Top Stanford Professor Weighs in on How Exercise Changes Your Metabolism

You are what you eat. I hate that. I'm like, you are what your body does with what you eat.

That's a good point. Say the things we do the most, those are the things we know the least.

Your body's going to dance different molecularly depending on your, like, just insulin sensitivity. A huge discovery.

It's engaging every organ in your body. Your muscle's a pretty big organ.

Could that higher insulin level mean that benefits aren't as big?

What's better, sprinting or Long distance running.

If you don't recognize the man with me, this is a guest arriving back, a very special guest, Professor Michael Snyder, one of my favorite scientists of all time. To give you a bit of background on him, he served as the chair of genetics at Stanford School of Medicine and is currently the director of Stanford Center for Genomics and Personalized Medicine. His lab is an unparalleled world leader when it comes to metabolism science. If you just look at his publication records, just a litany in Cell, Science, Nature, Really incredible. I had him before to talk about, uh, his 4 types of diabetes paper and the most viral aging paper ever published in Nature Aging. You can go back and watch those if you want. But today we have a 2-part interview, and in part 1, we're going to talk about what is undeniably my favorite exercise study of all time, published in Cell in 2020, on which he was senior author. I think we're going to build up to a graph, and this is going to be a big promise, but I think we can sell it, that is going to change the way you see the gym forever. So we'll see if we can collectively pay that off. Professor Snyder, thanks for coming back.

Wonderful to be here.

All right, I'm going to jump right into it. So this paper that I'm building up, it was titled The Molecular Choreography of Acute Exercise. Why'd you choose that title?

Well, because so many things happen and they seem to happen in an orchestrated fashion. So maybe we should describe what the study's about for a minute here. So what we did was we had a group of people, 30-some, run to their VO2 max. It's about an 8 to 12 minute run, but it's pretty exerting, if you've ever done this before. You start out slow and by the time you're done, you've gone full force. And so we measure people in incredible detail before they took off, if you will, and at the very end when they stopped, and then we followed them, you know, as they recovered throughout. And when we followed them, the way we do it is we do it in incredible detail, meaning we'll look at as many molecules as possible in their blood, their RNA, their proteins, their metabolites, their lipids, hormones, every cytokine, so immune markers, everything you can think of. We also profile the microbiome and things like that before they start, just so we understand them in incredible detail. And so that was the goal, is to get a very, very detailed look what happens when you do an acute bout of exercise. And we had a world-famous physiologist, uh, François Haddad, who actually did all the heart measurements and knew what to measure there. Uh, he's— that's really his specialty. Our specialty is the molecular measurements. And so we could try and get a really deep portrait, if you will, of what happens when people exercise to their, again, VO2 max, which you may or may not know is an important indicator of someone's lifespan. In fact, it's the best correlator out there.

Can you define VO2 max for us? Ask a couple more questions about the methodology.

Probably simplest way to think about it, it's, it's your burning, your efficiency, if you will, of respiration, taking oxygen, and you're pushing yourself, and it measures your heart rate. And I'll leave it kind of vague like that. Bottom line is it's, it's really looking at your efficiency, and it does drop gradually over age. But people have low VO2 max are in trouble. So I would encourage all your listeners to keep their VO2 max up. And actually, how do people do that?

So one, what was the, the actual exercise protocol that you subjected people to? Because I know people, if I don't ask that question, they're going to want to know, well, like, kind of like how they could replicate it. What are they going to do?

Yeah, that's a good point. You can measure it in different ways and you don't necessarily get the same answer. We did it by having people run on a treadmill with a slight incline. And so that's a pretty common way. Some people do it on bicycles. There are other ways of doing it. And you wear this mask and that's what's measuring your oxygen and CO2, if you will. So you can measure your efficiency. And you can get these things from a watch. They're not as accurate, but, you know, it's giving you some indications better than nothing, I would say. And so Well, that's the one we use. We use— this is a gold standard used at Stanford, so I guess I'll leave it.

There are different types of studies, uh, for people who don't know. Sometimes you have a pre-existing hypothesis and you want to test that, see, you know, true or false, you reject the null or not. Other times this is exploratory. Based on the way you just explained it, it sounded like this study was more exploratory in nature. You want to capture like this huge compendium of different things that are happening in people and then categorize what's going on. Is that a fair representation?

