After Ozempic: the revolution in peptide science

Jonathan Long tells us about 100,000 newly discovered peptides, gray-market risks, and the hunt for exercise in a pill
Nicholas Weiler
From Our Neurons to Yours Wu Tsai Neuro Podcast

Health influencers and scientists have both gone crazy for peptides.

The peptide health craze stems from a lot of online hype — centered on gray-market compounds that haven't been rigorously tested in humans and aren't regulated for safety or purity. But among scientists, there is a genuine "revolution" underway — spurred by technological developments revealing an order of magnitude more peptides in our bodies than we ever realized, and by the unexpected and unparalleled success of GLP-1 drugs like Ozempic.

To learn more about what’s driving this excitement – and how much of the peptide hype is really worth your attention – we spoke with Stanford biochemist Jonathan Long, an associate professor of pathology at Stanford Medicine and an Institute Scholar of Sarafan ChEM-H.

Editor's Note: After we went to press, Colorado biotech Enveda announced promising but early Phase 1 safety results for ENV-308, an oral drug engineered to mimic Lac-Phe — the "exercise in a pill" molecule Long's lab first characterized in 2022. The trial didn't test actual weight-loss or fitness effects, so the real thing isn't here yet — but Long, a scientific advisor to Enveda, calls it "an extremely exciting potential scientific breakthrough." Read more

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Jonathan Z. Long
Jonathan Long is an associate professor of medicine at Stanford Medicine, an affiliate of the Wu Tsai Neurosciences Institute, and Institute Scholar of Sarafan ChEM-H. 

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Episode credits

This episode was produced by Michael Osborne at 14th Street Studios, with sound design by Mark Bell. Social media strategy is by Julia Diaz, and additional editing by Nathan Collins. Our logo is by Aimee Garza. The show is hosted by Nicholas Weiler at Stanford's Wu Tsai Neurosciences Institute and supported in part by the Knight Initiative for Brain Resilience. 

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Transcript

Nicholas Weiler (00:10):

This is From Our Neurons to Yours, a podcast from the Wu Tsai Neurosciences Institute at Stanford University, bringing you to the frontiers of brain science. I'm your host, Nicholas Weiler. Today's episode is about peptides, and I want to start us off by asking you to hold on to two seemingly contradictory, but actually quite compatible ideas in your mind. Idea number one, health influencers have gone crazy for peptides. They're supposed to help build muscle, heal injury, restore youthful skin, you name it. People are injecting them, snorting them, doing who knows what. Problem is, other than established drugs like GLP-1 agonists and insulin, most of this peptide craze revolves around research-grade molecules people are buying on the gray market that have not been rigorously tested in human beings and are not regulated to make sure what's in the vial actually matches what's on the label.

(01:11):

Idea number two is that at the same time, there is a genuine and very well-founded enthusiasm about peptides within the scientific and pharmaceutical community. There's a revolution underway in our understanding of our biology and what's possible in drug development. This has been spurred by the unexpected and unparalleled success of GLP-1 drugs and by new technological developments that have revealed an order of magnitude more peptides in our bodies than we ever realized. Most of them, we have no idea what they do. To learn more about what's driving this excitement and how much of the peptide hype is really worth your attention, we're joined again by Stanford biochemist, Jonathan Long.

(01:55):

When we last spoke with Jon back in 2024, he told us about a remarkable peptide molecule that his lab had discovered called Lac-Phe. Essentially, what Jon found was that Lac-Phe levels in the blood spike after exercise. And this is true in multiple species, not just humans and mice, but sled dogs and race horses. Giving animals this molecule seems to mimic many of exercise's beneficial effects for our bodies and perhaps our brains. Raising the question, could this become some form of exercise in a pill in the future? So I wanted to talk with Jon about both of these phenomena that we've been discussing. Why are researchers and drug companies so excited about peptides? And what conversations is he having with friends and family about the accelerating peptide health craze? So that's where I started our conversation. Jon Long, welcome to From Our Neurons to Yours. It's great to have you back.

Jonathan Long (02:58):

Happy to be here. Thanks for having me.

Nicholas Weiler (03:00):

I'd love to start. I mean, what kinds of conversations are you having and are there common misconceptions about peptides that you have been hearing?

Jonathan Long (03:09):

Yeah, I think this is a very interesting space, both scientifically in terms of the actual basic science, as well as just in capturing the public's imagination. I mean, most of the conversations I've had with friends and neighbors and even other scientists have largely centered around this one peptide GLP-1, which you alluded to, and you mentioned GLP-1 is the peptide that is the basis of some of these incredible weight loss drugs, including Ozempic, for example, and now there's next generation versions coming online. I think the reason it's been so incredible is for a few different reasons. First of all, these GLP-1 based drugs are very, very effective for weight loss. And this is really sort of a once in a generation type of revolution in medicine that we've actually had a therapeutic agent that's safe and effective for weight loss. And then I think number two, it's fundamentally put peptides on the map.

(04:08):

And the reason for that is because prior to the approval of GLP-1s for metabolic disease, people though that you couldn't really therapeutically harness peptides for the reason that they were injectables. And every other drug that had been developed up to that point was an oral medicine that you would take by mouth. And so for a long time, people thought, "Well, you just can't have a widespread injectable medicine." There had been a few examples here or there, but it wasn't certainly a widespread phenomenon.

