Cambridge study solves weight loss drug paradox

Scientists at the University of Cambridge have resolved a longstanding puzzle in obesity pharmacology: why both activating and blocking the same receptor can lead to weight loss. The answer, published July 24 in Nature Metabolism, lies in two anatomically separate brain regions that respond in opposite ways to drugs targeting the glucose-dependent insulinotropic polypeptide receptor, or GIPR.cam+1

The Paradox Explained

Current weight-loss drugs take contradictory approaches to GIPR. Mounjaro and Zepbound, made by Eli Lilly ↗ 0.86%, stimulate the receptor alongside GLP-1R, while Amgen's ↗ 1.22% MariTide, now in phase 3 clinical trials, blocks it. Both strategies produce weight loss — a contradiction that has confounded researchers.medicalxpress+1

Using genetically engineered mice with GIPR selectively removed from different brain areas, the Cambridge team showed that GIPR agonists suppress appetite by acting on the brainstem, the region at the base of the brain that processes immediate fullness signals. GIPR antagonists, meanwhile, work through the hypothalamus, the brain's long-term energy balance center, where they release an inhibitory "brake" that otherwise limits the brainstem's ability to respond to satiety cues.cam+1

The study also found that blocking GIPR in the hypothalamus enhanced the weight-loss effects of both GLP-1 receptor agonists like semaglutide and emerging drugs targeting the amylin receptor, suggesting GIPR antagonists could serve as a booster for multiple classes of anti-obesity medicines.nature+1

Implications for Drug Design

"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," said Dr. Jo Lewis, the study's first author at the Institute of Metabolic Science.cam

Lewis added that the findings reinforce the centrality of the brain in obesity treatment. "Obesity drugs are not acting simply on the gut or pancreas. Instead, they have important effects on specific, identifiable brain circuits that regulate appetite and food intake," she said.cam

What Comes Next

The research, funded by the Medical Research Council and Wellcome, provides a mechanistic rationale for why MariTide's combination of GIPR antagonism and GLP-1 receptor agonism has shown efficacy in clinical trials. It also opens the door to new combination strategies — pairing GIPR antagonists with amylin-based therapies, for example — that could yield stronger weight-loss outcomes than any single drug alone.medicalxpress+3