Scientists solve brain “switch” mystery behind weight loss in possible game changer for obesity drugs
&imwidth=600&imheight=450&format=webp&quality=medium "Scientists solve brain “switch” mystery behind weight loss in possible game changer for obesity drugs")
Weight loss is not just about the drugs. It's in the brain. Image courtesy: Pexels/ Moe Magners Photograph: (Others)
Cambridge scientists found why activating and blocking a brain receptor can both cause weight loss. The drugs act on different brain regions, revealing new pathways for more effective obesity treatments.
Scientists at the University of Cambridge say they have resolved a long-standing puzzle in obesity research: how both activating and blocking the same brain receptor can reduce food intake and body weight. The study found that the answer lies not simply in whether the receptor is switched on or off, but in where it is located in the brain. The findings were published in Nature Metabolism under the title “Distinct brain regions mediate regulation of food intake in response to GIPR agonism or antagonism”. The study was led by Dr Jo Edward Lewis and colleagues at the University of Cambridge’s Institute of Metabolic Science.
The GIPR paradox
The receptor at the centre of this discovery is the glucose-dependent insulinotropic polypeptide receptor (GIPR), which is involved in regulating appetite, metabolism and blood sugar. GIPR is an important target in the development of obesity medicines. Drugs such as tirzepatide, sold as Mounjaro and Zepbound, activate GIPR alongside the glucagon-like peptide-1 (GLP-1) receptor. Other experimental medicines take the opposite approach by blocking GIPR. MariTide, currently in Phase 3 clinical trials, combines GIPR antagonism with GLP-1 receptor activation. The apparent contradiction has puzzled researchers for years. Why should both stimulating and blocking the same receptor contribute to weight loss?
It is the brain region that determines the outcome
Cambridge researchers used genetically engineered mice in which GIPR could be selectively removed from particular regions of the brain. One group lacked GIPR in the brainstem, while another lacked the receptor in the hypothalamus. A control group retained normal GIPR expression. The researchers then examined responses to GIPR agonists and antagonists, as well as GLP-1 medicines used alone and in combination. The experiments revealed two distinct mechanisms. When GIPR is activated in the brainstem, it suppresses appetite, reducing food consumption and body weight. Blocking GIPR in the hypothalamus, on the other hand, strengthens the brain’s response to signals indicating that the body is full.
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In the hypothalamus, GIPR appears to act as a brake on satiety signalling. Blocking the receptor releases that brake, allowing fullness signals to become more powerful and reducing food intake through a different pathway.
The researchers monitored food intake, body weight, fat mass, blood-sugar control and brain activity throughout the study. Their findings suggest that the same receptor can influence weight loss through different neural circuits depending on its location in the brain.
What the discovery means for future combination drugs
The researchers also found evidence that GIPR blockade could enhance the effects of medicines targeting the amylin receptor. This raises the possibility of combining different hormone pathways to produce stronger weight-loss effects. The findings could help researchers develop more precise obesity treatments that target specific brain circuits rather than treating GIPR as a single, uniform switch.
“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,” Lewis said.
The study was funded by the UK Medical Research Council and Wellcome. As the research was conducted in mice, the findings do not yet establish that the same mechanisms will operate identically in humans. However, the work provides a framework for developing the next generation of obesity medicines and reinforces the central role of the brain in regulating body weight.