Nicholas Weiler (04:34):

Well, insulin, obviously for people with diabetes, but that's a very serious life-threatening condition where people are taking these injections regularly.

Jonathan Long (04:44):

Exactly. And so the though in the pharma world was, "Well, insulin is sort of an outlier, that that's not representative." That in that case, if you're going to die or live, people will take a shot. But in general, people prefer taking their medicines by mouth. And the development of the GLP-1s totally changed that view and upended it to the point where some people prefer to inject themselves rather than take something by mouth.

(05:06):

And so suddenly this entire landscape of peptides as a therapeutic modality opened up because now it was no longer seen as impractical. And so even though scientists had been working on the space of peptides for over a hundred years, it's only been in the recent advent of the GLP-1s that now that science has been really opened up to sort of therapeutic modulation. That's why you're getting so much interest in people asking, "Okay, beyond GLP-1, what else can I inject in myself and what else can I do?"

Nicholas Weiler (05:35):

Right. If this one peptide has these miraculous effects on weight loss, are there other ways I could start tweaking my biology? What else can I inject into my bloodstream?

Jonathan Long (05:43):

Absolutely. Absolutely.

Nicholas Weiler (05:45):

For the purpose of this conversation, how would you define peptides? What makes a peptide different from some other small molecule drug?

Jonathan Long (05:53):

A peptide is a molecule that's in our body that's composed of individual amino acids strung together. And typically peptides are somewhere between say five and 50 amino acids. Now the reason that, for example, you can't take a peptide by mouth and you have to inject it is because these peptides, when they are put together in these chains of amino acids, if you eat them, they get digested in your stomach.

Nicholas Weiler (06:21):

They're food.

Jonathan Long (06:22):

They're basically food, exactly. And so they don't make into your bloodstream. And so you have to inject them. And the reason that peptides are important is because they're a class of chemical messenger in our bodies. So our bodies have something on the order of 30 trillion cells. And all those cells don't operate alone. They operate in our bodies. And so they got to talk to each other. And one of the ways that they do it is by secretion and then sensing of these peptide hormones. And so this represents sort of a fundamental chemical communication mechanism in our bodies. Over the last century, there have probably been on the order of call it a few dozen bonafide peptide hormones that have been discovered to date beyond GLP-1 and insulin as we've talked about. And then even beyond those, there are potentially others that people are making, engineering, or taking from even other sources like other animals or plants or other things like that. And so that's sort of what a peptide is and what it does.

Nicholas Weiler (07:21):

So we talked about the GLP-1s, we talked about the things that people are injecting. I realize we got a little off track of the original question of what are some misconceptions that you find yourself addressing when you talk to people?

Jonathan Long (07:33):

So I think that's a complicated question and one where understanding a little bit more of the history is helpful. Because classically, as you mentioned, there was insulin as a peptide that you would take if you had diabetes. And that clearly works. And I would say that over the last 50 or so years, the people that have been injecting themselves the most with different peptides are bodybuilders. And they were primarily interested in the role of anabolics in that. So they were injecting themselves with insulin, with IGF-1, insulin-like growth factor one, with HGH, human growth hormone. These are all peptides that stimulate growth in anabolism. They're bonafide peptide hormones in the human body. They are approved as drugs in certain cases. And so these bodybuilders go out and get them and they inject them and they use them to grow their muscles and for their bodybuilding shows.

(08:26):

And then I think that was sort of seen as a niche for a long time. And then you had these GLP-1s and now the world opens up. I would say that the science behind that history has been relatively rigorous so far. I mean, you shouldn't be doing N of one human pharmacology, but it was based on sort of real science of growth hormone and these peptides promoting anabolic states in the human body. Now what's happening is the sort of emerging classes of newer peptides that sort of get mixed together with some of these older classes of very well established peptide hormones. So these include peptides like BPC and other things like that. It's a little bit like the subprime mortgage crisis where you take good things, you mix it with bad things, you mash it all together and you can't tell what's good or bad anymore.

(09:13):

And in the same way, growth hormone, IGF, insulin, GLP, these are real endogenous human peptides found in our bodies that have real functions in the purported things that you're supposed to be injecting them for. And then along with that, there's all this other stuff that's sort of unregulated. I mean, things like BPC is not even an endogenous substance. It's some synthetic sequence from who knows where that doesn't have a cognate receptor as far as I know, doesn't have very well established clinical trial grade evidence for some function. And yet all of it sort of being mashed together under this generic category of peptide. And so I think that word peptide is both a way to anchor this whole area, but also a way of introducing confusion because there's really two buckets. There are the peptides that are real peptide hormones that are natural in the human body that have cognitive receptors that are required for the action.

(10:15):

And then there are just people making synthetic peptides that are sequence of amino acids that may or may not have functions where the evidence is much, much weaker than with what has been used historically.

Nicholas Weiler (10:26):

Yeah. Yeah. As I was thinking about all of this and the history of peptides and we brought up insulin, I was just at this amazing summer camp for kids with type one diabetes where my wife volunteers and just reminding myself insulin is a very serious drug, that it's one of the few drugs that has to be checked twice at the hospital. Opioids I think are one of the other ones. This is a very, very serious biological pathway that you're tweaking with. And so for some of these peptide drugs coming out or compounds that are research grade and so on, I worry a little bit that people are saying, "Oh, well, this is natural or this is part of how your body communicates."

