Cambridge researchers have discovered why both activating and blocking the same brain receptor can lead to weight loss. The findings could help scientists develop more effective obesity treatments and identify drug combinations that deliver greater benefits with fewer side effects.
In mouse studies, the effects depended on which area of the brain was targeted. Activating receptors in the brainstem reduced appetite, while blocking the same receptors in the hypothalamus produced similar weight loss through a different biological pathway.
More than 1 billion people worldwide live with obesity. The condition increases the risk of serious diseases, including type 2 diabetes, cardiovascular disease, and certain cancers. Although weight loss can lower some of these risks, achieving and maintaining significant weight loss through diet and exercise alone can be challenging.
How weight loss drugs target the brain
A new generation of obesity medications works by targeting receptors involved in appetite, food intake, and blood sugar regulation. By influencing these receptors, the drugs can reduce hunger, support weight loss, and improve blood glucose control.
Popular medications such as Wegovy and Ozempic activate a protein known as the glucagon-like peptide 1 receptor (GLP-1R).
Other treatments target both GLP-1R and a second receptor called the glucose-dependent insulinotropic polypeptide receptor (GIPR). GIPR has presented researchers with an unusual scientific puzzle because both activating and blocking the receptor can promote weight loss.
Some medicines, including Mounjaro and Zepbound, activate GIPR. Other therapies in development, such as MariTide, block the receptor. Despite producing opposite effects at the same receptor, both approaches may help reduce body weight.
Researchers at the Institute of Metabolic Sciences at the University of Cambridge investigated why these two strategies can have similar effects. Experiments in mice showed that GIPR agonists and GIPR antagonists act on different brain regions. The findings also suggested that both approaches could enhance weight loss when combined with certain GLP-1-based treatments.
Researchers track GIPR activity in key brain regions
To identify the brain circuits responsible for these effects, the researchers used genetically engineered mice in which GIPR could be selectively removed from specific regions.
One group of mice lacked GIPR in the brainstem, an area at the base of the brain above the spinal cord that helps regulate appetite and nausea. A second group lacked GIPR in the hypothalamus, a brain region that plays a central role in controlling hunger, energy balance, and body weight. Unmodified mice served as the control group.
The researchers treated the animals with different combinations of GIPR agonists, which activate the receptor; GIPR antagonists, which block it; and GLP-1 medications. They then measured food intake, body weight, body fat, blood sugar control, and brain activity.
Comparing the groups enabled the team to determine where each treatment produced its effects.
The results showed that GIPR agonists work primarily through the brainstem. Activating GIPR in this region reduced appetite and lowered body weight in the mice.
Blocking the brain’s fullness brake
GIPR antagonists appeared to follow a different pathway.
Rather than acting mainly through the brainstem, GIPR blockers promoted weight loss through the hypothalamus. In this region, GIPR appears to function as a “brake” that limits the brainstem’s response to signals indicating that the body is full.
Blocking GIPR effectively releases this brake, allowing satiety signals to produce a stronger appetite-suppressing effect.
The researchers also found evidence that GIPR blockade may increase the effects of emerging medications targeting amylin receptors. This raises the possibility that GIPR antagonists could eventually be used alongside several classes of obesity medication.
New insights into combination obesity treatments
The findings may help explain why treatments such as MariTide show promise. MariTide, which is currently being evaluated in Phase 3 clinical trials, combines GIPR antagonism with GLP-1 receptor activation.
Understanding how these separate brain pathways interact could help researchers design more powerful and targeted combinations of weight loss drugs.
The study’s lead author, Dr Joe Lewis of the University of Cambridge’s Institute of Metabolic Sciences, said: “Understanding which brain circuits respond to these drugs and how they respond may help us design better treatments that produce more weight loss with fewer side effects. These medicines may also have greater effects when combined with other obesity drugs.”
“Our study also strengthens the idea that the brain is central to obesity treatment. Obesity medications do not simply act on the gut or pancreas. They also have important effects on specific, identifiable brain circuits that regulate appetite and food intake.”
The research was funded by the Medical Research Council and Wellcome.
Source: www.sciencedaily.com