Scientists at the University of Cambridge say they have identified why both activating and blocking the same brain receptor can promote weight loss — a puzzle that has complicated research into the next generation of obesity drugs.
The receptor is known as the glucose-dependent insulinotropic polypeptide receptor (GIPR). It is already a major target in obesity medicine: some drugs stimulate it, while newer experimental treatments block it. Cambridge researchers found that these seemingly opposite strategies can work because GIPR does different things in different parts of the brain.
The findings, published July 24 in Nature Metabolism, point to the brain region — rather than simply whether GIPR is activated or blocked — as the key to understanding its effects on appetite and body weight.
Why has GIPR puzzled obesity researchers?
GIPR is part of the body’s system for responding to nutrients. It is activated by glucose-dependent insulinotropic polypeptide, or GIP, an incretin hormone involved in food intake, insulin secretion and metabolism.
The receptor has become particularly important because of the success of medicines that combine GIP and GLP-1 pathways.
Tirzepatide, marketed as Mounjaro and Zepbound, activates both the GIP receptor and GLP-1 receptor. At the same time, researchers have been developing drugs that do the opposite — block GIPR — while maintaining GLP-1 receptor activation.
One prominent example is MariTide, an experimental medicine combining GIPR antagonism with GLP-1 receptor agonism that is being studied in Phase 3 clinical trials.
That created an apparent contradiction.
If activating GIPR can contribute to weight loss, why would blocking the same receptor also make an obesity drug more effective?
The Cambridge study suggests the answer is that researchers had been looking at GIPR too broadly.
The key is where GIPR is located in the brain
The Cambridge team used genetically modified mice to remove GIPR from specific brain regions and then compared how the animals responded to GIPR agonists and antagonists.
The researchers focused on two areas:
- The area postrema (AP): a brainstem region involved in detecting circulating signals and regulating feeding-related responses.
- The hypothalamus: a brain region central to appetite, energy balance and hormonal signaling.
The experiments revealed that these two locations can produce very different outcomes.
When GIPR was activated in the area postrema, it contributed to appetite suppression.
When GIPR was blocked in the hypothalamus, the result was different: the blockade enhanced the effects of other appetite- and weight-regulating signals.
The study therefore suggests that GIPR is not functioning as a simple biological “on/off” switch.
Instead, its effect depends on which neural circuit contains the receptor.
How does activating GIPR reduce appetite?
The researchers found that GIPR activation in the area postrema contributes to the appetite-suppressing effects of GIP.
In mice lacking GIPR specifically in this region, the appetite-suppressing response to an acylated GIP agonist was reduced. The animals were also less responsive to the ability of acyl-GIP to prevent an aversive response triggered by peptide YY.
In simpler terms, the findings indicate that GIPR in the area postrema is one important route through which GIP signalling can influence food intake.
This helps explain why activating GIPR can be useful in weight-loss therapies.
But it does not explain why blocking GIPR can also help.
That requires looking at the hypothalamus.
Why does blocking GIPR also promote weight loss?
The second mechanism operates in a different part of the brain.
When researchers removed GIPR from the hypothalamus, mice showed enhanced weight loss when treated with the GLP-1 receptor agonist liraglutide.
More importantly, removing hypothalamic GIPR eliminated the additional weight-loss effect normally produced when a GIPR antagonist was combined with liraglutide.
This suggests that hypothalamic GIPR normally restrains or limits certain satiety-related signals.
Blocking the receptor appears to remove that restraint, allowing other weight-regulating pathways to have a stronger effect.
That provides a biological explanation for the seemingly contradictory drug strategies:
GIPR activation and GIPR blockade can both reduce weight, but through different brain circuits.
The Cambridge researchers describe these as distinct mechanisms rather than opposing versions of the same mechanism. (Nature)
What does this mean for drugs such as tirzepatide and MariTide?
The findings help put two very different drug strategies into context.
GIPR agonists
Tirzepatide combines GIPR activation with GLP-1 receptor activation. The Cambridge findings suggest that GIPR agonism can directly contribute to appetite suppression through specific brain regions.
GIPR antagonists
MariTide takes a different approach by combining GIPR blockade with GLP-1 receptor activation.
