Cambridge scientists solve brain switch mystery behind weight loss

Cambridge researchers have discovered why both activating and blocking the same brain receptor can lead to weight loss, according to a mouse study published in Nature Metabolism on August 15, 2026. The effect depends on which brain region is targeted: activating the receptor in the brainstem reduces appetite, while blocking it in the hypothalamus promotes weight loss through a different mechanism.

More than a billion people worldwide live with obesity, which raises the risk of type 2 diabetes, cardiovascular disease and cancer. Losing weight can lower some of these risks, but achieving substantial weight loss through diet and exercise alone is often difficult. A new generation of weight loss drugs acts on specific receptors involved in appetite, reducing food intake and helping regulate blood sugar.

Several widely used medications, including Wegovy and Ozempic, activate the glucagon-like peptide 1 receptor (GLP-1R). Other treatments act on both GLP-1R and the glucose-dependent insulinotropic polypeptide receptor (GIPR). Some drugs, such as Mounjaro and Zepbound, activate GIPR, while others, like MariTide, block it. Despite opposite effects on the same receptor, both approaches can promote weight loss.

Researchers at the Institute of Metabolic Science, University of Cambridge, used genetically engineered mice with GIPR removed from specific brain areas. One group lacked the receptor in the brainstem, another in the hypothalamus, and a third group of normal mice served as controls. The scientists treated the animals with combinations of a GIPR agonist, a GIPR antagonist and a GLP-1 drug, then monitored food consumption, body weight, fat mass, blood sugar control and brain activity.

The results showed that GIPR agonists primarily work through the brainstem, reducing appetite and body weight. GIPR antagonists, in contrast, promote weight loss through the hypothalamus, where GIPR acts as a brake limiting the brainstem's response to fullness signals. Blocking the receptor releases that brake, strengthening fullness signals. The researchers also found evidence that blocking GIPR could enhance the effects of emerging medicines targeting the amylin receptor, suggesting GIPR antagonists might strengthen several classes of obesity treatments.

The findings help explain why treatments such as MariTide, currently in phase 3 clinical trials combining GIPR antagonism with GLP-1 receptor agonism, can be effective. Dr. Jo Lewis, the study's first author from the Institute of Metabolic Science, said understanding which brain circuits respond to these medications could help design better drugs with more weight loss and fewer side effects. The research was funded by the Medical Research Council and Wellcome.