Absolutely. And in fact, that tends to be a hallmark of our research in general. I like to go into these things with the idea we know nothing or very little, which is true for exercise before we started this. I mean, we do know a certain amount, mind you, but it's not nearly what we should know. And I like to say the things we do the most— eat, sleep, exercise, maybe other activities— those are the things we know the least. And so I— the idea is to dive in deeper on some of these things and see what's really going on. And that was the basis of this, just see what happens when people do an acute bout of exercise. There are now other studies out there. There's a big one called MotorPAC that's studying people, uh, either doing strength training or aerobic training, meaning running kind of thing. Um, and basically they're, they're studying both acute bouts as well as what happens when you train for 12 weeks. So That's a very, very large study. It's a $200 million study. Our lab isn't quite that wealthy, so we did a much more focused one. The people we study, they're very well phenotyped, very well characterized. So we know what their insulin resistance is, which, as you know, is precursor to diabetes, things like that. So because we have all these measurements on them, we can try and see, tease out nuances that you wouldn't necessarily get just by taking an average person, watching them exercise. We can see, well, based on their characteristics, how do they perform? Perform, what's going on better.

I'm sure we will. You're foreshadowing what I'm building to, which I think you know the graph I'm probably speaking about. But before we get to that, you discovered like 4 basic clusters of how molecules in the body change with exercise. Now maybe I'm testing your memory a bit. I think it's been about 5 years since you published this paper, and you published dozens if not hundreds in between. But do you remember what those 4 clusters were? Can you describe them?

The first one, and the one that of course interests most people, is, you know, what happens, what's the burst of changes that occur? So what we're comparing things, you measure people immediately after they exercise and several time points thereafter. So we catch 'em right after, we call it 2 minutes, 15 minutes, 30 minutes, an hour later relative to baseline before they started exercising. And the first group of things are things that just burst up that are really high. And that one has a lot of the stuff you would expect. It has oxidative stress. So you, when you exercise, you really use your mitochondria a lot, your muscles in particular. So they're really working hard and you're trying to generate as much ATP. You're actually breaking down glycogen to make glucose. There's a lot going on. And we do see that actually happening there as well. A lot of metabolic shifts. You see shifts in, in like glycolysis and things like that. 'Cause your, your body's really consuming a ton of exercise when you run hard like that. You really are pushing yourself to the max. Incidentally, a little anecdote. Every time you do this, I do, I've done it quite a bit. Always think, oh, I could have gone a little harder. But anyway, but you're pretty exhausted even though, again, it sounds pretty short. And so there's inflammatory markers in there as well. So the oxidative stress we talked about, a lot of metabolic markers are in there, a lot of signaling molecules are there, and inflammation. And I know inflammation sounds bad. You think of inflammation as bad generally, and chronic inflammation is bad actually in general. Like, people with diabetes have chronic inflammation. I had it when before my diabetes was managed. You know, you don't want to have chronic inflammation, but these bursts of inflammation, they're thought to help reorganize your muscle. And I think to the title of the paper, your first question, there's just so many changes going on. That's the first one.

Before we get to the second pattern, I had a question that you've, you've foreshadowed, so I might as well click on it now because it's really important point that you just touched on, which is this idea of inflammation being bad chronically but actually really adaptive acutely. So you termed this in the paper, another brilliant turn of phrase, the fitness inflammatory signature. And if I understand correctly, that burst of inflammation, like having a high altitude peak, you could say, of inflammation with that drop quickly, is actually a signature of fitness and health. And those molecules that like maybe at baseline, if they're elevated, are harmful, they're signals to your body to adapt. So you do damage like at the macro level during exercise, you rip up your muscles, but also at the micro level, you have these inflammatory bursts that are signals to your body to like evolve and adapt. So that chronicity there is—

Yeah, absolutely correct. So this is a good burst, a good inflammatory burst. And believe it or not, the exact signaling molecules aren't quite the same either as when you think about chronic inflammation. And I don't— at least I don't fully understand all the details of this, meaning a common cold inflammation is very different from an exercise boost. The different cytokines that go off are very, very different. Some of that makes a lot of sense when you're trying to fight a virus. That's very different. From reorganizing your muscle. But it does involve your macrophages get in there. Your immune system is very, very engaged when you do this bout of exercise because again, it is bursting. And people are fit, they actually recover pretty quickly. So this inflammatory response comes back to baseline. And in fact, recovery is a good sign of fitness. I don't think we look at that enough in general, I would argue.

