As a chronic disease, obesity remains a pressing health concern, with close to one billion people living with obesity worldwide. Living with obesity can lead to other health conditions such as type 2 diabetes and heart disease and can negatively impact quality of life. With obesity rates on the rise globally, the time is now to better understand how human biology contributes to this complex disease so we can bring forward innovative treatment solutions that support sustained health and wellbeing.

Several FDA-approved treatments for obesity work by activating glucagon-like peptide 1 (GLP-1) receptors, which reduce food intake [1]. After experiencing an initial weight loss, patients may reach a plateau or regain weight [2]. To address the needs of people with obesity, we must explore underlying mechanisms and expand our understanding of the biology of metabolism. That’s why my colleagues and I are working to discover new pathways that might lead to major developments for patients living with this serious, costly, and life-long disease.

Distinct Design, Biology First and Genetics Informed

Building on our expertise in human genetics and biology and harnessing the large collection of clinical data housed in our subsidiary deCODE genetics, Amgen developed maridebart cafraglutide, or MariTide, as the first and only peptide-antibody conjugate under investigation for the treatment of obesity and related conditions. MariTide was designed to combine GLP-1 receptor agonism with GIPR (glucose-dependent insulinotropic polypeptide receptor) antagonism to deliver a molecule with the ability to engage both pathways. In preclinical studies, MariTide led to decreased body weight and improved metabolic parameters [3]. MariTide went on to show encouraging topline results in weight loss for patients in a 52-week Phase 2 study.

GLP-1 and GIP are incretin hormones that help regulate metabolism by stimulating insulin secretion in response to food intake, and they are involved in appetite regulation. Genome-wide association studies have identified GIPR variants associated with reduced activity that correlate with lower body mass index in humans [4]. Preclinical studies further demonstrate that genetic or pharmacological inhibition of GIPR prevents weight gain and leads to weight loss, supporting its role in body weight regulation [5].

Previously, we investigated the use of an anti-GIPR antibody and how it could be incorporated into a novel multi-specific molecule for obesity. MariTide is the result of our dedicated pursuit to find a peptide-antibody conjugate uniquely able to harness both GLP-1 agonism and GIPR antagonism. The antibody functions as a GIPR antagonist, blocking GIP signaling, while the GLP-1 agonist peptides activate the GLP-1 receptor [3].

The Role of a Dual Mechanism Molecule that Accesses the Brain and Reduces Weight in Mice with Obesity

In pursuit of key scientific questions, we reached out to Dan Drucker's laboratory, recognizing that his team had developed and characterized central nervous system (CNS)-specific GLP-1 receptor knockout mice—an ideal model for investigating the role of central GLP-1 signaling in MariTide’s mechanism of action. Following an initial call, we rapidly established a close collaboration, principal investigators and post-docs, and together authored this paper, Dan, Rola, Clarissa, and myself. Together, we reviewed the data, exchanged insights, and co-developed our interpretations. Collaborations like this are deeply motivating, as they bring together academic and industry expertise in a shared effort to advance our understanding of the molecule’s mechanism of action.

In the publication, “GIPR-Ab/GLP-1 peptide–antibody conjugate requires brain GIPR and GLP-1R for additive weight loss in obese mice” we explore the ways these hormone receptors and their presence in the CNS play a crucial role in weight regulation [6].  Research shows that GLP-1 and GIP bind to receptors in several areas of the brain and engage circuits that affect appetite and food intake. Building on that understanding, in preclinical models, we identified CNS sites directly and indirectly activated by an anti-GIPR antibody/GLP-1R agonist peptide-antibody conjugate and sought to examine the full contribution of both CNS GLP-1 and GIP receptors on weight loss and metabolic parameters.

In this preclinical study, we examined: (1) the brain distribution of the GIPR-Ab/GLP-1 peptide-antibody conjugate, (2) its effects on downstream neuronal activation, and (3) the requirement for intact CNS GIPR and GLP-1R signaling to achieve maximal weight loss.

