Cambridge scientists have solved the mystery of why both stimulating and blocking a particular 'switch' in the brain can help people lose weight – findings which could help boost the effectiveness of obesity drugs.

Published today in Nature Metabolism, the study in mice shows that the answer lies in where the switch is located: stimulating the switch in the brainstem suppresses appetite, while the same effect can be achieved by blocking the switch in the hypothalamus.

More than a billion people worldwide are living with obesity, which increases the risk of diseases such as 2 diabetes, cardiovascular disease and cancer. Weight loss can help mitigate these complications, but losing weight through diet and exercise alone can prove challenging.

In the past few years, a new generation of weight loss drugs has emerged that target particular receptors in the brain, reducing appetite and leading to weight loss, as well as helping control blood sugar levels. Several 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 one, the glucose-dependent insulinotropic polypeptide receptor (GIPR). However, some of these drugs, such as Mounjaro and Zepbound, stimulate GIPR, while others, such as MariTide, block it. Why these opposite actions have the same result has puzzled scientists.

Now, researchers at the Institute of Metabolic Science, University of Cambridge, have used mice to solve the puzzle, showing that the two different types of GIPR drugs act on distinct regions of the brain – but also that they can boost weight loss when combined with certain GLP-1-based weight-loss drugs.

The team used genetically engineered mice and selectively removed GIPR from different parts of the brain to see which regions were responsible for the effects of the obesity drugs. One group of mice lacked GIPR in the brainstem – the area at the base of the brain, just above the spinal cord, involved in appetite and nausea. A second group lacked GIPR in the hypothalamus, a major centre controlling hunger and body weight. The third, control group were normal, unmodified mice.

The researchers then treated these mice with various combinations of a GIPR agonist (which activates the receptor), a GIPR antagonist (which blocks the receptor) and a GLP-1 drug, and measured food intake, body weight, fat mass, glucose control and brain activity.

By comparing the responses of normal mice with mice lacking GIPR in different brain areas, they showed that GIPR agonists act on the brainstem to suppress appetite and reduce weight.

They then showed that GIPR antagonists help weight loss by acting on this receptor, but in the hypothalamus, where they release a 'brake' that otherwise limits the brainstem's ability to respond to signals telling us we are full. Blocking GIPR also appeared to boost the effect of emerging new drugs targeting the amylin receptor, suggesting that GIPR antagonists could potentially be used to strengthen several types of anti-obesity medicines.

The findings explain why drugs such as MariTide, currently in phase 3 clinical trials, which combines GIPR antagonism with GLP-1 receptor agonism, are effective, and suggests how to design even better combination therapies.

Understanding which brain circuits respond to these medications – and how they do so – could help us design better drugs that produce more weight loss with fewer side effects, and which might work in combination with other obesity medicines to even greater effect.

Our work also strengthens the idea that the brain is central to obesity treatment. Obesity drugs are not acting simply on the gut or pancreas. Instead, they have important effects on specific, identifiable brain circuits that regulate appetite and food intake."

Dr. Jo Lewis, study's first author, Institute of Metabolic Science, University of Cambridge

The research was funded by the Medical Research Council and Wellcome.

Source:

Journal reference:

Lewis, J. E., et al. (2026). Distinct brain regions mediate regulation of food intake in response to GIPR agonism or antagonism. Nature Metabolism. DOI: 10.1038/s42255-026-01575-z. https://www.nature.com/articles/s42255-026-01575-z