Weight-loss drugs are becoming more sophisticated, with newer treatments targeting several of the body’s appetite and blood sugar signals at once. But one part of that science has been difficult to explain: Some drugs appear to help by activating a particular receptor, while others may work by blocking it.
A new mouse study suggests those opposite strategies may affect different parts of the brain. Activating the receptor appeared to suppress appetite through the brainstem, while blocking it may strengthen fullness signals through the hypothalamus.
The findings could help researchers better understand how future obesity drugs might be combined or refined. But the study did not test whether either approach leads to greater weight loss, fewer side effects or better outcomes in people.
The research, conducted at the University of Cambridge and published in Nature Metabolism, focused on a receptor known as GIPR. It responds to GIP, a hormone involved in blood sugar control and appetite.
GIPR has become an important target in obesity treatment. Tirzepatide, sold as Mounjaro for type 2 diabetes and Zepbound for weight management, activates both GIP and GLP-1 receptors. Other drugs under development take the opposite approach by combining GLP-1 receptor activation with GIP receptor blocking.
That raised a basic question: How could activating and blocking the same receptor both help reduce food intake and body weight?
To investigate, the researchers used genetically engineered mice that lacked GIP receptors in selected parts of the brain. They then tested drugs that either activated or blocked the receptor, alone and in combination with a GLP-1 drug.
The results suggested the two strategies work through different brain regions.
Activating GIP receptors reduced appetite mainly through the brainstem, which helps process signals related to food intake, nausea and fullness.
Blocking the receptors appeared to work through the hypothalamus, a region that helps regulate hunger and body weight. The researchers believe blocking GIP activity there may remove a signal that otherwise limits the brain’s response to fullness cues.
Put simply, activating the receptor in one part of the brain may send a stronger signal to stop eating. Blocking it in another may help other appetite-control signals work more effectively.
The study also found that blocking GIP receptors strengthened the response to cagrilintide, an experimental drug that targets the amylin system. Amylin is a hormone released after eating that helps regulate fullness and how quickly food leaves the stomach.
That finding suggests GIP-blocking drugs might eventually be paired with more than one kind of obesity medication. But the study was designed to examine brain pathways in mice, not to determine whether a new drug combination would be safe or effective in patients.
“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,” said Dr. Jo Lewis, the study’s first author from the University of Cambridge’s Institute of Metabolic Science.
The findings also add to growing evidence that obesity medications do not act only through the digestive system or pancreas. They can affect specific brain circuits involved in hunger, fullness and food intake.
“Our work also strengthens the idea that the brain is central to obesity treatment,” Lewis said. “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.”
Still, the research does not show that activating GIP receptors is better than blocking them, or vice versa. Mice do not always respond to appetite-related drugs in the same way people do, and the study did not compare long-term weight loss, side effects or health outcomes in patients.
It also does not fully explain how existing or experimental obesity drugs work throughout the body. These medications can affect several organs, hormones and brain pathways at once.
For now, the study offers a possible explanation for a question that has puzzled researchers: Opposite actions at the same receptor may lead to similar results because they are working in different parts of the brain.
The research was supported by the U.K. Medical Research Council, Wellcome Trust, a Marie Skłodowska-Curie fellowship, a Gates studentship and a doctoral training studentship. University of Cambridge metabolic research facilities also received support from the Medical Research Council and Wellcome Trust.
One author reported consulting for Antag and Roche. The Gribble-Reimann laboratory hosts projects funded by AstraZeneca and previously received funding from Eli Lilly and Company. Two authors received sponsorship from AstraZeneca, Eli Lilly and Company, Mercodia and Sun Pharma to host a 2024 scientific meeting. Three authors are co-founders and shareholders in Volari Therapeutics. Two reported unrelated research funding from Eli Lilly and Company.