A brain switch discovery could improve obesity drugs by explaining why activating and blocking the same receptor can both aid weight loss.
Research in mice found that the outcome depends on where the receptor is located in the brain.
Activating it in the brainstem reduced appetite, while blocking it in the hypothalamus produced the same effect by acting on a different part of the brain.
Scientists at the University of Cambridge said the findings could help improve obesity treatments.
Dr Jo Lewis, the study’s first author from the Institute of Metabolic Science at the University of Cambridge, said: “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.”
More than one billion people worldwide are living with obesity, which raises the risk of conditions including type 2 diabetes, cardiovascular disease and cancer.
A newer generation of weight-loss medicines targets receptors in the brain to curb appetite, promote weight loss and help regulate blood sugar.
Medicines including Wegovy and Ozempic stimulate the glucagon-like peptide 1 receptor, known as GLP-1R. This protein acts like a switch that affects appetite and blood sugar regulation.
Other treatments target both GLP-1R and the glucose-dependent insulinotropic polypeptide receptor, known as GIPR.
However, drugs including Mounjaro and Zepbound activate GIPR, while treatments such as MariTide block it. Scientists have previously been unable to explain why both approaches can reduce weight.
Researchers at the Institute of Metabolic Science used genetically engineered mice to investigate which areas of the brain were responsible for the effects.
Their findings also showed that both types of GIPR drug can boost weight loss when combined with certain GLP-1-based treatments.
One group 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 the receptor in the hypothalamus, a part of the brain that helps control hunger and body weight. A third group consisted of unmodified mice.
The animals received different combinations of a GIPR agonist, which activates the receptor, a GIPR antagonist, which blocks it, and a GLP-1-based treatment.
Researchers then measured food intake, body weight, fat mass, blood sugar control and brain activity.
The results showed that GIPR agonists work in the brainstem to reduce appetite and weight.
GIPR antagonists were found to act in the hypothalamus by releasing a biological “brake” that limits the brainstem’s response to signals of fullness.
Blocking the receptor also appeared to boost the effects of emerging medicines targeting the amylin receptor, suggesting GIPR antagonists could strengthen several types of obesity treatment.
The findings help explain why MariTide, which combines blocking GIPR with activating GLP-1R, can support weight loss. The treatment is undergoing phase 3 clinical trials.
Researchers said understanding the separate brain pathways could help guide the design of more effective combination treatments.
