Here's a puzzle that has vexed obesity-drug developers: some weight-loss drugs activate a receptor called GIPR, while others block it — and both approaches help people lose weight. How can opposite actions produce the same result?
Scientists at the University of Cambridge's Institute of Metabolic Science, writing in Nature Metabolism, say they've solved it: the receptor does different jobs in different parts of the brain.
Two regions, opposite effects
Using mice engineered to remove GIPR selectively from specific brain areas, the team found:
- Stimulating GIPR in the brainstem suppresses appetite.
- Blocking GIPR in the hypothalamus enhances weight loss by releasing a “brake” that normally limits satiety signals.
So an agonist and an antagonist can each drive weight loss — just through different circuits.
“Understanding which brain circuits respond to these medications could help us design better drugs that produce more weight loss with fewer side effects,” said Jo Lewis, PhD.
Why it matters
The finding helps explain why GIPR-activating drugs like tirzepatide (Mounjaro, Zepbound) work — and why an experimental GIPR-blocking approach, combined with GLP-1 (as in the Phase 3 candidate MariTide), also shows promise. Mapping these circuits could guide the next generation of obesity drugs. This is preclinical animal research, not a treatment.