Researchers headed by a team at the Institute of Metabolic Science, University of Cambridge, have solved the mystery of why both stimulating and blocking a particular receptor, or switch, in the brain can help people lose weight. Their study in mice indicated that the answer lies in where the receptor, called GIPR, is located. The results showed that stimulating this switch in the brainstem suppresses appetite, while the same effect can be achieved by blocking it in the hypothalamus. The researchers say their findings could help in the development of more effectiveness therapeutic strategies.

Jo Lewis, PhD, at the Institute of Metabolic Science at the University of Cambridge, said, “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.” Lewis is first author of the team’s published paper in Nature Metabolism, titled “Distinct brain regions mediate regulation of food intake in response to GIPR agonism or antagonism.”

More than a billion people worldwide are living with obesity, which increases the risk of diseases such as type 2 diabetes (T2D), cardiovascular disease (CVD) and cancer. Weight loss can help mitigate these complications, but losing weight through diet and exercise alone can prove challenging.

In the past few years, a new generation of weight loss drugs has emerged that target particular receptors in the brain, reducing appetite and leading to weight loss, as well as helping to control blood sugar levels. Several of these drugs, such as Wegovy and Ozempic, work by stimulating the glucagon-like peptide 1 receptor (GLP-1R).

Other weight loss drugs act on both this receptor and on GIPR. “The development of dual agonists for the glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) has been a landmark moment in the treatment of type 2 diabetes and obesity,” the authors wrote.

However, some drugs, such as Mounjaro and Zepbound, stimulate GIPR, while others, such as the Phase III-stage MariTide, block it. Why these opposite actions have the same result has puzzled scientists. “… for reasons that are incompletely understood, in preclinical and clinical studies, adding either a GIPR agonist or GIPR antagonist to GLP-1R agonism causes additional weight loss,” the team continued. “There is emerging evidence that GIPR agonism and antagonism exert their paradoxically similar effects on weight loss via distinct neuronal populations.”

The investigators’ newly reported preclinical research has now shown that the two different types of GIPR drugs act on distinct regions of the brain, but also that they can boost weight loss when combined with certain GLP-1-based weight-loss drugs. For their reported study the team turned to genetically engineered mice and selectively removed GIPR from different parts of the brain to see which regions were responsible for the effects of the obesity drugs.

One group of mice lacked GIPR in the brainstem—the area at the base of the brain, just above the spinal cord, involved in appetite and nausea. A second group lacked GIPR in the hypothalamus, a major center controlling hunger and body weight. A third, control group included normal, unmodified mice. The researchers treated the mice with various combinations of a GIPR agonist (which activates the receptor), a GIPR antagonist (which blocks the receptor) and a GLP-1 drug, and measured food intake, body weight, fat mass, glucose control and brain activity.

“We knock out Gipr in either the area postrema (AP) or hypothalamus of mice (Gipr^AP-KO  and Gipr^hypo-KO, respectively) and compare body weight and food intake responses to GIPR agonists and antagonists, alone and in combination with the GLP-1R agonist liraglutide,” they wrote in summary.

By comparing the responses of normal mice with mice lacking GIPR in different brain areas the investigators showed that GIPR agonists act on the brainstem to suppress appetite and reduce weight. They then showed that GIPR antagonists help weight loss by acting on this receptor in the hypothalamus, where they release a “brake” that otherwise limits the brainstem’s ability to respond to signals telling us we are full. Blocking GIPR also appeared to boost the effect of emerging new drugs targeting the amylin receptor—such as cagrilintide (Cagri)—suggesting that GIPR antagonists could potentially be used to strengthen several types of anti-obesity medicines.

“Overall, our results suggest that the AP is responsible for the appetite-suppressing effects of GIPR agonism but that GIP receptors in the hypothalamus underlie the ability of GIPR antagonism to enhance the weight loss effects of GLP-1R and amylin receptor agonists,” they stated. “GIPR antagonism and Gipr^hypo-KO also sensitize to cagrilintide-induced weight loss.

The findings explain why drugs such as MariTide, which combines GIPR antagonism with GLP-1 receptor agonism, are effective, and suggests how to design even better combination therapies. And as the authors noted, “Future work is still, however, required to identify the neuronal networks underlying GIPR interactions in the AP and hypothalamus and their crosstalk with other appetite-regulating circuitry.”

Lewis said the work strengthens the idea that the brain is central to obesity treatment, commenting, “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.”

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