Scientists have identified a new way to supercharge the GLP-1 receptor agonist semaglutide, opening the door to boosting the drug's weight-loss power and helping long-term users push past plateaus that not even this "wonder drug" can circumvent.
Researchers from the US National Institutes of Health (NIH) investigated how semaglutide works within neurons, using fluorescence imaging to track the drug's influence on intracellular activity in living brain tissue. By inhibiting or removing selected signaling molecules, they pinpointed the precise chemicals that play a pivotal role in weight loss.
“We know much less about the nuts and bolts of what goes on within the neurons that these medications target," says co-corresponding author Andrew Lutas, an investigator at NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). "By digging into these mechanisms, we’re beginning to answer some of these questions."
They found that the drug's weight-loss power is closely tied to levels of the signaling molecule cyclic adenosine monophosphate (cAMP) in the area postrema – the region of the brain critical for controlling appetite and regulating metabolism. You might also know it as the "toxin detector" that triggers nausea and vomiting.
“It was not an all-or-nothing phenomenon," says co-corresponding author Michael Krashes, senior investigator at NIDDK. "We observed that cAMP responses across cells varied on a continuum."
While this discovery was made using a mouse model, it's the first time scientists have been able to identify individual neurons doing the heavy lifting in weight loss, paving the way to developing therapeutics that target those specific nerve cells.
It could also help scientists understand why some people have greater weight-loss results from semaglutide than others, and why most people will eventually plateau while taking the drug. And, in turn, improve outcomes for both issues.
The researchers found that while some neurons had sustained elevated levels of cAMP, others spiked and then dropped – which the team suggests could be due to those cells having "internalized or degraded" their GLP-1 receptors. Fortunately, they were able to counter this temporary rise in those neurons with roflumilast – a phosphodiesterase-4 (PDE4) inhibitor traditionally used to treat chronic obstructive pulmonary disease (COPD).
By inhibiting PDE4, roflumilast blocked the degradation of cAMP, manipulating the neurons into maintaining elevated levels of this key signaling molecule. Giving these cells a helping hand to sustain cAMP levels could also mean less frequent administration of the medication.
The authors note that the fluorescence technique limited them to a short window of observation. Their next move will be to observe neuronal activity under the influence of GLP1s for longer periods, from a few days to weeks.
"Our systematic characterization of semaglutide’s signalling mechanisms in the hindbrain reveals the intracellular signalling architecture through which semaglutide engages cAMP and calcium to regulate body weight, providing avenues for improving obesity therapeutics," the researchers note.
The study was published in the journal Nature Metabolism.
Source: National Institutes of Health
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