Brain cells best known for making animals hungry may also help GLP-1 drugs produce their full weight-lowering effects, according to a new mouse study that challenges a common assumption about what happens in the brain during weight loss.
Researchers found that female mice needed functioning AgRP neurons, brain cells involved in hunger, to experience the full weight loss seen during treatment with GLP-1 receptor agonists. Rather than simply becoming less active during treatment, these neurons appeared to become more active as the animals lost weight.
The study, published in the Proceedings of the National Academy of Sciences, does not show that the same thing happens in people. It also does not mean GLP-1 medications work by making people hungrier. Instead, the findings suggest that hunger-related brain cells may play a more complicated role in weight loss than researchers previously understood.
AgRP neurons normally become more active when the body senses that energy is running low. They help increase hunger and encourage eating, which is one reason scientists have often viewed them as part of the body’s effort to resist weight loss.
The new study suggests they may also have another role.
Researchers treated mice with GLP-1 receptor agonists while tracking changes in body weight, food intake and metabolism. They also used genetic methods to remove or silence AgRP neurons.
When those neurons were disrupted, the mice did not lose as much weight during treatment. That suggested the cells were helping the drugs produce their full effect rather than simply working against them.
“This completely changes how we think about the mechanism involved in these medications and provides new insight into the biology underlying their long-term effects, opening an avenue for the development of more efficient drugs,” said Mateus d’Ávila, a Ph.D. candidate in neuroscience at Yale School of Medicine and first author of the study.
One possible explanation is that the brain responds to the calorie deficit created during GLP-1 treatment by activating these hunger-related neurons. The cells may then help coordinate some of the body’s broader response to weight loss.
That does not mean researchers have discovered the single reason GLP-1 drugs work. Medications such as semaglutide act on several systems involved in appetite, digestion and body weight. The new findings instead point to another piece of that larger picture.
The results also varied depending on factors including sex, diet and how the researchers altered AgRP neuron activity. That is another reason the findings should not yet be generalized to people taking GLP-1 medications.
The study was conducted in mice, with much of the work focused on females. Researchers will need human studies to determine whether the same brain response occurs in people and whether it has any practical implications for future treatments.
“By identifying a previously unrecognized neural mechanism involved in sustaining weight loss, our work provides new biological insights that could eventually help researchers design therapies that are even more effective or have fewer side effects,” d’Ávila said.
For now, the study adds nuance to the idea that successful weight loss simply requires turning down hunger signals. Some of the brain cells that normally encourage eating may also take part in the body’s response to GLP-1 treatment.
The research received support from a CAPES-Fulbright doctoral fellowship, an NIH equipment grant, the Yale Center for Molecular and Systems Metabolism, the U.K. Medical Research Council and the Biotechnology and Biological Sciences Research Council. One researcher also reported personal financial support from Fundação Estudar, Programa de Líderes and the Fondazione Dompé Rita Levi-Montalcini Award.