It is generally believed that their effect on body weight is partly related to appetite suppression, but a new study with mice shows that long-term weight loss does not depend solely on hunger suppression.
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In a new study published in the journal PNAS, scientists found that so-called “hunger neurons” in the brain may need to remain functional for semaglutide to produce its full weight-reducing effect.
At first glance, this finding seems contradictory. Why would a weight-loss drug depend on brain cells that stimulate hunger?
Mateus d’Ávila, a scientist at Yale University, and colleagues studied brain cells that help regulate the body’s energy balance. Scientifically, they are called AgRP neurons. These cells activate when the body starts to lack energy.
“AgRP neurons are often simply called hunger neurons, but that is an oversimplified description,” d’Ávila told ScienceAlert. “Previous work from our lab at Yale and other scientists has shown that these neurons coordinate a much broader body response to energy deficiency, including how the body mobilizes and uses stored energy, such as fat.”
Mice ate less, but weight returned
The researchers disrupted the activity of these cells in female mice using several different methods. Then the animals were given semaglutide.
Semaglutide mimics the effect of a natural hormone released after eating. This hormone sends a signal to the brain that the body is already full. The drug reduces appetite, slows stomach emptying, and helps regulate blood sugar levels.
During the study, mice with disrupted “hunger neuron” activity treated with semaglutide continued to eat less.
However, despite the reduced food intake, the metabolic response necessary for long-term weight loss weakened. Within 15 days, the mice regained the lost weight.
Meanwhile, mice with normally functioning neurons maintained their weight loss.
The most interesting part of the experiment was that the mice that regained weight still ate less. In some cases, they even consumed slightly less food than other mice but were unable to maintain the reduced weight.
This showed that in female mice, the full effect of semaglutide on weight cannot be explained solely by reduced food intake. Disruption of AgRP neuron activity also reduced energy mobilization from fat tissue.
Not only hunger signals matter
The scientists confirmed this result by conducting additional experiments. They found that disrupting “hunger neuron” activity or blocking the signaling pathway that helps the body mobilize stored fat also weakened semaglutide’s effect on weight.
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The researchers also found that long-term semaglutide treatment altered cellular activity, energy use, and connections with other neurons in AgRP cells.
However, the study has important limitations.
The experiments were conducted on mice, not humans, and the most pronounced effect was observed in female mice. In males, under the tested conditions, the same result was not found. The study results were also influenced by the animals’ diet and the method used to disrupt neuron activity.
“This is a preclinical mechanistic study, so our results should not currently be used to decide how people should use semaglutide or other GLP-1 drugs,” emphasized d’Ávila.
The scientists also did not directly compare semaglutide with older appetite-suppressing drugs. Therefore, it is still too early to say that this mechanism explains why semaglutide may help maintain reduced weight longer.
Previous studies showed different effects
Previous studies help explain why the new study’s results were so unexpected.
A 2025 study with mice showed that fast-acting GLP-1 drugs quickly suppressed AgRP neuron activity. The stronger the suppression of these neurons, the more food intake decreased. Artificially reactivating the neurons partially increased the mice’s food intake.
Another study previously described by ScienceAlert revealed a separate group of neurons in the brainstem that were necessary for semaglutide’s effect on appetite and body weight but were not required for nausea-like side effects.
The new study does not contradict these findings about short-term appetite suppression. Rather, it reveals another mechanism related to long-term treatment.
It turned out that normally functioning AgRP neurons helped female mice maintain semaglutide-induced weight loss even while the drug continued to suppress their appetite.
More research will be needed to determine whether a similar system operates in humans.
If this mechanism is confirmed, it could help explain why different people respond differently to the same drug and potentially aid in developing more effective treatments.
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