We're gonna get into some of the recovery molecules later, but I cut you off after cluster 1. So then what was cluster 2, 3, and 4?

Yeah, so Cluster 2 was a little more delayed response, things coming up a little bit slower. Cluster 3 was things that went down and then came back up, and Cluster 4 was things that came down and certainly didn't come up in that 1 hour that we looked. I assume they came back a day later or so. In fact, we know they did, and they had different classes of molecules. And so I will try and remember them if I can. Cluster 3 was some very interesting molecules, leptin and ghrelin. Those are two molecules involved in appetite. And it's known that you initially suppress your appetite while, you know, right after you exercise, but you get hungry later. And so these molecules, they're called the hunger molecules, leptin and ghrelin. And basically what's also interesting is that they, well, yeah, they can come from different organs, but your gut's certainly a major one. And that's another thing I'd like to actually emphasize from the study. Every part of your body is involved when you exercise. It's not, you know, you just think maybe your lungs or your legs if you're running, but you're really engaging all aspects of your body. So we're seeing liver molecules, kidney, all these things. That's the advantage of the sort of global approach, if you will, this exploratory approach. You're trying to look at everything. And to me, that was one of the most remarkable parts of the study, that your entire body is engaged, your liver from the metabolic side, your kidney, your muscle, and I don't think people appreciate, but even your brain is very, it's a pretty important metabolic organ. I think again, very underappreciated. And if you look at some of the molecules that changed, some that were in this first cluster that burst up, those are omega-3s. These are these signaling molecules that are important for cognition, things like DHA, EPA. This might be getting in the weeds a little much, but they basically, they, they, went up when you signal. And then there were in this class of molecules that went down that and didn't recover quickly. Well, those are other kinds of fatty acids. Those are triglycerides and things like that. And that's probably due to energy consumption. Again, you're— when you run to your max, you're consuming energy any and every way you can. Your amino acids are— you're breaking down proteins and making amino acids and then consuming them.

Yeah, I wanna double-click on that because that was another thing I found in the paper that was extraordinary. Which is— so you mentioned triglycerides, which are the, like, the fat fuel circulating around in your body. There's like free fatty acids, but generally they have the storage form, you know. And the fatty acids, which are like major energy molecules in the body, you'd think with exercise they'd just be consumed and dropped. But there was this divergence which you just mentioned, which was that like some went down and some went up. So if I recall correctly, like saturated fats went down in particular, the idea being that they're used for fuel. But then the omega-3 fats, the polyunsaturated omega-3 fats, they weren't consumed for fuel. They themselves served— well, they could be energy substrate instead as signaling molecules. So you got this divergence where the saturated fats went down and the omega-3s went up because you used one for energy and the other one was the anti-inflammatory, uh, response. So that after you get that fitness inflammatory signature you then can quell it quickly, right?

Yeah, you're spot on. These are— we don't— all fatty acids aren't the same. I mean, that's— people tend to lump the stuff all together, but they're not. Some are used for energy consumption. It's exactly what you said, Nick. And then the omega-3s, they really are signaling molecules. They may have other functions in the brain, too. It's pretty clear for those who don't know, the fish oil or omega-3 have a lot of omega-3s.

And so—

and that's very beneficial. It's one of the few areas where I think supplements have been shown to be effective. I think supplements probably are effective in lots of ways. They just haven't always been shown. And anyway, omega-3s, there's a lot of studies and, and certainly foods with omega-3s are very beneficial for cognition, all kinds of things. And actually eyes, believe it or not, most of your omega-3s in your brain and your eyes. So who would guess, right, that exercise would be beneficial this way. But if you think about people who are very fit, they, they have good cognition in general. And in fact, this is why we think exercise is so important. It really does affect every aspect of your body. It does— well, some of the things we saw change are probably not emphasized in the paper are apoptosis pathways. So meaning some cells are probably breaking down some of these bad cells, if you will. And there's something called mitophagy or mitochondria eating up the bad ones. We think that this burst of exercise probably helps your overall mitochondrial function. You make a lot of reactive oxygen species from your mitochondria when they're pumping full force. And that's why we see the oxidative stress, we think. But you also probably stress out and get rid of a lot of the bad mitochondria, at least so the hypothesis goes. And natural selection of mitochondria. Yeah, yeah, basically that's how I view it anyway. That's not been shown by the way, but I think, you know, your mitochondria, mitochondria get damaged as you get older, but your DNA, mitochondrial DNA, thanks to these reactive oxygen species, that's just part of how they work. And so if we can select out the good mitochondria, and again, as the hypothesis goes, that maybe that helps keep us functionally longer. And of course, you know, less fatigue and such.

