The receptor for GLP-1 is not exclusively expressed in regions of the brain that control appetite and food intake and glucose regulation. They're pretty densely expressed throughout the brain. And this is including regions that are in the reward circuitry in the brain, the mesolimbic pathway. There's receptors in the midbrain VTA, the striatum, nucleus accumbens. One of my favorite brain regions is the hippocampus, which has a lot of GLP-1 receptors. So there's definitely possibility of applications for these drugs or different GLP-1 receptor agonists for substance abuse disorder and potentially even memory disorders and dementia. And there's a lot of certainly preclinical data to support that.
The clinical data are just ongoing and starting to come out now. And part of the idea with the applications of GLP-1 receptor agonist to things other than appetite suppression has to do with the capacity of these drugs to get into the brain.
This is somewhat of a controversial topic in our field of research. The first generation of GLP-1 drugs, so 2005 to 2012, we collected some preclinical evidence in rodents suggesting that a large part of the mechanism of action for food intake suppression was through brain action. So the drugs would get into the brain, activate receptors. Whether these newer generation GLP-1 drugs like Ozempic, Wegovy are getting into the brain is less clear. Really, again, controversial. So some studies, mostly preclinical, exclusively preclinical, will tag the peptides with a fluorescent molecule and try to look at where it accumulates in the brain, and you see a lot of it clump into what's called the circumventricular organs, where there's no blood-brain barrier protecting the brain from the circulation. So there's a school of thought that these drugs are acting primarily in those circumventricular organs, but those studies are tricky because fluorescent molecules fade and the brain has autofluorescent signal. So we could be missing something with those fluorescent studies. There's better ways to do this, but it's expensive and complicated, where you radiolabel the peptides with like carbon-14 and you can actually determine if it's getting into the brain and where. Those studies, Elizabeth Rhea, Bill Banks and colleagues at University of Washington are starting to do some of those, and it looks like some of the early generation of GLP-1 drugs readily get into the brain and some of the newer ones less clear. Maybe it takes a little bit longer, but the jury is still out.
Where they're getting into the brain is not something we have a clear understanding of at this point. I'm sort of veering us toward reward and reinforcement and memory because even though those are topics that come up in the context of drug seeking, of pleasure seeking, and on and on, in the context of food, you know, what we consider rewarding and what we crave are very closely related, and memory for what we think is going to soothe us or satisfy us at the level of food also seems to be a strong component. I know you've worked in these areas, but as a way of getting directly there, I'm very curious how the GLPs are actually suppressing hunger. If let's assume that it doesn't get into the brain, that these drugs aren't getting into the brain.
So, if I take a full dose or a micro dose of a GLP-1 drug, what is the sensation that people report? I've never actually taken one, so I don't know. Okay. But I hear like presumably it's satiety, but does that mean fullness? People will talk about reducing food noise in air quotes. What is this at the level of biology?
So the GLP-1, normal physiological GLP-1 that we secrete in the body likely has a paracrine mechanism of action.
Could you describe paracrine?
Yeah. So the vagus nerve innervates our GI tract and there's receptors for GLP-1 on the terminal. So right where the nerve is contacting the gastrointestinal tract, there's GLP-1 receptors, and this paracrine mechanism is where the GLP-1 is released from these L cells in the intestines and immediately act on nearby receptors that are expressed on the vagus nerve. So that's one mechanism through which GLP-1, both the GLP-1 drugs as well as our physiological GLP-1, may be producing this feeling of satiation. So the vagus nerve communicates a lot of within-meal signals that contribute to us stopping eating. Right? At some point we get full. This process is called satiation. GLP-1 is a big player in that process.
Not exclusively through the vagus nerve, but probably largely through the vagus nerve through this paracrine mode of action. So this sends a signal to the brainstem. That's the first site in the brain where the vagus nerve signals that the animal's had enough food at this point. The stomach's starting to expand. There's nutrients entering the intestines, and there's sort of a symphony of signals that some act through the vagus nerve, some don't, but eventually lead to this feeling of fullness and meal termination, and GLP-1 is one instrument in that symphony.
Does it turn off the desire for food as well? Like people will talk about less food noise, and I know many people who are taking these drugs, some of whom are really bullish about also exercising, some who aren't. So we'll get to that a little later. But they all talk about reduced food noise, which tells me that before there was noise, and I don't know because I haven't asked them whether they were aware of that noise. So I'm trying to imagine, having never taken one of these, what that noise is. I mean, when I see blueberries, I want to eat them. But when I see bread or a steak or something, I may or may not want to eat them depending on when I ate last, time of day, this kind of thing. So, what is food noise?
I am not someone who experiences food noise either. So it's a bit of a strange idea to me.
But I've certainly heard, same as you, anecdotal evidence of people who are taking GLP-1 based drugs and are saying that, wow, it really, really canceled the food noise. Whether that's based on receptor binding in the brain in higher order brain regions that are involved in memory and cognition, hippocampus, prefrontal cortex, we don't know. Again, I think that's one of the big gaps in this field is understanding where the drugs are acting. Are they getting to these regions in the brain that are involved in higher order cognitive processes that may mediate the food noise, or is this basically just a gut-vagus satiation mechanism? There's a lot to uncover in that area still.