The new study offers a potential explanation for why that strategy can work: blocking GIPR in the hypothalamus can make the weight-loss effects of GLP-1 receptor activation stronger.
This is an important distinction. It means researchers may not need to decide whether GIPR is inherently “good” or “bad” for weight loss.
Instead, they can ask a more precise question:
What does GIPR do in each relevant neural circuit?
The researchers also found a connection to amylin drugs
The findings could extend beyond GLP-1-based treatments.
The Cambridge team found that GIPR antagonism and removal of hypothalamic GIPR also increased sensitivity to cagrilintide, an amylin receptor agonist used in experimental weight-loss research.
That raises the possibility of combining GIPR antagonism with medicines that act through other appetite-regulating pathways.
The potential advantage is not simply adding more drugs. Understanding how their neural circuits interact could help researchers design combinations in which each medicine strengthens a different part of the body’s weight-regulation system.
Could this lead to better obesity treatments?
Potentially, but the findings are still at the preclinical stage.
The study was conducted in mice, using genetically engineered animals in which GIPR could be selectively removed from particular brain regions. That provides strong evidence for the mechanisms being studied in animals, but it does not establish that the same circuits will behave identically in humans.
That limitation is particularly important when discussing future obesity drugs.
A promising mechanism in mice can fail to translate into an effective or safe human treatment. Human obesity is influenced by a complex combination of biology, behavior, environment, genetics and metabolism.
The Cambridge researchers themselves frame the findings as a way to guide future drug development rather than as proof of a new treatment.
Why the discovery could change how obesity drugs are designed
The broader implication is that researchers may be able to move away from treating a hormone receptor as though it has one universal function throughout the body.
Instead, future drugs could be designed around specific neural circuits.
That could eventually help researchers pursue three goals:
- Greater weight loss: By combining drugs that influence complementary brain pathways.
- Fewer side effects: By avoiding unnecessary activity in circuits that produce unwanted effects.
- More precise combinations: By pairing drugs based on how their individual neural mechanisms interact.
Dr. Jo Edward Lewis, the study’s first author, said understanding which brain circuits respond to these medicines could help researchers develop drugs that produce greater weight loss with fewer side effects and potentially work more effectively in combination.
What the study does — and does not — prove
The research provides a compelling explanation for the GIPR paradox, but several caveats matter.
What it shows:
- GIPR agonism and antagonism can act through different brain regions.
- GIPR in the area postrema contributes to appetite suppression by GIP agonists.
- Hypothalamic GIPR contributes to the additional weight-loss effects produced by GIPR antagonism alongside GLP-1 receptor agonism.
- GIPR antagonism can also enhance the effects of the amylin receptor agonist cagrilintide in mice. (Cambridge Repository)
What it does not show:
- That GIPR antagonists will outperform existing obesity drugs in humans.
- That targeting these brain regions will necessarily reduce side effects.
- That the same mechanisms will operate identically in people.
- That a new drug based on this mechanism is ready for clinical use.
Those questions will require human research.
The bigger lesson: obesity drugs act on the brain
The study adds to a growing understanding of obesity medicines: their effects cannot be explained solely by what happens in the stomach, intestine or pancreas.
The brain plays a central role in interpreting hormonal and metabolic signals and translating them into changes in hunger, fullness and food intake.
The Cambridge researchers argue that this makes understanding individual brain circuits increasingly important for obesity drug development.
The GIPR paradox may therefore have been less of a contradiction than researchers initially thought.
The same receptor can produce different outcomes because it is embedded in different neural circuits.
That insight could give drug developers a more precise map for designing the next generation of obesity treatments.
TL;DR
Cambridge researchers have offered an explanation for a puzzling feature of obesity drug research: both activating and blocking GIPR can contribute to weight loss.
Their experiments in mice found that the outcome depends on where the receptor is located. GIPR activation in the area postrema helps suppress appetite, while blocking GIPR in the hypothalamus can enhance weight loss produced by GLP-1 and amylin receptor agonists.
The finding could help researchers design more targeted combination treatments. But because the experiments were conducted in mice, it is too early to assume the same mechanisms will translate directly to human obesity treatment.