I want to return to that The title, just to kind of give people my impression of every time I reread it, because there's very few papers I reread. This one I reread often. It has a deeper meaning for me every time. So the first time I read it, some of the things I've already communicated kind of struck me, like this, like, divergence pattern of the saturated and unsaturated fats. But then I'll come across, like, data on how omega-3s are turned into all these different hormones. So, like, one's called— the details aren't important— but 12-HEPE and how that changes brown fat metabolism and muscle metabolism. That are derivatives of omega-3, so then you have that cascade, or you're talking about mitophagy, you know, the idea that these aren't just little engines, they're traded between cells, they go through fusion and fission cycles, and then like you can partition away the damaged components and then get cleared during exercise. Again, detail's not important, but like every time I look back at this, there's just another layer of the complexity of the choreography that is just like humbling.

Yeah, I'll be honest with you. I reread it every now and then, in part because we're doing other exercise studies. And I learn from this when I go back and look at our own study because there is a lot in there. And you can also see it in new context. So for example, one of my colleagues, Jonathan Long, discovered a molecule, LAC-Phe. It's a combination of lactose and phenylalanine. Very interesting molecule. Turns out it was in our study as an unknown. Tone. So we didn't know what it was at the time, but it was one of the top-induced molecules in that first class. Yeah, class that burst up. And he went on to discover— he found this in mice, you know, called us up and said, can you check here? And sure enough, it was one of our top molecules. And what he did, a beautiful characterization showing it has all these functions, mostly around the area of appetite.

Wasn't it— it wasn't related to metformin? Wasn't there data on that, like, was mediating the effect of metformin, or am I making that up?

No, you're correct. It also— there's a complex relationship here between, yeah, lact fee and metformin and, and potentially diabetes. And so there's an interaction there. Very interesting. Yeah.

All right, I'll have to go back and dig into that. I remember there was also like a related molecule that was like a— they have these all, all these different like molecular complexes. So here is lactate and phenylalanine. I think there was another one that was like an amino acid, maybe it was phenylalanine complex to beta-hydroxybutyrate. Right, that then came out later. I don't know if that was your group.

Uh, he had one. I think that's correct. I don't remember all his molecules. He's piling them up rather quickly. Um, taurine, of course, is turning out to be a pretty important molecule too. Um, so I, I think this also reflects the nature of biology, meaning we have all these molecules in our body and they probably serve multiple functions. And I, I actually do believe that. Meaning they're signaling molecules in some context. You mentioned omega-3s, but they can also be structural molecules in other ways and, you know, help support your membranes, things like this. So I think it's the nature of biology that we use a lot of these things at once. We discovered this a long time ago that, you know, some glycolytic enzymes can also be DNA regulators. So they bind, they associate with chromatin and regulate transcription. So, Molecules can have multiple function, and that's why taking these broad approaches can reveal new things that you might not otherwise expect. So there is a lot to unpack in the study. Again, I'm glad you're still finding it enjoyable. I do too, believe it or not, especially as we roll out more studies. And in fact, we could talk at one point, you know, there's a raging thing out there. What's better, sprinting long-distance running. And we are running a study to test exactly that. It's your hypothesis.

What do you think?

I think sprinting. I think it gives you— because I think that strength, I think the response you get from a strength exercise and sprinting, if you think about, is a strength exercise. Now, we may have them going too long. They sprint for about a minute. That's pretty intense. And they do it 10 times versus running about the same workload., but for 40 minutes straight, we call it moderate intensity, although it could be harder for some people. They're supposed to be at a certain level anyway. So, so far the data are still coming. We're still characterizing that, but the VO2 max is turning out better on the sprinters. So I'm a believer sprinting is probably better. The tricky part with sprinting, of course, is not injuring yourself.

So how could somebody, if they can't sprint— so I used to be a runner and I love doing, say, hill sprints. They felt terrible, but they felt great afterwards. I now have, uh, right knee problems, so I can't do your— my conventional hill sprints anymore. How could I, or people maybe with not great joints, replicate that intensity in a way that is safe?

