GIPR-Ab/GLP-1 peptide–antibody conjugate requires brain GIPR and GLP-1R for additive weight loss in obese mice
Glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide 1 receptor (GLP-1R) are expressed in the central nervous system (CNS) and regulate food intake. Here, we demonstrate that a peptide-antibody conjugate that blocks GIPR while simultaneously activating GLP-1R (GIPR-Ab/GLP-1) requires both CNS GIPR and CNS GLP-1R for maximal weight loss in obese, primarily male, mice. Moreover, dulaglutide produces greater weight loss in CNS GIPR knockout (KO) mice, and the weight loss achieved with dulaglutide + GIPR-Ab is attenuated in CNS GIPR KO mice. Wild-type mice treated with GIPR-Ab/GLP-1 and CNS GIPR KO mice exhibit similar changes in gene expression related to tissue remodelling, lipid metabolism and inflammation in white adipose tissue and liver. Moreover, GIPR-Ab/GLP-1 is detected in circumventricular organs in the brain and activates c-FOS in downstream neural substrates involved in appetite regulation. Hence, both CNS GIPR and GLP-1R signalling are required for the full weight loss effect of a GIPR-Ab/GLP-1 peptide-antibody conjugate.
Authors
- Matt Kanke (ORCID: https://orcid.org/0000-0002-7227-3054)
- Shu-Chen Lu (ORCID: https://orcid.org/0009-0003-7113-3185)
- Murielle M. Véniant (ORCID: https://orcid.org/0000-0002-1881-8252)
- Veena A. Thomas (ORCID: https://orcid.org/0000-0002-5202-6697)
- Larissa Atangan
- Artem Shkumatov
- Chi-Ming Li
- Rajaa Hussien (ORCID: https://orcid.org/0000-0001-5741-4915)
- Daniel J. Drucker (ORCID: https://orcid.org/0000-0001-6688-8127)
- Glenn Sivits (ORCID: https://orcid.org/0000-0002-9621-5449)
- Rola Hammoud (ORCID: https://orcid.org/0009-0003-7184-1050)
- Clarissa M. Liu
- Renée Komorowski (ORCID: https://orcid.org/0000-0002-6233-4036)
- Kevin D. Cook (ORCID: https://orcid.org/0000-0003-3079-4174)
- Elizabeth A. Killion (ORCID: https://orcid.org/0000-0002-9321-3886)
- Tongyu Liu (ORCID: https://orcid.org/0000-0002-8579-2144)
- Amy Tang
- Aerielle B Ben
Institutions
- Amgen (United States) (US)
- Lunenfeld-Tanenbaum Research Institute (CA)
- Bioanalytica (Switzerland) (CH)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2025-04-29
- DOI
- https://doi.org/10.1038/s42255-025-01295-w
- Citations
- 14
- Primary Topic
- Diabetes Treatment and Management
- Type
- article
- Field-Weighted Citation Impact
- 18.13
Funders
- Amgen
- Novo Nordisk
- Canadian Institutes of Health Research
- Banting and Best Diabetes Centre, University of Toronto
- CIHR Skin Research Training Centre