"Activation or Inhibition—Both Work!" Scientists Unravel the Dual Mechanisms Behind GIPR-Mediated Weight Loss

When it comes to weight loss, the "miracle drug" of recent years cannot be ignored.Semaglutide, which belongs to the pancreasHyperglycemiaGlucagon-like peptide-1 receptor (GLP-1R) agonists: GLP-1 is one of the incretin hormones, which can help regulate metabolism and reduce appetite by stimulating insulin secretion, thereby achieving weight loss.

The incretin hormone family can be regarded as a treasure trove in the human fight against obesity. Another member, the glucose-dependent insulinotropic polypeptide receptor (GIPR), has also garnered significant attention as a new target in recent years. For instance, the dual-target anti-obesity drug tirzepatide is a dual agonist of GIPR and GLP-1R.

Interestingly, in the study, scientists found that GIPR is quite a peculiar target because whether it is antagonized or activated, it can lead to weight loss. And although the underlying mechanism pathway remains unclear, the endpoint seems to be consistent.

I really can't figure it out, what exactly is GIPR doing?

The journal *Nature Metabolism* published two papers. The first paper, from the Gutgesell team in Germany [1], revealed that the pathways behind GIPR agonists and antagonists are entirely different: GIPR agonists primarily act on GABAergic neurons, while GIPR antagonists are completely dependent on GLP-1R signaling, with both differing in...Central Nervous SystemThe groups of neurons activated in the system are completely different.

Another paper comes from the Amgen team [2], in which the researchers developed a GIPR-Ab/GLP-1 peptide antibody conjugate drug. This drug can only fully exert its anti-obesity efficacy when both GIPR and GLP-1R are present in the brain, confirming the viewpoint of the previous paper.

The co-agonistic effects of GLP-1R and GIPR have been demonstrated by tirzepatide. Readers who have followed clinical data should know that its anti-obesity effects are quite remarkable. Long-acting GIPR agonists alone can reduce appetite and promote weight loss, and the mechanisms of action of GIPR agonists and GLP-1R agonists do not overlap. When used together, they achieve a synergistic effect where 1+1>2.

Interestingly, GIPR antagonists have also achieved appetite suppression and weight loss effects in experimental animals, and when combined with GLP-1R agonists, the treatment is even more effective. AMG133, a newly announced drug that successfully completed Phase 1 clinical trials and has now entered Phase 2, is a bispecific hybrid antibody capable of simultaneously activating GLP-1R and antagonizing GIPR.

However, we are not very certain about the mechanism behind GIPR antagonism. The Gutgesell team conducted research on the differences between the effects of GIPR agonists and antagonists.

Researchers found that after knocking out GIPR throughout the body of mice, both the anti-obesity effects of GIPR agonists and antagonists disappeared, and drug administration no longer suppressed the mice's intake of a high-fat diet; however, if only the GIPR expressed in central GABAergic neurons was knocked out, GIPR agonists became ineffective, but GIPR antagonists still retained their anti-obesity effects.

However, when GLP-1R was knocked out in mice, the anti-obesity effect of the GIPR antagonist disappeared, indicating that the GIPR antagonistic pathway is dependent on the GLP-1R signaling pathway.

This point can also be confirmed by single-nucleus RNA sequencing results. Sequencing data from nearly 300,000 cells showed that the transcriptional responses induced in the brain by GIPR antagonism and agonism are almost completely opposite. The transcriptional response triggered by GIPR antagonism in the dorsal vagal complex (DVC) of the brainstem is strikingly similar to that induced by GLP-1R agonists, with both regulating gene expression related to synapse formation and neural plasticity. However, this phenomenon seems to be specific to the brainstem and does not hold true in the hypothalamus.

In another study, the Amgen team explored the mechanism behind GIPR-Ab/GLP-1 peptide-antibody conjugates (i.e., AMG133), which can block GIPR and activate GLP-1R, demonstrating effective and well-tolerated anti-obesity effects in mice, monkeys, and humans. This conjugate is based on a fully human anti-GIPR monoclonal antibody (GIPR-Ab) and is conjugated with two GLP-1 analogs.

The researchers found in the experiment that the efficacy of GIPR-Ab/GLP-1 requires the simultaneous presence of GIPR and GLP-1R in the central nervous system, which is consistent with the conclusion of the previous paper. The experimental results showed that GIPR-Ab/GLP-1 mainly exists in the circumventricular organs (CVO), and c-Fos protein can serve as a marker reflecting GIPR-Ab/GLP-1-stimulated neuronal activity.

Anti-obesity drugs have entered a new era, with GIPR and GLP-1R undoubtedly being the superstars in the spotlight. A thorough understanding of the mechanisms behind them will pave the way for the development of new therapies.

References:

[1]Gutgesell, R.M., Khalil, A., Liskiewicz, A. et al. GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice. Nat Metab (2025). https://doi.org/10.1038/s42255-025-01294-x

[2]Liu, C.M., Killion, E.A., Hammoud, R. et al. GIPR-Ab/GLP-1 peptide–antibody conjugate requires brain GIPR and GLP-1R for additive weight loss in obese mice. Nat Metab (2025). https://doi.org/10.1038/s42255-025-01295-w