(11:15):

It is possible to really, really mess up your biology. And that sort of doesn't even include the fact that because they're not regulated, people are buying this stuff on the internet and have no idea what's in those vials.

Jonathan Long (11:28):

Oh, for sure. I think you're right. I think there's, look, there's a category of a peptide where the level of evidence as you're talking about is like A+ evidence. And insulin is told in that bucket and it's like the difference. Insulin is literally the difference between life and death. And then there's just like a whole host of other peptides that don't come nearly close to that level of evidence. I mean, we talked about BPC, we're talking about collagen peptides that people are selling in buckets and you're eating all this kind of stuff. And so for somebody who's in the science, it's sort of a very confusing and complicated area just because there's so many different peptides that are all lumped together.

(12:10):

For example, you don't have a letter grade with each peptide for what is the degree of evidence? Do you have a clinical trial showing the efficacy you're showing in what would be normally considered a standard level of evidence in the sciences? Or is it just somebody selling something? And I think of course then there's also other sort of financial interests associated with people trying to just sell stuff and that sort of makes the whole space kind of complicated.

Nicholas Weiler (12:36):

So I don't think we need to spend too much time telling people. Hopefully this audience knows probably don't inject yourself with something that we don't know if it's safe or effective and it's not regulated. So you don't know if there's lead in the stuff you're injecting yourself. But just because there is this sketchy sort of health and wellness peptide craze that's not that founded in solid research yet doesn't mean peptides aren't super fascinating. As you were saying earlier, there's this whole space that's opened up with the GLP-1s and with some new technologies I think that your lab in particular is implementing and sort of at the frontiers of where we're discovering more and more about what these peptides are. There are more of them than we ever realized. They do all kinds of things in our bodies that are really exciting. And it seems like it's a huge area of discovery. I've heard people call it a peptide revolution. So I'd love to hear you talk a little bit about that. What makes peptides so special?

Jonathan Long (13:36):

So from a basic science perspective, this is a very interesting and active area where a lot of people are looking at it. The sort of classical view is that you only had these few dozen peptide hormones that have been discovered that act on these cognitive receptors. And this encompasses all of the peptide hormone biology that there is. And what we're learning now with more modern approaches and modern technologies, that doesn't seem to be the case, that there may be more as you're alluding to. And part of the evidence for that comes from this incredible technology that we've discussed before, mass spectrometry, that allows you to look in, for example, human fluids or in the human body and detect molecules with greater sensitivity than you could before.

(14:22):

And when we do that, what we're finding is that there are many, many more peptides than we thought there were produced from many different organ systems that weren't though or cells types that weren't thought to produce peptides. And that raised an interesting question of, well, what are they all and do they do anything? And have we discovered all of the relevant neuropeptides and peptide hormones to be discovered?

Nicholas Weiler (14:46):

What order of magnitude are we talking about when you say we've discovered lots more peptides?

Jonathan Long (14:50):

At least tenfold or more. Or I would say like 10 to a thousand fold in that range.

Nicholas Weiler (14:56):

So we think there are now hundreds of thousands?

Jonathan Long (14:59):

Well, okay. We have to be careful what we're talking about. We can classically in textbooks, let's say that there's on the order of 50 real peptide hormones that we know are very real that are like the insulins and GLPs. And I could go and enumerate about 50 of these. Across different studies now, we can detect many, many more than that. We can detect, call it 500 would be 10X, 5,000, 50,000 in this range. Depending on what study you look at, this is the range that we can detect. Now, the simple detection of these things doesn't mean that they do anything. It just says that they exist. But suddenly the landscape of what exists is much, much larger than you thought it was before. The most reasonable framing is that it's not unreasonable to imagine that some of these other ones might be another GLP-1 or another insulin that has been heretofore overlooked because the detection capability just wasn't there.

(15:54):

And so the most pressing question. So we're still in the first few innings of this much longer ballgame now where we're detecting on the order of, call it roughly 10 to 100,000 peptides in different fluids. And then the question becomes, what do they do? Are they regulated? Most other peptide hormones and other real peptide signals, they change dynamically depending on when you last ate or when you slept or all these other things. Do these have that characteristic physiologic regulation pattern? Do they do anything if you take them and administer them to model systems or give it to cells, for example? Do they have a cognate receptor that they bind to and activate to initiate downstream signaling cascade? And what happens if you remove them from systems? Do they have any sort of disease implication? For example, part of the reason why insulin's so important is because people that can't produce insulin, they become diabetic.

(16:53):

And so it's totally unclear for all these other ones whether a similar sort of disease association's there. So undoubtedly, a lot of these are just things that you can detect that may be floating around in low abundance that aren't biologically meaningful. On the other hand, some of them may really be like the next insulin type molecule just waiting to be discovered. And I would say that sort of fairly captures both sides of that argument.