I don't know for sure, I'm not a trainer, but I actually switched from running. I used to be a runner, and about 9 years ago I shifted from running to strength training. Now I still bike everywhere because I'm in Palo Alto, it's very easy to bike around, so I get my aerobic quick exercise that way. I bike to work every day. I lift weights every morning, including this morning, and I have heavy days and light days. You can't just do strong heavy days or you'll, you know, you'll hurt yourself. But you alternate. And I have an amazing trainer. He's actually a world champion. They run something called Happy Body. So a little plug there, I suppose. Anyway, yeah, these guys are amazing. And so I had sore knees and now Now, I think they're more arthritic, so I don't know exactly the nature of yours, Nick. But when I shifted to the strength training with these trainers, it basically cleared it up 100%. And it's counterintuitive because you're holding all these heavy weights and you're squatting up and down on these knees that were used to be pretty sore. And suddenly they're all— it took about a month, but they were getting better and then they gradually totally went away. And I think it's because you're strengthening your muscles around your joints. Strength. And I think that helps. And, and that these particular exercises I do, they, they actually have a lot through your spine and your shoulders and things, which are things that go as you get older. So I, you know, I'm no young guy, so I want to make sure I keep all that stuff functioning well. So I do all this weightlifting every day. Um, so maybe that would work for you.

I don't know. I'll tell my backstory on why my knees are screwed up is, uh, it's very long. I'll give you the short version because it'll save me time. People are going to ask about it if they don't know already. I was actually diagnosed with osteoporosis at age 20. So I started distance running at age 17, and within a few years, my bones started to break. And it was very weird because I had no fractures as a kid. It turned out I have a very rare mutation in a gene called LRP5, involved in how osteocytes remodel bone to mechanical loading. So, it was actually the distance running because I was running marathons and halves and doing 80-mile weeks as a teenager and my bones couldn't remodel to keep up. So, I ended up developing low bone density. That's since recovered, but there was a series of injuries that kind of flooded out of that plus some weird vestigial tissue I had called a plica. It's kind of like an appendix in your knee and I had to get surgery on that. And now, there's a little cavity that swells up when I do too much intense work. Yeah. So, I have a long, weird background. My bones are better now, but the one thing I can't do in terms of exercise is run anymore, which is a shame because I loved it.

But that aside, anyway, so I don't know if there are any exercises you could do to at least partially compensate. I doubt that. Like you say, it sounds like it's more the risk of injury.

It's the pain of like training hard, making progress, and then getting an injury and being out for like 6 weeks. You're just like, oh, that's happened so many times that now I just don't do it. Although I don't do a ton of steady-state cardio, but I do when I do it, like rowing, which you get up to pretty high intensities on a rowing erg.

But do you use your knees when you're rowing?

Yeah, I use my knees because it's not like high impact. And, uh, and I, you know, if your form is good, you won't hurt your back, won't hurt your knees. So I don't do like long cardio workouts anymore. Like I used to go run like, you know, 80-mile weeks, 20-mile runs every week, like long, long runs. Now if I do cardio, it's like more in the sprint area. It's like I'll do, you know, circuit.

Yeah, I'm a big believer now in sprinting. That was why we did the study. That was the hypothesis. So that one did have a hypothesis, which was sprinting, because I do think you need to exert your muscles a little more of the strength.

And you keep your cardio like the molecular adaptations enable you to keep a lot of like general cardiovascular fitness. Fitness, I always feel like testing it every now and then. So like, you know, my last apartment, I lived on the 37th floor. And sometimes I just like, even with grocery, just go up those 37 flights. And even though I don't do any steady-state cardio, it just felt fine. Wasn't out of breath. So I don't think— I think it's a myth that you need to do like steady-state cardio to have good cardiovascular fitness. I think you can work in even like 2-minute blocks and build it up. But I want to get back to maybe one of the most interesting things in the study, in my opinion, which is that a person's insulin sensitivity can not only alter— well, actually, we'll get to the inversion in a minute, but it can alter how people, like, how these clusters respond. So something I want to just highlight for people is, like, during exercise, uh, insulin tends to go up, uh, because you're driving glucose into the muscles. That's again normal. And, um, ghrelin, the hunger hormone, tends to go down. But in people who are insulin resistant, insulin went up more and ghrelin decrease was smaller. So that's a lot of jargon. Can you unpack what the implications of that might be? Because I can speculate, and they're interesting.

