nat. Timo Müller
Director, Institute for Diabetes and Obesity (Helmholtz Munich)
Professorship for Molecular Pharmacology of Energy and Glucose Metabolism at the Medical Faculty of Ludwig Maximilian University of Munich
Walther Straub Institute for Pharmacology and Toxicology
Ingolstädter Landstrasse 1
D-85764 Neuherberg
Phone: +4989 3187 2106
Email: timodirk.mueller@helmholtz-munich.de
Robert M. Gutgesell et al.: GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice. DOI: 10.1038/s42255-025-01294-x, Nature Metabolism
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