Nicholas Weiler (17:17):

Well, I was taken with what you said earlier on that these are how our cells signal to each other. It's one of the ways in which the cells in our bodies and our organs send messages to each other. They basically take proteins and clip them or generate these short protein signals. And it's sort of where we're suddenly able to intercept the biological chatter, so to speak, between many of our cells and organ systems. And I think I've read, and correct me if I'm wrong on this, that the thinking is that this is a much more ancient signaling system than, for example, the neurotransmitters that we often talk about on this show being a sort of brain and nervous system oriented show, that this goes beyond that evolutionarily speaking. This is the original language of cells speaking to each other.

Jonathan Long (18:07):

This is an interesting question that I've wondered about. And I know that that's sort of what is talked about. I think it's fair to say that it's very ancient. This is one of the most ancient forms of biological communication between two cells. The idea that you have these peptides that are loaded up in the vesicles that are then exocytose in a regulated way that then release a signal. This is a very, very ancient form of cellular communication. And evidence for that goes, for example, if you go and look at C. elegans, this worm model system, they got lots of neuropeptides as a mechanism of regulating even organismal homeostasis there. So this is a very, I mean, from a scientific point of view, this is a very ancient, very old, very classical way that cells communicate to each other.

Nicholas Weiler (19:06):

Give us a sense of what some of the functions that we're starting to understand from these peptides might be. Just to give us a sense of, we've got the GLP-1s, this is a receptor and it has to do, it is actually related to the insulin pathway. The GLP-1s are promoting release of insulin to get blood sugar into cells and organs, if I'm not getting that backwards.

Jonathan Long (19:31):

That's correct. Yep.

Nicholas Weiler (19:32):

So what are some of the other functions of some of these peptide signaling molecules that have been discovered in the past few years?

Jonathan Long (19:39):

Yeah. So I think that first of all, the idea that many peptides control feeding, just like GLP-1 is something that we're starting to get a better appreciation about. Because as the GLP-1 therapeutics have come online, a lot of people now recognize the control of feeding and body weight to be a therapeutically actionable space. And they're wondering, "Well, if GLP-1 is a peptide that can suppress my feeding and control my body weight, what else is there?"

(20:05):

So there's a lot of other peptides that are actively in clinical development now that are seeking to modulate various processes related to feeding or energy expenditure as a means of modulating body weight. Another class that's actively being developed right now are other incretins like GIP as well as glucagon. And those are peptide hormones that are either being investigated alone or in combination with GLP-1. And those are thought to either suppress food intake or increase energy expenditure to reduce body weight.

(20:35):

Outside of metabolism, peptides are important in sort of behavioral processes and many other aspects of brain health and brain function. For example, many of the neuropeptides that have been described today regulate various behaviors, anxiety, pain, many other sort of central processes. And then beyond that, there's also very many sort of peripheral processes, for example, that are related to inflammation like substance P, or other endocrine peptides that sort of relate to endocrine and hormonal function like in the hypothalamus, adrenal, pituitary axis and other processes like that. So there's a lot of various aspects of physiology beyond metabolism that peptide hormones regulate.

Nicholas Weiler (21:23):

And you talked before about how for many years, the pharmaceutical industry hadn't really considered peptides as a viable medicine just because they generally require injections. Now that that assumption seems to have fallen, what makes peptides appealing as a way of tackling some of these more complex physiological things like feeding behavior and things like that? How do they compare to small molecules and other kinds of drugs?

Jonathan Long (21:55):

So peptide engineering is a field that's just taken on a new life of its own. Because what you have in these peptides are defined amino acids in a linear sequence. And this means that it's conceptually relatively straightforward to engineer the thing because you can literally go amino acid by amino acid and start to ask what changes each amino acid have on a function. And so for example, the Ozempic now is a super engineered version of the natural human GLP peptide. You add a lipid to one of the amino acids, you change a few other amino acids and now it's super stabilized. And that becomes an interesting mechanism of trying to therapeutically develop these. You take a natural peptide that's short-lived and you do this kind of chemical engineering to make it longer lived and you ask what happens when you do.

Nicholas Weiler (22:47):

And that's how you get from needing a daily injection to weekly injection and that kind of thing.

Jonathan Long (22:52):

Correct. Correct. Or I mean, in the case of the GLP-1, they're even infusing them to antibodies. And MariTide being developed right now by Amgen is purported to be like a once every six month injection. So there's a proximal question there of half-life engineering where you extend the half-life and you ask what effects it has. And what's interesting about that is that it's actually surprising what you can get. For example, a lot of the pharmacology that we're seeing with GLP peptides and sort of the long-lived GLP peptides is way beyond what the natural GLP-1 system does. And so what you actually get is sort of super pharmacology as a result of that. And that's sort of an interesting speed that has not really been explored before. The second aspect is that people are making these so-called, it's a complicated chemical name. They call it unimolecular polyagonist.

(23:43):

What that means is you're basically fusing peptides together in an unnatural way. So to give you an example, Ozempic right now is a GLP-1 peptide that's super long-lived. The next version of that that Eli Lilly has developed and is now approved is called Tirzepatide. And Tirzepatide, what it is a fusion of GLP and another incretin hormone, GIP, in the same molecule. So that's why it's called unimolecular. And it's called polypharmacology because it's two different targets, multiple targets downstream of that. It's both GLP receptor and GIP receptor. And again, what happens when you start to fuse these peptides together in this way is that you start to get interesting new pharmacology that you didn't get just from the individual components alone. And so now, for example, in the biotech space, they're talking about pentapeptides. You fuse five different peptides together with GLP-1 and you get this mega thing that's supposed to be like a super metabolic drug.

