Study reveals how GLP-1 drugs trigger weight loss in brain cells

Researchers at the National Institutes of Health have gained new information into how popular weight-loss drugs known as GLP-1 receptor agonists work inside brain cells. Their discovery demonstrated why patients respond differently to treatment and why the effects often level off over time.

The study, conducted in mice, explored the intracellular activity triggered by semaglutide, a GLP-1 drug widely used to treat obesity and type 2 diabetes. Scientists identified key signalling processes inside neurons that appear to play a central role in the drug’s ability to reduce weight.

These findings could help researchers develop more effective therapies and potentially extend the benefits of existing GLP-1 medications.

Exploring the brain’s response to semaglutide

While scientists already understand that GLP-1 drugs affect appetite-related regions of the brain, far less has been known about what happens inside the neurons themselves once the medication starts working.

“We know much less about the nuts and bolts of what goes on within the neurons that these medications target. By digging into these mechanisms, we’re beginning to answer some of these questions,” said co-corresponding author Dr Andrew Lutas, an investigator at NIH’s National Institute of Diabetes and Digestive and Kidney Diseases.

We know much less about the nuts and bolts of what goes on within the neurons that these medications target

The research team used fluorescence imaging techniques to observe intracellular activity in living brain tissue taken from mice. The experiments were led by first author Dr Claire Gao, a postdoctoral fellow at NIH’s National Institute of General Medical Sciences.

By selectively blocking or removing signalling molecules within the cells, the scientists were able to see which biological pathways were most closely linked to weight loss.

Key molecule linked to weight-loss effects

Researchers found that semaglutide’s weight-loss effects depended heavily on increased levels of cyclic adenosine monophosphate (cAMP) within the area postrema, a region of the brain associated with appetite control.

However, the response was not uniform across all neurons.

“It was not an all or nothing phenomenon. We observed that cAMP responses across cells varied on a continuum,” said co-corresponding author Dr Michael Krashes, a senior investigator at the National Institute of Diabetes and Digestive and Kidney Diseases.

Researchers found that semaglutide’s weight-loss effects depended heavily on increased levels of cyclic adenosine monophosphate (cAMP) within the area postrema

Some neurons maintained elevated levels of cAMP while semaglutide was present. Others showed only temporary increases, which may have occurred because the cells internalised or degraded their GLP-1 receptors.

The team also investigated whether these responses could be prolonged. By using roflumilast, a drug that inhibits the naturally occurring enzyme PDE4 responsible for breaking down cAMP, they found they could push more neurons towards a sustained response.

Potential implications for future treatments

The findings raise the possibility that GLP-1 drugs could eventually be modified or combined with other therapies to extend their effectiveness and reduce the frequency of dosing.

Researchers believe manipulating cAMP signalling may also help overcome the treatment plateaus experienced by many patients using GLP-1 medications, although more research will be needed before these approaches could be applied clinically.

Researchers believe manipulating cAMP signalling may also help overcome the treatment plateaus experienced by many patients using GLP-1 medications

The current study was limited by the technology available, allowing scientists to observe intracellular signalling in brain tissue for only a few hours at a time.

In future research, the team hopes to use emerging techniques to examine how GLP-1 drugs affect neurons over much longer periods, potentially spanning days or weeks.