The insulin one's pretty obvious. As you point out, you're breaking down glycogen when you exercise, which is a polymer of glucose, and you make glucose. And then as a consequence, you're, you, you know, you'll, your insulin gets secreted from the pancreas because it senses the glucose and and helps with that. It helps your muscles take it up. And so for insulin-resistant people, they basically, particularly in the muscle, they, which is where most forms of insulin resistance sits, you actually don't respond to insulin and your glucose builds up. So what's happening in insulin-resistant people, their glucose levels are building up and body, you know, sees that and makes more insulin to try to pump it into your muscle and other, other areas of the body. And that's really what's going on. So that makes a lot of sense. And all the downstream signaling—

sorry to interrupt, but can there be negative consequences of that? And I don't want to, like, lead people to think that if they have insulin resistance, exercise is bad. However, the whole idea of insulin resistance and then hyperinsulinemia— so high insulin to compensate— the reason it causes metabolic dysfunction is because different organs and tissues are differentially insulin resistant. So could that higher insulin level relative to a lean person mean that— I'm not going to say there's damage from exercise, but that the benefits aren't as big?

I guess it's possible, but I would still argue you should exercise because most people who are, say, insulin resistant, to be honest, they're often overweight. And so exercising helps burn fat, makes it lower. And believe it or not, exercise— we have another study where we showed exercise improves your insulin resistance. So we actually think, and, and we think the increased muscle mass is part of that. So I think overall it does help you to do this, even if there— it's possible there might be short-term issues going on in other organs. But I, I I haven't thought about that so much because I think the benefits just vastly, vastly outweigh.

Oh, I'll be clear. I agree 100% with Professor Snyder. This is where my nerdy speculation maybe doesn't interact great with what I want people to take away practically. So people, please set aside maybe that question if it didn't resonate with you. Don't be scared away from exercise for sure. That said, now I want to get to, to me, what was the grand finale of the paper. So the inversion patterns. I'm going to show them on screen now. Perhaps remember them, they were Figure 6B from the paper, basically showing— and I hope people appreciate how amazing this is— that there are patterns of molecules. We talked about a bunch of them right now that not only do they have a different response in people who are insulin sensitive, which is the blue line, versus insulin resistant, which is the red line, but they can be completely inverted. Inverted, which means a given molecule, if you're exercising, if you're insulin sensitive, could go up, and if you're insulin resistant, could go down. What does that mean?

Yeah, well, again, a lot of it's related to this, um, glucose control part, and your whole metabolic system is tied together. I'm trying to remember all the ones that showed the inverted pattern, but the ones that, um, went up for insulin resistance definitely were things glucose related. And lipids, you know, as you know, your, your fatty acids, things are all tied in to your whole glucose control. So I think they do go hand in hand that way. There were some interesting molecules. I'm trying to remember now, Nick. Thousands of molecules change. Yeah.

Yeah. So it was just more the phenomenon, like people talk about, like, let's like analogize it to diet. Like, you are what you eat. I hate that. I'm like, you are what your body does with what you eat. And I think that extends to basically like every other intervention that we have, be it cold exposure, heat exposure, exercise, and diet. It interacts with the host. And so just the mere fact that you could have changes in, say, gene expression patterns that go in opposite directions based on your level of insulin sensitivity, to me is remarkable. And then ties back into this whole like molecular choreography. Like you're gonna dance different, your body's gonna dance different molecularly depending on your like just insulin sensitivity. It's more just appreciating how remarkable that is. That alone I think is a huge discovery.