(24:41):

And we'll see where... I mean, that's sort of the iteration that it's gotten to and we'll sort of see where that's gone. So I would say that in the space of peptide engineering, it's become a whole cottage industry. And it's quite incredible and surprising what kind of new activities you can get, both from the half-life extension of existing peptides, as well as doing combinations where fusing different peptides together to get new pharmacologies.

Nicholas Weiler (25:04):

And this is because they're these short sequences of amino acids, and so easier to get your head around what are they and modify this one place, this other thing, compared to other kinds of small molecules which are just much bigger and more complicated.

Jonathan Long (25:20):

Absolutely. I think that the way to think about peptides is these are like Lego blocks. And it's just a matter of, it's a very modular unit. The amino acid as a basic unit is very modular and you can stitch them together in all sorts of different ways. And it's very easy to stitch them together. The chemistry is very easy, invented by Bruce Merrifield, solid phase peptide synthesis. And so it means that testing combinations in a pseudo rational way is now much easier. By contrast, the small molecule drugs that you're talking about, opioids and some of these other things, these are sort of intact, complicated mega monsters that you need to deconstruct and reconstruct and you can't do it in an easy modular way. And so that just presents just much more a greater challenge from a chemical perspective because the unit of forming that molecule is not so modular.

Nicholas Weiler (26:09):

And the other thing that people are doing, if I understand correctly, is taking a target that we want to drug, let's say there's a receptor or something, and saying, "Well, can I just design a peptide that's calculated to fit in some hole in that target?" So again, this peptide engineering making it possible to do sort of custom biology in a way.

Jonathan Long (26:33):

Yeah. I mean, the AI approaches to sort of peptide engineering and design have been exploding as you know recently. I mean, there's whole companies now where the whole thing is we can use AI to rationally engineer a peptide to bind to a certain receptor pocket in an unusual way. In a biased way maybe, which means that it'll stimulate a certain pathway downstream of that receptor, not some other one. Whether that will actually work out still remains to be seen. It's still a little bit too early to tell, but that is sort of the promise of that space.

Nicholas Weiler (27:03):

Well, let's talk a little bit more about the area that your lab has been focusing on, which is this idea of can we bottle the benefits of exercise? Or I think you said exercise in a pill form. So trying to understand what are the biological pathways, some of which are peptides, some of which are not, that are engaged when we exercise. And we know that exercise is one of the best things we can do for our health in all kinds of ways from longevity, neurodegenerative diseases, heart disease, all these different things benefit from exercise. And I have to say, and just to sort of get this out of the way, I think when you talk about exercise in a pill, that is simultaneously very appealing. I had to force myself to get up early and go work out this morning. And taking a pill would've been easier, but also a little unsettling. I think people have a little bit of a reaction of like, are we shortcutting the hard work here? Is this a Wall-E kind of future we're talking about? What's your response to that? Why do we need exercise in a pill?

Jonathan Long (28:04):

Well, I would say that again, sort of the historical view here helps a lot. And in particular, this conversation that we just had with GLPs helps a lot because before you had Ozempic as a medicine, weight loss was a willpower thing. And people who couldn't do it were somehow weak-willed. It was a non-biological reason for this, non-physiologic reason. And I think the advent of weight loss drugs tell you and illustrate to you exactly what you just talked about for exercise, which is that on the one hand, it's an incredible tool that allows people that, for example, cannot achieve the weight loss that they need to or cannot achieve sort of the blood test that they need to. It enables them to suddenly be able to do that and opens up new horizons for them. And at the same time, it opens up some uncomfortable discussions about what this is.

(28:55):

And I think what GLP did for weight loss, what statins did for cholesterol, what antihypertensives did for blood pressure, we need that type of tool to harness the benefits of physical activity. Because why would you not want such a tool if it were accessible to you? And so I just think I sort of view it as the natural progression of science is to understand processes and then harness them for the benefit, especially people that, for example, cannot achieve those benefits on their own or need help to achieve those benefits. And exercise amongst all the different interventions is sort of one of the most remarkably beneficial for our health. And so why not try to therapeutically harness that if we can?

Nicholas Weiler (29:39):

Right. Yeah. And you make a great point about not everyone is able to exercise. What if you're elderly and frail? What if you are in a wheelchair? There are various reasons why it might be difficult. And as you say, let's understand the biology. Let's get the benefits that we can.

Jonathan Long (29:55):

I also think, just to make one other comment about that, I think normally when you think about what... In our lab, when we think about exercise and the health benefits, we typically think about cardiometabolic benefits. But I think in your world, there's a lot of benefits of exercise in the brain that you would certainly like to capture and harness independent of the physical activity itself. For example, exercise is really good for mood. It's really good to prevent the onset of neurodegenerative diseases. If we could harness that or even further augment that therapeutically, it's not necessarily to say that it's just another tool in your arsenal that could benefit a lot of these sort of exercise adjacent processes.

