Researchers at the University of Cambridge have identified why two opposing approaches to targeting the glucose-dependent insulinotropic polypeptide receptor (GIPR) can each produce weight loss. The findings, published in Nature Metabolism, emerge from studies conducted in genetically engineered mice designed to help researchers understand how various obesity medications function in the brain.
Obesity affects more than a billion people globally and significantly increases the risk of serious health conditions including type 2 diabetes, cardiovascular disease, and certain cancers. While weight loss can reduce these health risks, achieving substantial reductions through conventional diet and exercise methods often proves challenging. Contemporary weight loss medications work by targeting specific brain receptors involved in appetite regulation, with some of the most widely prescribed treatments including Wegovy and Ozempic, which activate the GLP-1 receptor. Other medications activate or block GIPR, a receptor whose dual functionality had puzzled scientists.
The research team used mice in which GIPR was selectively removed from specific brain regions to track how different treatments affected appetite and weight. When GIPR was activated in the brainstem, the region responsible for appetite and nausea regulation, appetite decreased and body weight declined. Conversely, blocking GIPR in the hypothalamus, which controls hunger and body weight regulation, also produced weight loss but through a distinct mechanism. In the hypothalamus, GIPR appeared to function as a regulatory brake on fullness signals; blocking it allowed these satiety signals to operate more powerfully.
The findings suggest opportunities for developing more targeted and potent drug combinations. Medications like MariTide combine GIPR antagonism with GLP-1 receptor activation, leveraging both pathways. Researchers also identified evidence that blocking GIPR could potentially enhance the effectiveness of drugs targeting the amylin receptor, indicating broader possibilities for combination therapies. Dr. Jo Lewis, the study’s lead author, emphasized that these discoveries highlight the brain’s central role in obesity treatment and could guide the development of medications with improved efficacy and fewer adverse effects.
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