One of obesity medicine’s stranger puzzles is that drugs which activate a receptor called GIPR and drugs which block it can both help people lose weight. Cambridge scientists say they now know why: the receptor works through two different parts of the brain.
Researchers at the University of Cambridge’s Institute of Metabolic Science studied the GIP receptor (GIPR) in genetically engineered mice, selectively removing it from specific brain regions. They found that activating GIPR in the brainstem directly reduces appetite, while blocking GIPR in the hypothalamus releases a “brake,” letting the body’s fullness signals work more powerfully. Two opposite drug actions, two brain circuits, same result. The work was published August 15, 2026 in Nature Metabolism.
Why it matters for real drugs
GIPR is a hot target. Eli Lilly’s Mounjaro/Zepbound (tirzepatide) is a GIPR agonist combined with GLP-1, while Amgen’s MariTide pairs a GIPR antagonist with GLP-1 and is in Phase 3 — opposite approaches both aimed at weight loss. Understanding the separate circuits could explain those results and guide better combinations.
The bigger picture
“Understanding which brain circuits respond to these medications…could help us design better drugs that produce more weight loss with fewer side effects,” said first author Jo Lewis. As the obesity-drug field races ahead, mapping exactly where and how these medicines act in the brain is key to the next generation — though this is mechanistic mouse research, not a new treatment.