Nicholas Weiler (30:35):

Absolutely. Well, let's talk a little bit about Lac-Phe. You told us last time on the show about these really cool experiments you did where you tested blood from humans and mice and race horses and sled dogs after intense exercise and identified this molecule that seems to be elevated after we work out, and you can give it to mice in the lab and it suppresses their appetite and has positive effects on obesity and so on. And you've been learning more about this over the last couple of years since we last talked. I wonder if you could just give us an update on what you've been learning about the mechanisms of this molecule over the past couple of years.

Jonathan Long (31:16):

Sure. So I can give you sort of two updates, one on the basic science front and then one on the human translation front. So on the basic science front, we've been working on this pathway, this Lac-Phe molecule originally we described as being a lactate derived molecule produced during intense exercise, rise in your blood, goes to your brain to suppress feeding. So one question was, how does it suppress feeding in the brain? Last year we published a new paper in Nature Metabolism describing how it activates certain hypothalamic circuits. These are very classical feeding circuits in a region of the brain called the hypothalamus. And what it does there is it suppresses the action of AGRP neurons, which are these orexigenic neural populations. It activates anorexigenic POMC neurons. These have been very classically described as feeding neurons previously. And it activates these neurons to regulate feeding.

Nicholas Weiler (32:08):

And so that's interesting. Yo said anorexigenic, and that makes me think of anorexia. Are these related or are these just related words that mean different things?

Jonathan Long (32:16):

Related words that mean different things. So the anorexia is a very interesting but also complicated topic. And it's not clear whether any of these pathways I'm talking about really relate to anorexia in the colloquial sense of the term, but it's just anorexigenic meaning that it suppresses feeding. So it works in the brain in this particular feeding region, the hypothalamus. The other thing that we've learned is I told you it's produced by exercise, but where does it actually come from? It turns out it's primarily produced in your gut and specifically in your intestinal epithelial cells, which is a particular population of cells in your gut.

(32:53):

And so this is not just any periphery to brain circuit. It's actually representing a gut to brain feeding circuit. And then the last thing that we've learned on the basic science side is we've learned that there are other stimuli that can dramatically increase Lac-Phe levels. So we described originally how sprint exercise can increase Lac-Phe. And we think that's from not only lactate producer in muscles, but potentially from gut hypoperfusion and therefore increased lactate production there.

Nicholas Weiler (33:19):

So when more blood is going to your gut?

Jonathan Long (33:21):

Not enough blood because the blood is going to your muscles so you can run. Exactly. But we actually found that metformin is a very strong inducer of Lac-Phe levels. So metformin is a very, very widely prescribed and widely used anti-diabetic drug. And what we found is that both mice and people that are on metformin also have increased Lac-Phe levels and that Lac-Phe explains part of metformin associated weight loss. So that's sort of a very quick summary of what we learned on the basic science side. We've both learned where it comes from, which is the gut, where it acts in the brain, which is hypothalamus, and a few other regulators of its activity, which include exercise and metformin.

(34:00):

I think what's been most interesting to me from a more translational perspective is that actually there was a recent first in human infusion trial, a phase one trial of Lac-Phe in Denmark. So this was a group at the University of RS. They recently completed the study. The results are still pending. So I don't know what it is, but they took healthy human volunteers, about 30 of them, and they infused to these individuals Lac-Phe. And they asked what happens and they've taken all sorts of measurements. And so I'll be as excited as anyone to learn the result of that clinical study.

Nicholas Weiler (34:34):

Oh, me too. Yeah. Well, definitely let me know when that comes out. We'll have you back on and talk about what that means.

Jonathan Long (34:40):

Sure.

Nicholas Weiler (34:41):

It connects to what I wanted to ask you next, which is how do you see this sort of fitting into this broader picture we've been talking about? We have our GLPs, which also are doing appetite suppression. It seems like Lac-Phe is acting in part as an appetite or maybe largely as an appetite suppressant. How does Lac-Phe fit into this landscape now that we've got GLPs on the scene? And then after I ask that, I'll ask you what else is out there? What are some other things you've got your eyes on?

Jonathan Long (35:09):

I think it's an interesting question because there's sort of two lenses to view that question. One lens is through sort of a feeding lens, and then another lens is just from a peripheral signals lens. So maybe let me tell you about the feeding lens first. Well, we start to understand just in terms of how do our bodies regulate how much we eat? This is not sort of written anywhere, but this is sort of my view, which is that if your brain were left to its own devices, you would just be an eating machine. It would just be unrestrained eating.

Nicholas Weiler (35:39):

Some days it does feel like that.

Jonathan Long (35:42):

And part of our body system of constraining feeding in the brain is by the production of peripheral signals that then go up to our brain and tell it to stop eating. And so what you end up having are in general, lots and lots of different peripheral signals that are cross-talking your brain, most of which are in the directionality of stop eating. And so I think GLP-1 is sort of one of those. Lac-Phe is another one. There's many others, leptin, other gut peptides like PYY, CCK, GDF15. So there's many signals that all sort of suppress feeding. They're all sort of peripherally derived and go to your brain. So I think that's how you think about Lac-Phe in that context. Lots of peripheral signals produced from different places induced by different physiologic stimuli, including nutrients or exercise or stress that then tell your brain, "Stop eating."

Nicholas Weiler (36:32):

And you could imagine wanting some kind of stack of these in the future to say, "Well, I want to target this and that and a little bit of this," and just sort of put those all together.

