Cambridge researchers have uncovered why both activating and blocking the same brain receptor can promote weight loss. The findings may help scientists develop obesity treatments that are more effective and potentially work better in combination.
The mouse study, published in Nature Metabolism, found that the outcome depends on which part of the brain is targeted. Activating the receptor in the brainstem reduced appetite, while blocking the same receptor in the hypothalamus produced a similar weight loss effect through a different mechanism.
More than a billion people around the world are living with obesity, a condition that raises the risk of diseases including type 2 diabetes, cardiovascular disease and cancer. Losing weight can reduce some of these risks, but achieving substantial weight loss through diet and exercise alone can be difficult.
How Modern Weight Loss Drugs Target the Brain
A new generation of weight loss medications has emerged in recent years that act on specific receptors involved in appetite. By influencing these receptors, the drugs can reduce food intake, promote weight loss, and help regulate blood sugar.
Several widely used medications, including Wegovy and Ozempic, activate a protein receptor called the glucagon-like peptide 1 receptor (GLP-1R).
Other obesity treatments act on both GLP-1R and another receptor known as the glucose-dependent insulinotropic polypeptide receptor (GIPR). This second target has presented scientists with an unusual puzzle.
Some medications, including Mounjaro and Zepbound, activate GIPR. Others, such as MariTide, block it. Despite producing opposite effects on the same receptor, both approaches can help promote weight loss.
Researchers at the Institute of Metabolic Science, University of Cambridge, set out to understand why. Their experiments in mice revealed that the two types of GIPR drugs work through different regions of the brain. The researchers also found that these approaches can increase weight loss when paired with certain GLP-1-based weight loss medicines.
Tracking GIPR Activity in Different Brain Regions
To identify the brain regions responsible for these effects, the team used genetically engineered mice in which GIPR had been selectively removed from specific areas.
One group lacked GIPR in the brainstem, the region at the base of the brain just above the spinal cord that is involved in appetite and nausea. Another group lacked the receptor in the hypothalamus, an important brain region involved in regulating hunger and body weight. A third group consisted of normal, unmodified mice that served as controls.
The scientists treated the animals with different combinations of a GIPR agonist (which activates the receptor), a GIPR antagonist (which blocks the receptor) and a GLP-1 drug. They then monitored food consumption, body weight, fat mass, blood sugar control and brain activity.
Comparing the different groups allowed the team to pinpoint where each treatment was acting.
The results showed that GIPR agonists primarily work through the brainstem. Activating GIPR in this region reduced appetite and led to lower body weight.
Blocking a Brain Brake on Fullness
GIPR antagonists followed a different route.
Instead of acting primarily through the brainstem, the researchers found that blocking GIPR promoted weight loss through the hypothalamus. In this region, GIPR appears to function as a kind of ‘brake’ that limits how strongly the brainstem responds to signals indicating that the body is full.
Blocking the receptor effectively releases that ‘brake’, allowing fullness signals to have a stronger effect.
The researchers also found evidence that blocking GIPR could enhance the effects of emerging medicines that target the amylin receptor. This suggests that GIPR antagonists might eventually be useful for strengthening several different classes of obesity treatments.
Clues to More Powerful Obesity Drug Combinations
The results help explain why treatments such as MariTide can be effective. MariTide, currently in phase 3 clinical trials, combines GIPR antagonism with GLP-1 receptor agonism.
Understanding how these separate pathways interact could also help researchers design more effective combinations of obesity medicines in the future.
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.”
The research was funded by the Medical Research Council and Wellcome.
