New Obesity Drugs Defy Logic – And Succeed

Drugs that both activate and block the GIP receptor reduce weight through different brain mechanisms, offering a new direction for targeted obesity treatments.

Drugs that target the receptors for the hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) have proven effective in treating obesity and type 2 diabetes. While GLP-1 and GIP receptor agonists stimulate these receptors to produce therapeutic effects, it is surprising that substances designed to block the GIP receptor, known as antagonists, can also promote weight loss.

A research team from Helmholtz Munich, the German Center for Diabetes Research (DZD), and Ludwig-Maximilians-Universität München (LMU) has now shown that GIP receptor (GIPR) agonists and antagonists reduce body weight and food intake by engaging entirely different mechanisms in the brain. These insights could support the development of more precisely targeted medications for obesity.

The study, led by DZD scientist Prof. Dr. Timo Müller, reveals that both GIPR agonists and antagonists act through distinct neural pathways to influence appetite and energy balance. The findings, published in Nature Metabolism, result from a collaborative effort involving researchers from Helmholtz Munich, the DZD, the Walther Straub Institute of Pharmacology and Toxicology, LMU, and the pharmaceutical company Eli Lilly.

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 that 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.

Reference: “GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice” by Robert M. Gutgesell, Ahmed Khalil, Arkadiusz Liskiewicz, Gandhari Maity-Kumar, Aaron Novikoff, Gerald Grandl, Daniela Liskiewicz, Callum Coupland, Ezgi Karaoglu, Seun Akindehin, Russell Castelino, Fabiola Curion, Xue Liu, Cristina Garcia-Caceres, Alberto Cebrian-Serrano, Jonathan D. Douros, Patrick J. Knerr, Brian Finan, Richard D. DiMarchi, Kyle W. Sloop, Ricardo J. Samms, Fabian J. Theis, Matthias H. Tschöp and Timo D. Müller, 29 April 2025, Nature Metabolism.
DOI: 10.1038/s42255-025-01294-x