Jonathan Long (36:42):

Exactly. And the central circuits through which they act are overlapping, but also different. And so they're non-redundant pathways of periphery to brain communication. I think another way of understanding them, another lens is through the individual molecules themselves. And what I mean by that is that GLP originally was found as an incretin, which means that it stimulates insulin secretion. Later on, it was then shown to be therapeutically very interesting as an anti-obesity drug that suppresses feeding. But now they're starting to emerge an even more interesting literature about potential anti-inflammatory actions of GLPs and other actions in the liver to prevent the accumulation of liver fat and fibrosis. And so what I would say there is that then what you have are these individual ligands, in this case GLP, that actually has pleiotropic downstream activities of which feeding is just one. And in the same way for Lac-Phe, even though we originally found this in the context of feeding, just like they found GLPs in the context of insulin secretion, that's not to say that this is going to be the only function here.

(37:45):

And as we're learning more about it, we're actually finding other effects, particularly in the brain. And other people are reporting other effects. Some people about Lac-Phe being good for reducing risk of colitis and IBD as an anti-inflammatory agent in the gut. Others, there was a recent paper reporting an anxiolytic effect of Lac-Phe, which means that it suppresses anxiety in certain mouse models. So it's another action in the brain. And as we think about the effects of exercise broadly, there's many different effects. It's sort of unclear whether those effects may be ascribed to a single molecule or multiple molecules. But at least my view of Lac-Phe is that even though we originally found it in a feeding context, it's likely to have many other effects more broadly than that.

Nicholas Weiler (38:26):

It's such an important point to remember. And we bring this up all the time on the show talking about things like dopamine. Just because experiments focus on particular outcomes of dopamine or particular functions of dopamine, because that's a thing you can measure in mice, doesn't mean that that's the only thing it's doing. It's doing lots of different things in different contexts. And the same thing is likely to be true, maybe even more so for a lot of these peptides.

Jonathan Long (38:51):

And I think this is just generally true in all of scientific discovery in peptide space and elsewhere. For example, I mean, other very famous neurotransmitters like acetylcholine were originally discovered in these biochemical assays where they contract smooth muscle in a dish. And certainly acetylcholine does that. But now our interpretation of acetylcholine as a neurotransmitter is fundamentally different and shaped by cholinergic neurotransmission. That sort of idea of an initial discovery in one space in an eventual application, an eventual breadth of application in many different processes is not new. And I sort of view Lac-Phe in the same way.

Nicholas Weiler (39:55):

I want to continue this, talk a little bit about the benefits of exercise, this vision of some of the benefits of exercise in a pill or maybe in an injectable more likely. What are some of the things you have your eyes on? You mentioned the clinical trial with Lac-Phe, which is very exciting. What else is out there in this space that's targeting various aspects, various beneficial aspects of exercise?

Jonathan Long (40:20):

So there's a lot of work even here at Stanford, for example, work from Helen Blau that's targeting prostaglandin signaling in the context of exercise for regeneration and repair. And then sort of zooming out a little bit broader beyond individual pathways, there's still this very, very large nationwide effort called MOTRPAC, of which MOTRPAC stands for Molecular Transducers of Physical Activity. And Stanford is actually one of the major sites there with Steven Montgomery in genetics and pathology being one of the lead principal investigators. And their goal is to map systematically all of the molecular changes in exercise in both rodent models as well as human models. The rat exercise data was recently published in Nature, I think a year or two ago. And now some of the human data are starting to come out and that's going to be a very exciting resource.

Nicholas Weiler (41:11):

Is that something where we saw Human Performance Alliance is involved in that effort or is that separate?

Jonathan Long (41:18):

It's separate, but adjacent, very adjacent. So MOTRPAC was actually originally an NIH study that was started about 10 years ago now that was trying to map sort of molecular transducers of exercise. That's a very long-term project where the readouts are now starting to become sort of disclosed and disseminated more generally.

Nicholas Weiler (41:39):

Do you know of any other molecules in this space, particularly in the exercise space that are actually moving into clinical trials or are already in clinical trials?

Jonathan Long (41:48):

Yeah. I think the best example is a peptide hormone called Apelin. Apelin is a peptide that acts on a cognitive receptor called the Apelin receptor. It's a peptide hormone, exercise inducible, seems to have very favorable metabolic effects in that it suppresses body weight and food intake, but also preserves muscle mass, at least in preclinical studies. And so there's actually a biotech here in the Bay called BioAge that's seeking to develop Apelin as a therapeutic target. And their pitch is sort of this sort of exercise mimetic type of molecule. I would say that that's sort of the closest one that I'm aware of. I think there are some other efforts around the country, but nothing in particular comes immediately to mind.

Nicholas Weiler (42:38):

So you paint this very exciting picture of where we are in discovery in this space. There are so many different peptides. We're learning a lot more about what they do, how to harness them, what are some ways that we could engineer them and make synthetic peptides to improve human health. And one of the reasons why I wanted to have this conversation with you is just to sort of do a gut check, so to speak. There's all this enthusiasm out there in the public, as I said, on podcasts and on Reddit, if you look in the right places and in these influencer spaces about using these peptides. And it strikes me that it's not wrong, it's just maybe a little premature. It's gotten ahead of the science. There's a big eagerness to say, "Now that we can see what this GLP-1 stuff can do, how transformative it can be, what else is out there?"

