Research on GLP1 Signaling in the brain
How does GLP1 signal the brain? We take a look at related research to try and learn more.
GLP1 receptor agonists have a lot of effects, but some of the most important effects are in the brain.
While people originally thought that GLP1s worked primarily in the gut or by doing things like delaying digestion, it's becoming clearer that GLP1's pronounced effects are on the brain.
Check out our quick explainer
Discussions starting as early as 2018
While the idea that GLP1 is primarily a brain drug is under-discussed, it isn't new – back in 2018 this was already being discussed:
Secreting insulin is obviously an important part of the benefits for type 2 diabetics that use GLP1s, but people that use it repeatedly note the absence of "food noise" – a phrase that describes people whose relationship with food causes them to think about it constantly.
One thing that stood out from this commentary was the idea that GLP1 is likely to be penetrating the brain-blood barrier:
it is critical to keep in mind that the long-acting GLP-1R agonists exendin-4 and liraglutide can penetrate the central nervous system and access blood-brain barrier–protected sites to influence GLP-1–mediated responses such as food intake and body weight (20), thus adding complexity to the puzzle.
While this quote is specifically about early GLP1s (exendin-4 i.e. exenatide and Liraglutide i.e. Victoza/Saxenda), it is likely that the entire class of drugs works this way – Ozempic, Wegovy, Zepbound and others likely work the same way.
Research revisiting GLP1/Brain interaction in 2021
More recently, researchers took another stab at trying to understand the relationship between GLP1 and the brain in 2021:
While it's quite difficult to understand the effects of GLP1 on the brain in totality (outside of being a specialist), there are many areas of the brain that produce GLP1 and have receptors (i.e. the bits that are "agonized"):
The conclusions are neatly summed up (emphasis added):
In summary, there are multiple brain regions and neural circuits by which GLP‐1 controls food intake and body weight. GLP‐1 activity within these circuits may also contribute to proper blood glucose control. However, the pleiotropic nature of GLP‐1 might be subject to species variability as well as a dependence upon the source of GLP‐1 (i.e. whether GLP‐1 is derived from the periphery or CNS, both the periphery & CNS, or when using a specific designer long‐acting GLP‐1 receptor agonist). A primary focus of GLP‐1 action in the brain has revolved around hypothalamic sites of action (with an emphasis on the arcuate and paraventricular nuclei). However, there are also emerging and important roles for extra hypothalamic sites in the effects of GLP‐1, including hindbrain, midbrain and forebrain regions. Although these data highlight a growing understanding of GLP‐1 action in the brain, they also raise several questions for future investigation.
As with many other fields of research related to the brain, we're still a long ways from understanding how GLP1 interacts with the brain completely, but it seems the research is moving in the right direction.
Mentions of the GLP1/brain interaction in 2024
More recently published research surveys are more likely to focus on the interaction between GLP1 RAs and the brain as well:
Building on previous research, this survey finds that:
GLP-1 and multiple GLP-1 RAs cross the blood-brain barrier5 and mitigate neurological injury by several mechanisms that include attenuation of inflammation, neuroapoptosis, and oxidative damage that can improve neuronal function and attenuate neuronal injury and loss.6–8 In addition, insulin plays a critical role in brain homeostasis, and GLP-1 RAs may upregulate the expression of insulin receptors in the brain.
While this research does not constitute a trial or the results of a longitudinal survey, the evidence across many different studies is starting to grow that GLP1s can be beneficial for improving brain-linked conditions.
