GIPR weight loss drugs act through separate brain circuits, mouse study finds
Cambridge researchers say opposing GIPR drug strategies reduce weight in mice by acting in different parts of the brain.
By Priya Raghavan · Science Reporter
3 min read
GIPR weight loss drugs that appear to work in opposite ways may reduce weight through different brain circuits, according to University of Cambridge researchers. The mouse study, published in Nature Metabolism, could help explain why some obesity medicines activate the GIP receptor while others block it.
The finding matters because newer obesity treatments increasingly combine targets involved in appetite and metabolism. Cambridge said the results point to the brainstem and hypothalamus as separate sites where GIPR-based drugs can influence eating and body weight.
More than 1 billion people worldwide live with obesity, which raises the risk of type 2 diabetes, cardiovascular disease and cancer, according to Cambridge. Weight loss can reduce those risks, but diet and exercise alone are often difficult to sustain.
How do GIPR weight loss drugs work in the brain?
GIPR stands for glucose-dependent insulinotropic polypeptide receptor, a protein receptor targeted by some anti-obesity medicines. In the Cambridge study, activating GIPR reduced appetite through the brainstem, while blocking GIPR promoted weight loss through the hypothalamus.
The brainstem sits at the base of the brain and is involved in appetite and nausea, according to the researchers. The hypothalamus is a key control center for hunger and body weight.
Several drugs used or studied for obesity act on the GLP-1 receptor, including Wegovy and Ozempic, Cambridge said. Other medicines target both GLP-1R and GIPR: Mounjaro and Zepbound stimulate GIPR, while MariTide blocks it.
That split has raised a basic scientific problem: why would turning the same receptor on and shutting it off both be linked to weight loss? Cambridge researchers said their experiments show the answer depends on where in the brain the receptor is being targeted.
What the mouse study tested
The research team used genetically engineered mice in which GIPR was removed from specific brain areas. One group lacked the receptor in the brainstem, another lacked it in the hypothalamus, and a control group had no such modification.
The mice were then given different combinations of a GIPR agonist, which activates the receptor; a GIPR antagonist, which blocks it; and a GLP-1-based drug. Researchers measured food intake, body weight, fat mass, glucose control and brain activity.
By comparing the groups, the team found that GIPR agonists needed the brainstem to curb eating and reduce weight. GIPR antagonists instead worked through the hypothalamus, where Cambridge said blocking the receptor removed a restraint on the brainstem’s response to fullness signals.
The researchers also reported that blocking GIPR seemed to strengthen the effect of drugs aimed at the amylin receptor, another target being studied for obesity treatment. Cambridge said that suggests GIPR antagonists may be useful in combination with more than one class of anti-obesity medicine.
What it could mean for obesity medicines
Cambridge said the results help explain why MariTide, now in phase 3 clinical trials and designed to combine GIPR antagonism with GLP-1 receptor agonism, can be effective. The study does not report a human trial; its evidence comes from experiments in mice.
Dr. Jo Lewis, first author of the study at Cambridge’s Institute of Metabolic Science, said understanding the brain circuits involved could support drugs that produce greater weight loss with fewer side effects and work better alongside other obesity medicines. Lewis also said the work supports the view that obesity drugs act on identifiable brain circuits controlling appetite and food intake, rather than only on the gut or pancreas.
This story draws on original reporting from Medical Xpress.