1. We showed that mGIPR-Ab was detected in circumventricular organs (CVOs) in the brain, including the median eminence at the base of the hypothalamus and the area postrema in the hind brain. Biodistribution of mGIPR-Ab was consistent across mice and was significant in comparison to mice treated without antibodies.
2. Although mGIPR-Ab was primarily seen in CVOs, c-Fos activation was seen in multiple neural substrates involved in food intake control. c-Fos is a protein used as a marker of neuronal activity to show responsiveness to the mGIPR-Ab.
3. Finally, we showed that both the GIPR and GLP-1R in the CNS are essential for maximizing weight loss following the GIPR-Ab/GLP-1 peptide-antibody conjugate administration. Deletion of GIPR in the CNS combined with GLP-1 agonist treatment led to diminished weight loss effect, further illustrating both receptors are needed for greater weight loss results.

Understanding the roles of GIP and GLP-1 pathways in the CNS is a paradigm shift in the understanding of mechanisms that contribute to obesity and potentially the medications we use to treat it. The mGIPR-Ab/GLP-1 conjugate we used in this preclinical study proved to be active in the brain, and when administered directly to the brain, mGIPR-Ab effectively reduced body weight and food intake. These findings are significant and support the hypothesis that both CNS GIPR and GLP-1R are essential for maximum weight loss.

This is a particularly exciting insight—it not only reinforces the importance of central GIPR and GLP-1R in regulating energy balance but also opens the door to designing next-generation therapeutics that target these pathways.

Obesity is a complex biological disease and a root cause of many other conditions and diseases. Managing obesity is key to making strides to improve related conditions as well. As we work towards this goal, we can build upon the knowledge gained in this study to further our exploration of GIPR/GLP-1 pathways in the brain and their downstream effects on weight management.

References:

[1] Drucker, D. J. (2018). Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metabolism, 27(4), 740–756. https://doi.org/10.1016/j.cmet.2018.03.001

[2] Ard, J., Fitch, A., Fruh, S., & Herman, L. (2021). Weight Loss and Maintenance Related to the Mechanism of Action of Glucagon-Like Peptide 1 Receptor Agonists. Advances in Therapy, 38(6), 2821–2839. https://doi.org/10.1007/s12325-021-01710-0

[3] Véniant, M. M., Lu, S.-C., Atangan, L., Komorowski, R., Stanislaus, S., Cheng, Y., Wu, B., Falsey, J. R., Hager, T., Thomas, V. A., Ambhaikar, M., Sharpsten, L., Zhu, Y., Kurra, V., Jeswani, R., Oberoi, R. K., Parnes, J. R., Honarpour, N., Neutel, J., & Strande, J. L. (2024). A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings. Nature Metabolism, 6(2), 290–303. https://doi.org/10.1038/s42255-023-00966-w

[4] Berndt, S. I., Gustafsson, S., Mägi, R., Ganna, A., Wheeler, E., Feitosa, M. F., Justice, A. E., Monda, K. L., Croteau-Chonka, D. C., Day, F. R., Esko, T., Fall, T., Ferreira, T., Gentilini, D., Jackson, A. U., Luan, J., Randall, J. C., Vedantam, S., Willer, C. J., & Winkler, T. W. (2013). Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. Nature Genetics, 45(5), 501–512. https://doi.org/10.1038/ng.2606

[5] Killion, E. A., Wang, J., Yie, J., Shi, S. D.-H. ., Bates, D., Min, X., Komorowski, R., Hager, T., Deng, L., Atangan, L., Lu, S.-C., Kurzeja, R. J. M., Sivits, G., Lin, J., Chen, Q., Wang, Z., Thibault, S. A., Abbott, C. M., Meng, T., & Clavette, B. (2018). Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models. Science Translational Medicine, 10(472), eaat3392. https://doi.org/10.1126/scitranslmed.aat3392

[6] Liu, C. M., Killion, E. A., Hammoud, R., Lu, S.-C., Komorowski, R., Liu, T., Kanke, M., Thomas, V. A., Cook, K., Sivits, G. N., Ben, A. B., Atangan, L. I., Hussien, R., Tang, A., Shkumatov, A., Li, C.-M., Drucker, D. J., & Véniant, Murielle M. (2025). GIPR-Ab/GLP-1 peptide–antibody conjugate requires brain GIPR and GLP-1R for additive weight loss in obese mice. Nature Metabolism, 1–16. https://doi.org/10.1038/s42255-025-01295-w