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.
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