How Do GLP-1s Change Brain Signaling?
From intracellular pathways to neural circuits, a new study mapped the mechanisms of GLP-1 agonist, semaglutide.
Glucagon-like peptide 1 (GLP-1) therapies have been life-changing for some, but not for all.
A new study may help us to understand why. Researchers from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) mapped how semaglutide drives weight loss in the brain. The study was recently published in Nature Metabolism.
The rise of GLP-1s and the variability mystery that followed
GLP-1 is a naturally occurring hormone released by gut cells following a meal. Upon release, it induces satiety and helps regulate blood glucose; GLP-1-based drugs leverage this mechanism to treat diabetes.
This class has also proven beneficial outside of its original scope. The first, and most infamous, repurposing of GLP-1s was for weight management; the approval of semaglutide in 2021 was the catalyst for the weight-loss medicine movement.
However, real-world data has demonstrated significant variation in weight-loss response to GLP-1 drugs; hyper-responders lose more than 15% of their total body weight, while hypo-responders lose less than 5%.
Researchers have identified that GLP-1 drugs act on the area postrema (AP) to suppress appetite and exert metabolic effects that contribute to weight loss. But the specifics of this mechanism and how it may vary between individuals are yet to be established.
The area postrema
The AP is located in the brain stem, within the dorsal vagus complex (DVC). It sits outside of the blood–brain barrier, and responds to circulating signals, including metabolic hormones such as GLP-1, to regulate appetite, nausea, and autonomic responses.
Gs signaling supports semaglutide’s brain effects
GLP-1 therapies are reported to mediate weight-loss effects via Gs-coupled G protein-coupled receptors (GPCRs). The team started by exploring this mechanism in key brain regions.
Using viral genetic manipulation, they disrupted Gs signaling in different regions of the DVC. Mice with disrupted signaling throughout the DVC did not lose weight, but mice with spared AP signaling remained responsive to semaglutide.
The team examined Fos protein expression, an indicator of neural activity. In control mice, semaglutide increased Fos expression in the AP and the nucleus of the tractus solitarius, another part of the DVC. But mice with disrupted signaling throughout the DVC exhibited reduced neural activity in these regions, supporting the theory that semaglutide requires intact Gs signaling in this area for neuronal activation.
Following selective Gnas knockout in GLP-1 receptor-expressing cells, the team reassessed the brain's response to semaglutide.
Relevance of Gnas in GLP-1 response
Gnas encodes the Gs alpha protein, the first intracellular signaling molecule downstream of the GLP-1 receptor.
In wild-type mice treated with semaglutide, the AP and downstream brain regions showed increased neuronal activation, but in Gnas-knockout mice, activity was comparable to that of the non-treatment group.
Next, the researchers homed in on neurons. “We know much less about the nuts and bolts of what goes on within the neurons that these medications target,” said Dr. Andrew Lutas, co-corresponding author and NIDDK investigator.
They monitored neuron activity in living brain sections from the knockout and wild-type mice. Compared with neurons from Gnas-knockout mice, neurons with normal Gs signaling showed stronger activation following semaglutide administration.
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Semaglutide results in neuron activation, but how?
The team aimed to categorize semaglutide-induced signaling as spike-dependent or spike-independent.
Spike-dependent vs spike-independent signaling
Spike-dependent signaling relies on action potentials (electrical spikes) that are generated when the membrane potential reaches a specific threshold. Spike-independent signaling operates through continuous changes in membrane potential, and no threshold needs to be met for neuronal communication to occur.
After blockade of action potentials, or “spikes,” close to half of the cells in both the wild-type and Gnas-knockout neurons continued to respond to semaglutide, suggesting the drug may work via both spike-dependent and independent signaling. In Gnas-knockout neurons, responses were weaker, supporting previous evidence that Gs signaling is required for semaglutide to exert its full effects.
Researchers followed the process further down the pathway and monitored cAMP levels inside neurons following semaglutide wash.
cAMP messenger
Cyclic adenosine monophosphate (cAMP) is the secondary messenger for Gs-coupled GPCRs.
Initially, neurons were categorized into two types. Close to one-third were classified as transient responders; cAMP increased and quickly decreased. The remaining were sustained responders. However, these distinct categories were later deemed inappropriate, as further analysis showed that individual cells sit on a much broader spectrum.
“It was not an all-or-nothing phenomenon. We observed that cAMP responses across cells varied on a continuum.” — Dr. Michael Krashes, co-corresponding author and senior investigator at the NIDDK.
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To investigate sustained responders, the team blocked GLP-1 surface receptors. In theory, if the sustained cAMP response resulted from cell-surface activation, it would stop; if it resulted from receptors that had been internalized (or inaccessible), it would persist. Again, results following semaglutide wash were mixed: ~49% of the cells no longer responded, but ~44% had a sustained response, and the remaining handful exhibited transient increases in cAMP.
The team’s line of questioning, now focused on variable cAMP responses to semaglutide, led them to inhibit phosphodiesterase 4 (PDE4), an enzyme that degrades cAMP. Following inhibition, cAMP responses were amplified. “PDE4 inhibition not only abolished transient cAMP responses, but also increased the percentage of sustained responders,” said the study authors.
On the other hand, when mice were engineered to continuously degrade cAMP, semaglutide no longer reduced food intake or body weight, supporting that cAMP signaling is a mechanistic requirement rather than an associated response.
But when mice were treated with semaglutide and a PDE4 inhibitor, weight loss did not increase. While cAMP signaling plays an important role in the brain’s response, and thus therapeutic response to semaglutide, this suggests that other mechanisms were at play.
Other brain regions and signaling pathways could answer remaining questions
Each new answer led to a new question. But through this, the researchers identified the external lateral parabrachial nucleus, a brain “relay” station that processes survival signals, including satiety, as a region of interest in semaglutide response. Additionally, they found that Gq signaling, alongside Gs signaling, contributes to neuronal responses in some pathways.
However, the experiments were conducted on animals over a short period, and further work is required to confirm the mechanisms of GLP-1 drugs in humans.
In understanding the mechanisms by which GLP-1s induce weight loss, the ultimate goal is the ability to optimize and personalize therapies to provide consistent benefits for patients.
Reference: Gao C, Geneve IC, Rodriguez-Gonzalez S, et al. Semaglutide drives weight loss through cAMP-dependent mechanisms in GLP1R-expressing hindbrain neurons. Nat Metab. 2026. doi: 10.1038/s42255-026-01534-8
This article is a rework of a press release issued by the National Institutes of Health. Material has been edited for length and content.
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