(43:29):

How would you advise listeners or just anyone, how would you speak to that tension between people being really eager to optimize their biology, get more healthy, and get fit, and where the science really is right now?

Jonathan Long (43:46):

I think it's very easy to get excited when you don't have data. And this is something that I see all the time as a faculty member doing science here. The best and most exciting time for a project is before you do an experiment.

Nicholas Weiler (44:01):

Right. Because anything is possible.

Jonathan Long (44:03):

Because anything's possible. That's the most creative time. That's the most interesting, exciting time. And then as data come in, then you start to ground yourself about what the reality is. And where we are is really in that first phase. There's a lot of excitement and a lot of real data coming in on GLP-based medicines, on not just Ozempic, but the next generation versions of that, Tirzepatide, Retatrutide, the /peptide subreddit, is all about Reddit these days. And then for all these other aspects, could you enhance your mood? Could you enhance your cognition? Could you enhance your immune system? Could you enhance all these other things? That's certainly much more speculative. So I think it doesn't have to be binary. You can hold both sort of truths together, which is that we're in an incredible time in research and medicine where peptides are now a thing.

(44:56):

And you couldn't have said that 10 years ago. And peptides and especially GLP-based medicines are doing things that are totally incredible that we would've never imagined that they could do. At the same time, beyond GLP, the data are very sparse. And I think those are truths that we can and should try to hold simultaneously. That's not to say that that future won't happen. It's just to say that it's not happening right now. And it might certainly take much longer to get the level of evidence that you would need. For example, most people don't realize that the first GLP to actually get approved in a person was Byetta in the early 2000s. So we've had GLP-based medicines for almost 20 years now. I think that's sort of the history that people need to understand is that in the '80s, GLPs were discovered. The first GLP medicine was approved 20 years later.

(45:47):

And now we're at a place in 2026 where we've had 20 years of GLP-based medicines. And that's the level of data that needs to be accumulated before you can talk about things like Tirz or Reta. And so when people come on with new things, I mean, this is for us too with molecules like Lac-Phe. I mean, we are back in where GLP was in 1980, and we have to remember that timeline. And the timeline is not because the development is slow or that we're hiding something. It's that it just takes a long time to figure some of this stuff out. That sort of appropriate perspective would be helpful. As both, I think the enthusiasm is good for this new space and I also think it should be tempered with knowledge of the history.

Nicholas Weiler (46:29):

Yeah. Yeah. And what I would hate to see is people hurting themselves or injuring themselves and sending this space back because of concerns over these peptides are toxic when really it's just these unregulated compounds.

Jonathan Long (46:44):

The regulation of this space is a whole other interesting discussion that we haven't talked about, but I think is interesting to think about. And the history here, it also comes back to history. So for example, here there's a molecule that's known called dinitrophenol, which was actually a weight loss drug that people were taking. And what it does is activates your mitochondria and you get hot and you start to lose weight by burning off your fat. That was actually a molecule discovered here at Stanford in the 1930s, but it was unregulated at the time. And people started to overdose and they died from dinitrophenol. And what happened as a result of that was the FDA came as a result of that. And then you had regulation of drug substances as a different category than regulation of food substances. And peptides is interesting from a regulatory perspective because neither of those categories fit what is happening right now in the peptide landscape.

(47:36):

And so my speculation would be that if someone, for example, were to start taking some peptides and start dying, or if it really did cause harm in a serious way, that what we would need to have at a federal level is fundamentally new regulatory infrastructure to deal with this category that right now the FDA, or for example, the USDA does not cover.

Nicholas Weiler (47:57):

Right. Well, when those changes happen, when we get these new results, we will be giving you a call and having you back on the show. Jon, thank you so much for joining us on From Our Neurons to Yours.

Jonathan Long (48:08):

Great. Thanks so much.

Nicholas Weiler (48:12):

Thanks again so much to our guest, Jon Long. He is a associate professor of pathology at Stanford Medicine and an institute scholar at Sarafan ChEM-H, the Institute for Chemistry, Engineering, and Medicine for Human Health. To read more about his work, check out the links in the show notes. If you enjoyed this episode, be sure to subscribe for more conversations from the frontiers of brain science. We also love hearing from listeners. If you have thoughts about the show or questions about the brain you'd like to hear us discuss on a future episode, send us an email. We're at neuronspodcast@stanford.edu, or leave us a comment on your favorite podcast platform. While you're at it, please give us a rating and share the show with your friends. It might seem like a small thing. I know every podcast in the world asks this, but it is tremendously valuable for us to be able to bring more listeners to the frontiers of neuroscience.

(49:05):

Coming up on From Our Neurons to Yours.

Carolyn Bertozzi (49:09):

When I give lectures to a non-scientific audience, I often show a slide with an M&M on the slide just to make exactly this point that cells have a sugar-coating. But then I switched to another image of the planet earth because I don't want people to think the sugars on our cells are as simple as they are on the M&M.

Nicholas Weiler (49:34):

From Our Neurons to Yours is produced by Michael Osborne at 14th Street Studios with sound design by Mark Bell. Our social media strategy is by Julia Diaz. Additional editing by Nathan Collins. Our logo was designed by Amy Garza. I'm Nicholas Weiler. Until next time.

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