Yeah, I 100% agree. And again, it comes back— first of all, there are thousands of molecules, you know, changing. It's engaging every organ in your body, your liver, you know, pathways, your— again, your brain, your muscle. Your muscle is a pretty big organ when you go across all the muscle. All these areas, they're all engaged when you exercise. And I forgot to say, but some of the things that were very interesting to change too was like nitric oxide. So for those of you who don't follow the sort of thing, that's important for endothelial cell function. And we didn't see nitric oxide per se because we didn't measure that, but we could follow the transcriptional pattern that shifted. And I think one of the biggest benefits of exercise is getting your vascular system, including your microvascular system, flowing. And that's what happens when you're exercising hard. And that's another reason why I like the intense training because I do think it puts more, if you will, stress on the system, forcing blood through your both, you know, macro and microvascular system. Nitric oxide has all these benefits for your endothelial function and your microvascular system. And so it's not only important throughout your body, it's important for your brain. In fact, some people say the main, what the most important thing you could do for your brain is keep up your microvascular system. Not from blood, but from other sorts of flow, I guess. Well, blood flow near the brain. You have a blood-brain barrier, but you get the idea that you would keep this flow going. And this nitric oxide is induced. It's an important signaling molecule. I think most people in the field know it, but most ordinary folks don't because who studies biochemistry at this level? But I think that's one of the important areas. While we were talking, I looked up and I hit myself on the head. It was ubiquitin remodeling pathway. It was one of those those things that shifted. And why is that a big deal? Well, that affects protein degradation. Again, this whole remodeling concept shows difference between insulin sensitivity and resistance. And, and it is the case— we have other studies here too where insulin resistance is just— things don't work as well. You do go haywire. And we see this, uh, in virtually every study we've looked that insulin-resistant people do not behave the same as insulin-sensitive folks. And so, and it's usually in the form of dysregulation. You're just not— and I suspect at a molecular level, this is not shown, it's just glycosylation you're throwing around on signaling molecules and such, and that's making your body not function as well. But to your point, Nick, it's happening throughout your body. Involving all these different organ systems.

To echo what I think I heard you say is that in the state of insulin resistance, it's going to probably go with high levels of blood sugar, and those sugars can attach to things. That's what glycosylation is, which can lead to just complete inversions and changing of these signaling pathways, one of which you mentioned, which is basically like a renewal and repair pathway, this kind of like autophagy, but something dissimilar. So in insulin resistance, exercise should be triggering this,. But because you just have this unhealthy metabolic milieu with a bunch of sugar that's disrupting things, it could impair it if, you know, at least somewhat, if not completely, which is not good. So I guess the optimistic way to look at this—

I don't think it's impairing completely because most processes are still happening, but they're often dampened. And as you point out, there are some that inverted or went in different directions. So there is, there, there is some shifts. Yeah. In general, there's just less control over what you're going to do.

I think this could paint a very pessimistic picture for people who like are struggling with obesity. And I want to like name the elephant in the room, at least for me, which is not, it's not like a lived experience I can have. However, I think an optimistic way to look at it is, is this is so much more complicated than like calories, energy in, energy out. And these states, be you lean and insulin sensitive or have obesity, they have a way of like self-perpetuating, which also means though, if you break the cycle, you can get into like a new steady state that also self-perpetuates. Actually, there, you mentioned leptin. I'll send you the paper. A paper just came out on what causes leptin resistance, which has been like a mystery for 76 years. But basically, if you have obesity and your fat cells are too big, it sends these little packages, little letters, extracellular vesicles with codes in them, microRNA, that go to the brain and write the code of either leptin resistance or leptin sensitivity. The consequence therefore is if you have leptin resistance in the brain— again, we're talking about brain— you tend to be hungrier and expend less energy. But it's the big fat cells in obesity that are writing that code. So once you shrink them, then you write the code of being less hungry and expending more energy relative to your body size. I can send you the paper, it's fascinating.

But, um, yeah, that particular one I didn't see. It was microRNA. Last week, pretty, pretty cool.

So this paper that we're talking about came out in 2020, and I feel like in the last 5 years alone there's been an explosion of interest in different sects, one of which is microRNA. So little codes of nucleic acids like little half DNAs that have been sliced that don't code for proteins but regulate molecules, many of which we talked about. So yeah, anyway, getting off—

yeah, no, it, it's pretty fascinating. Yeah. And again, it also emphasizes those are your fat cells. I, I do like this concept you're saying though about, you know, people shifting their, their homeostatic system if when you come be obese, you're shifted a certain way. But I, I agree with you 100%. You should be able to get people to shift back. And for some people, the trigger are these GLPs— lose weight, get, you know, brought back into a more what's perceived as a more normal homeostatic system. But yeah, I mean, it is true there are people out there— I always find this fascinating— there are people who are very, very obese but are metabolically normal. Meaning they're by all the metabolic standards, they seem fine. So they've figured out how, you know, it's this personalized metabolic system. Their system is clearly adjusted to handle that. Yeah. Now I'm still not saying it's a good idea to be obese and metabolically normal. I suspect that puts strains in other areas. But, um, yeah, anyway, that there are these things out there. And yeah, but I think we can shift people But I think what the exercise study shows, every study we run now, it's pretty clear it affects, you know, when you start shifting metabolism, you're involving all your different organ systems. And again, we're, we're just integrated systems.

