Cambridge scientists have solved the mystery of why both stimulating and blocking specific ‘switches’ in the brain can help people lose weight. The discovery could help improve the effectiveness of obesity drugs.
Published today is natural metabolismStudies using mice show that the answer lies in the position of the switch. Stimulating a switch in the brainstem suppresses appetite, while blocking a switch in the hypothalamus can achieve the same effect.
More than 1 billion people worldwide live with obesity, which increases the risk of diseases such as diabetes, cardiovascular disease, and cancer. Weight loss can help reduce these complications, but it can be difficult to lose weight through diet and exercise alone.
In recent years, a new generation of weight loss drugs has emerged that target specific receptors in the brain, reducing appetite, resulting in weight loss, and helping to control blood sugar levels. Some of these, such as Wegovy and Ozempic, work by stimulating a protein “switch” known as the glucagon-like peptide 1 receptor (GLP-1R).
Other weight loss drugs act on both this receptor and a second receptor, the glucose-dependent insulinotropic polypeptide receptor (GIPR). However, some of these drugs, such as Mounjaro and Zepbound, stimulate the GIPR, while others, such as MariTide, block the GIPR. Scientists are puzzled as to why these opposite actions produce the same results.
Now, researchers at the University of Cambridge’s Institute of Metabolic Sciences have solved this puzzle in mice, showing that two different GIPR drugs act on different areas of the brain. They also showed that weight loss can be promoted when combined with certain GLP-1-based weight loss drugs.
The research team used genetically engineered mice to selectively remove GIPR from different parts of the brain to determine which regions are involved in the effects of obesity drugs. One group of mice lacked GIPR in the brainstem, an area at the base of the brain just above the spinal cord that is involved in appetite and nausea. The second group lacked GIPR in the hypothalamus, a key center that controls hunger and weight. The third control group was normal, unmodified mice.
The researchers then treated these mice with various combinations of GIPR agonists (which activate the receptor), GIPR antagonists (which block the receptor), and GLP-1 drugs, and measured food intake, body weight, fat mass, glucose control, and brain activity.
By comparing the responses of different brain regions in normal and GIPR-deficient mice, researchers showed that GIPR agonists act on the brainstem to suppress appetite and reduce body weight.
They then showed that GIPR antagonists help people lose weight by acting on this receptor, but they also release a “brake” in the hypothalamus, limiting the brainstem’s ability to respond to satiety signals. Inhibiting GIPR also appears to enhance the efficacy of new drugs targeting amylin receptors, suggesting that GIPR antagonists could be used to potentiate several anti-obesity drugs.
The findings explain why drugs such as MariTide, currently in phase 3 clinical trials, which combine GIPR antagonism and GLP-1 receptor agonism, are so effective and suggest ways to design better combination therapies.
Understanding which brain circuits respond to these drugs and how they respond could help design better drugs that produce more weight loss with fewer side effects, and may have even greater effects when combined with other obesity drugs.
Our study also strengthens the idea that the brain is central to obesity treatment. Obesity drugs don’t just affect the intestines and pancreas. Rather, it has important effects on specific, identifiable brain circuits that regulate appetite and food intake. ”
Dr Joe Lewis, lead author of the study, Institute of Metabolic Sciences, University of Cambridge
This research was funded by the Medical Research Council and Wellcome.
sauce:
Reference magazines:
Lewis, J.E.; others. (2026). Different brain regions mediate the regulation of food intake in response to GIPR agonism or antagonism. natural metabolism. DOI: 10.1038/s42255-026-01575-z. https://www.nature.com/articles/s42255-026-01575-z
