Cambridge Researchers Uncover the Secret to Opposite Effects on Weight Loss

Obesity is a growing concern worldwide, with over a billion people affected by this condition. The consequences of obesity are severe, including an increased risk of type 2 diabetes, cardiovascular disease, and cancer. While losing weight can reduce some of these risks, achieving substantial weight loss through diet and exercise alone can be challenging.

A new generation of weight loss medications has emerged in recent years, targeting specific receptors involved in appetite. By influencing these receptors, the drugs can reduce food intake, promote weight loss, and help regulate blood sugar. Several widely used medications, including Wegovy and Ozempic, activate a protein receptor called the glucagon-like peptide 1 receptor (GLP-1R).

However, other obesity treatments act on both GLP-1R and another receptor known as the glucose-dependent insulinotropic polypeptide receptor (GIPR). This second target has presented scientists with an unusual puzzle. Some medications, including Mounjaro and Zepbound, activate GIPR, while others, such as MariTide, block it. Despite producing opposite effects on the same receptor, both approaches can help promote weight loss.

Researchers at the Institute of Metabolic Science, University of Cambridge, set out to understand why these two types of GIPR drugs work in opposite ways. Their experiments in mice revealed that the two types of GIPR drugs work through different regions of the brain. The researchers also found that these approaches can increase weight loss when paired with certain GLP-1-based weight loss medicines.

To identify the brain regions responsible for these effects, the team used genetically engineered mice in which GIPR had been selectively removed from specific areas. One group lacked GIPR in the brainstem, the region at the base of the brain just above the spinal cord that is involved in appetite and nausea. Another group lacked the receptor in the hypothalamus, an important brain region involved in regulating hunger and body weight. A third group consisted of normal, unmodified mice that served as controls.

The scientists treated the animals with different combinations of a GIPR agonist (which activates the receptor), a GIPR antagonist (which blocks the receptor), and a GLP-1 drug. They then monitored food consumption, body weight, fat mass, blood sugar control, and brain activity. Comparing the different groups allowed the team to pinpoint where each treatment was acting.

The results showed that GIPR agonists primarily work through the brainstem. Activating GIPR in this region reduced appetite and led to lower body weight. GIPR antagonists, on the other hand, followed a different route. Instead of acting primarily through the brainstem, the researchers found that blocking GIPR promoted weight loss through the hypothalamus. In this region, GIPR appears to function as a kind of ‘brake’ that limits how strongly the brainstem responds to signals indicating that the body is full. Blocking the receptor effectively releases that ‘brake’, allowing fullness signals to have a stronger effect.

The researchers also found evidence that blocking GIPR could enhance the effects of emerging medicines that target the amylin receptor. This suggests that GIPR antagonists might eventually be useful for strengthening several different classes of obesity treatments.

Understanding how these separate pathways interact could also help researchers design more effective combinations of obesity medicines in the future. According to Dr. Jo Lewis, the study’s first author, ‘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.’

The research was funded by the Medical Research Council and Wellcome. The findings of this study may help scientists develop more effective treatments for obesity and provide new insights into the complex mechanisms underlying this condition.