Yeah, for sure. But before I wrap up, what are one or two non-negotiables do you think when it comes to exercise for people, like routines that you would recommend, bearing in mind you're not a trainer?

Yeah, do it. Number one, you gotta do it. And I think for a lot of people, they say it's the pattern. You got to get— you can't— people who try to do it, you know, sometimes in the morning, sometimes afternoon, evening, what have you, really the number one thing, you get a pattern. By the way, back on another interesting point from our glucose, from a very different study, you just reminded me of this. We had found that people are insulin resistant insulin-resistant benefit better from exercise in the morning in terms of glucose control than insulin-sensitive. The party line is you should exercise in the afternoon to get maximum benefit. But for insulin-resistant, it seems actually from a study we have, people who exercise in the morning have lower glucose the next day. So for them it's better. So this timing issue is— but having said that, exercising at all is better than not exercising. So that's number one.

It sounds like the logic there though, you're saying is because they're behind metabolic 8-ball, this is a way of like setting their system in a more positive direction from the beginning of the day.

And we think you can improve your insulin resistance. In fact, we know you can by increased activity. So this is an area that, yeah, where building muscle and such does help. Um, so what are the things to do? Yeah, number one, exercise and finding a routine. That's the, the hardest part is motivation to get getting people out there to do it. For me, I do it in the morning. I'm not sure if that's the best time for me, but I do it because it fits nicely with my routine. Actually, it makes you feel good. You make these endorphins and stuff. And so then I feel better through the rest of the day knowing I've exercised in the morning. In fact, I can tell the difference between the days I exercise and those I don't in terms of how I feel. Like you and your steps, you can feel pretty good once you handle those those 15 floors. Obviously, I think, you know, if you're starting from scratch, trainers really do help. I think they help in two ways. They make sure you would, you know, handle things properly. And if you do start hurting yourself, I have a tendency to try and work my way through something. Like if I start getting a sore shoulder, that's not always a good thing. Sometimes it's a matter of adjusting the technique. Like I say, I lift weights, and so adjusting the technique is good. So trainers can help with that. And I have, as I say, amazing ones that are set. Trainers are also good because they motivate you. When you know you're gonna see your trainer, somehow you just make sure you put in the effort. So, you know, I guess that's just the psychological part. I exercise between 40 to 50 minutes a day, first thing in the morning. And to be honest, I also take walks after my meals for my glucose control, as we've talked about in previous podcasts, 'cause I am diabetic and that does help suppress my glucose spikes. So I try and be active. And by the way, there's some other, while we're on exercise, there's some other studies about people who, you know, work in offices all day and sit all day. Well, there are these exercise snacks that we recommend where mostly they're in the form of get up, you gotta get up and walk. Some of them are in the form, we're trying to run a study now where people would to do squats, actually, believe it or not, for 3 minutes, which is quite a bit intense, actually. That's a little more the strength idea. So, and the— but anyway, the point is you should really break up your sitting, and that would be maybe another—

yeah, I was— I don't know if I'm gonna do it. I was putting together a holiday gift guide. One of my, uh, colleagues is Twisting Mark for doing it, and the first thing I thought of was— and I'm using it right now, it's like $99— um, like a standing standing desk. It's just so great. You can like, you know, adjustable standing desk and get it for like $80, $90. And, uh, yeah, yeah, you are standing now, right?

Like move around.

Yeah, I don't— I— there's some people that I have, uh, meetings with who like, like the walking treadmill. I find that, well, especially if I'm interviewing someone, a little distracting, but I just feel more energized. I think I bring more energy to conversations when I'm like, I've activated my body. I get sleepy when I sit. Yeah. So I Do you want to direct people to anywhere in particular to learn about your research, get involved, etc.?

I'm easy to find, Snyder Lab. We have all kinds of studies out there. We do studies with wearables, studies with environmental exposures. We're happy to talk about some of these on future podcasts. Maybe you may know I'm big on smartwatches, and I left my ring up there, but I'm going to get it. So feel free to join some of our studies. They're a lot of fun. You may learn— most people who join them wind up actually improving their health, believe it or not, at least by certain—

I believe it.

So, so yeah, if you're in the Bay Area, some of them are pretty intense, but if you're remote, there's some of the studies are easy, like the wearables.

I have an intense audience. All right, well, thank you for your time, and, uh, we'll be signing off.