A newly published animal study explains why both stimulating and blocking the same receptor can lead to weight loss, while other research explores methods to mitigate common side effects of popular weight-loss medications. The findings were presented at the Society for Neuroscience meeting in San Diego and published in the journal Nature Metabolism.
Understanding GIPR Drug Mechanisms
A study published in Nature Metabolism on March 17, 2025, by researchers at the University of Cambridge investigated the function of drugs that target the glucose-dependent insulinotropic polypeptide receptor (GIPR).
"GIPR agonists reduce appetite by acting on GIPR in the brainstem. Conversely, GIPR antagonists achieve appetite suppression by blocking GIPR in the hypothalamus."
The study, conducted in mice, found that GIPR agonists reduce appetite by acting on GIPR in the brainstem. Conversely, GIPR antagonists achieve appetite suppression by blocking GIPR in the hypothalamus, which removes a brake on satiety signals originating in the brainstem.
These findings provide a mechanistic explanation for drugs such as MariTide, which combines GIPR antagonism with GLP-1 receptor agonism. The researchers also suggested that GIPR antagonists could potentially enhance the effects of other anti-obesity drugs that target the amylin receptor. The research was funded by the Medical Research Council and Wellcome.
Addressing Side Effects of GLP-1 Agonists
Separate research presented at a Society for Neuroscience meeting in San Diego focused on mitigating adverse effects associated with GLP-1 receptor agonists, a class of drugs that includes medications used for weight reduction. A common side effect leading to patient discontinuation is severe nausea and vomiting.
Investigating Nausea and Emesis
Warren Yacawych's team at the University of Michigan conducted research aimed at modifying GLP-1 drugs to suppress appetite without causing gastrointestinal discomfort. Their investigation focused on two brain stem regions affected by GLP-1 drugs: the emetic center, which coordinates nausea and vomiting responses, and an area that monitors food intake and signals satiety.
The team attempted to direct GLP-1 primarily to the satiety center while minimizing its influence on the emetic center in mice. This approach prevented sickness but also inhibited weight loss, suggesting that some cells within the emetic center are involved in the weight-loss mechanism.
Collaborative Approaches
A team led by Ernie Blevins at the University of Washington administered a low dose of a GLP-1 drug in combination with oxytocin, an appetite suppressant, to obese rats. This combined treatment resulted in weight loss without observable signs of sickness.
Investigating Thirst Regulation
Researchers identified that a reduction in thirst is another side effect of GLP-1 drugs. Derek Daniels and his team at the University at Buffalo investigated how GLP-1 drugs influence thirst mechanisms. In a study involving Brattleboro rats, which have a genetic mutation causing chronic thirst, the researchers observed a substantial decrease in water consumption when the rats were given GLP-1 drugs. Brain studies indicated several distinct neural areas that regulate thirst but do not appear to influence appetite.
GLP-1 and the Reward System
A team from the University of Virginia identified that GLP-1 drugs also act upon a brain region involved in both addiction and emotional reward. Delivering GLP-1 to this specific area in mice reduced their desire for certain stimuli.