Scientists explain why activating and blocking the same brain receptor both trigger weight loss
Cambridge researchers using mice have found that a receptor called GIPR causes weight loss through opposite mechanisms depending on which brain region it acts on. The discovery could help design more effective obesity treatments that work well in combination.
Researchers at the University of Cambridge's Institute of Metabolic Science have resolved a puzzle surrounding obesity drugs: why both activating and blocking the same receptor, GIPR, can lead to weight loss. The mouse study was published in the journal Nature Metabolism.
More than a billion people worldwide live with obesity, a condition linked to higher risks of type 2 diabetes, cardiovascular disease and cancer. In recent years, a new generation of medications acting on appetite-related receptors has emerged. Some, like Wegovy and Ozempic, activate the GLP-1 receptor, while others also act on a second receptor, GIPR.
That second target created an odd contradiction: drugs such as Mounjaro and Zepbound activate GIPR, while others, including MariTide, block it — yet both approaches promote weight loss.
Two different brain pathways
To investigate, the researchers used genetically engineered mice lacking GIPR either in the brainstem or in the hypothalamus, alongside normal mice as controls. The animals received various combinations of a GIPR activator, a GIPR blocker and a GLP-1 drug, while scientists tracked food intake, body weight, fat mass, blood sugar control and brain activity.
The results showed that GIPR activators work mainly through the brainstem, reducing appetite. GIPR blockers, however, act through the hypothalamus, where the receptor normally functions as a kind of brake limiting how strongly the brainstem responds to fullness signals. Blocking the receptor releases that brake, allowing fullness signals to have a stronger effect.
The team also found that blocking GIPR could enhance the effects of emerging amylin receptor-targeting medicines and improve outcomes when combined with GLP-1 drugs. This helps explain the effectiveness of MariTide, currently in phase 3 clinical trials, which combines GIPR blocking with GLP-1 receptor activation.
Dr. Jo Lewis, the study's first author, said understanding which brain circuits respond to these medications could help design better drugs with more weight loss, fewer side effects, and stronger effects when combined with other obesity treatments. The research was funded by the Medical Research Council and Wellcome.
