Cambridge study maps how opposite GIP receptor actions in brainstem and hypothalamus both drive weight loss

Researchers at the University of Cambridge have identified why both activating and blocking the glucose-dependent insulinotropic polypeptide receptor (GIPR) can reduce body weight in mice. The study, published in Nature Metabolism, shows that the two approaches act through separate brain regions and distinct mechanisms.

More than a billion people worldwide live with obesity, which increases the risk of type 2 diabetes, cardiovascular disease and cancer. Current medications such as Wegovy and Ozempic target the GLP-1 receptor, while others including Mounjaro and Zepbound activate GIPR and MariTide blocks it. Until now it was unclear why opposite actions on the same receptor could produce similar weight-loss outcomes.

Using genetically engineered mice that lacked GIPR in specific brain areas, the team tested a GIPR agonist, a GIPR antagonist and a GLP-1 drug, alone and in combination. Mice without GIPR in the brainstem did not lose weight when given the agonist, indicating that activating the receptor in this region reduces appetite and drives weight loss.

In contrast, mice lacking GIPR in the hypothalamus did not respond to the antagonist. The researchers found that in the hypothalamus GIPR normally acts as a brake that dampens the brainstem's response to fullness signals. Blocking the receptor releases this brake, allowing satiety signals to have a stronger effect.

The study also showed that GIPR antagonism can enhance the weight-loss effects of GLP-1-based drugs and of emerging amylin-receptor treatments. MariTide, which combines GIPR antagonism with GLP-1 receptor agonism, is currently in phase 3 clinical trials.

Dr Jo Lewis, first author from the Institute of Metabolic Science, said understanding the distinct brain circuits could help design drugs that achieve greater weight loss with fewer side effects and that work better in combination with other obesity medicines. The research was funded by the Medical Research Council and Wellcome.