#313 - AMA #62: Protein’s impact on appetite and weight management, and uric acid's link to disease and how to manage levels
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Hey everyone, welcome to a sneak peek Ask Me Anything or AMA episode of The Drive Podcast. I'm your host, Peter Attia. At the end of this short episode, I'll explain how you can access the AMA episodes in full along with a ton of other membership benefits we've created. Or you can learn more now by going to peterattiamd.com forward slash subscribe. So without further delay, here's today's sneak peek of the Ask Me Anything episode. ♪

Welcome to Ask Me Anything, episode number 62. I'm once again joined by my co-host, Nick Stenson. In today's episode, we're going to focus on two different topics, uric acid and protein. We've spoken about both of these in prior episodes, but today's conversation focuses on a different aspect of them. When it comes to uric acid, we discuss how one should look at uric acid levels and

and what the relationship is between your uric acid level and various disease states, most notably, of course, cardiovascular disease. What we try to establish here is not the obvious correlation between high levels of uric acid and disease, but more the idea of causality. Because of course, if uric acid is causally related to cardiovascular disease, then lowering uric acid would indeed lower the risk of cardiovascular disease.

We then move on to protein, which of course is a topic we've covered many times in the past, but here we talk about it in a different way, which is we ask the question and explore all of the literature that examines the relationship between protein and appetite and its impact on satiation. We discuss what happens when someone is not getting enough protein and what to understand about the relationship between protein deficiency and obesity. We discuss how much protein someone might need to avoid deficiency, which amino acids are important, and

and how one might compare protein sources. If you are a subscriber and want to watch the full video of this podcast, you can find it on the show notes page. And if you're not a subscriber, you can watch a sneak peek of the video on our YouTube page. So without further delay, I hope you enjoy AMA number 62.

Peter, welcome to an AMA. How are you doing? I'm good. Thanks for having me back. By the way, you never comment when I say that. Thanks for having me back. Like it's such a stupid thing to say. I don't know why I say it. It's just natural probably for you, but yes, it's one of those if you're not here, it's a lot different of an episode for sure. Well, speaking of that, there is something that I've been waiting to talk to you about,

may or may not have been due to your fashion or lack of fashion choices. Does that help ring another bell? Fanny pack. Yes. Do you want to let people know what you were rocking and how big that thing was? Unless we're planning to do a dedicated AMA on the utility of the fanny pack. I don't know that we want to go down this rabbit hole.

Are you worried that you have to justify it with a full 90 minute podcast to why you should be wearing that in the first place? Well, I mean, north of 25,000 people voted in dis favor of the fanny pack, which look, I would bet that the same number of people who think that the fanny pack is a faux pas are

are probably equal in proportion, not necessarily the same people, but equal in proportion to the number of people who think HRT causes breast cancer or TRT causes prostate cancer. And so it requires deep, thorough, nuanced discussion to explain the merits of certain approaches. And I think the fanny pack is no exception. That was quite a leap that you made there, which I didn't see coming. The biggest argument against the fanny pack that I saw was

A photo where you had the big old fanny pack on and your phone in your pocket. So what's the point of the fanny pack if the phone's not even going in there? That was one photo for the most part. The phone is in the fanny pack. I think in that moment, the phone out of habit was just placed back in my pocket. It was just a weak, weak moment on your part.

I mean, there is a slight friction to the fanny pack because you have to undo the zipper to put it in and then put it back in. And if you think I'm going to use this phone again in five seconds, sometimes it's just easier to put it in your pocket. All right. Well, I was very amazed at how many times the fanny pack showed up on YouTube.

social media that i'm not even paying attention to but somehow you are and you keep sending me these pictures of me with a fanny pack all over the place i mean it was shocking how much it made the rounds and a little alarming as well but that's all right we'll save it for another podcast but for this ama we're going to touch on two different topics the first is one we've spoken about before

But it's been a really long time. And actually, since then, a lot of new information has come out. And that's on uric acid, which is a blood-based biomarker. A lot of times when people think about uric acid, they naturally go to gout. However, we'll cover it as it relates to diseases, metrics that you look at for yourself and your patients.

And then from there, we'll go into protein, obviously a topic we've covered in great detail. But for this conversation, we're going to cover a piece that we haven't before. And it's something we get asked about a lot, which is the relationship between protein and appetite. And so I think we'll cover some pretty interesting effects of protein and how they're unique to protein compared to other macronutrients.

on appetite, energy expenditure, and what that means for protein intake, weight control, and how different types of proteins compare within that. So I think it should be a pretty interesting conversation. But with that said, anything else you want to add before we get started? No, I think this is a really interesting couple of topics that are also somewhat adjacent in terms of the relationship between protein and uric acid, which obviously we'll discuss.

Yeah. And also I assume you had a lot of protein in your fanny pack in those photos. Is that correct? I did. That's one of the beauties of the fanny pack is you can transport protein. There you go. You should have led with that. And I think people would have been a little more understanding. Yeah.

All right. Well, I think it'd be helpful to start off on the uric acid, just reminding people briefly, what is uric acid? Why should people even care about this metric? Great question. Look, I think uric acid is probably something that many people have seen on a blood test. It's not something that is commonly ordered, but it wouldn't surprise me if people have at least seen it once or twice on a blood test.

And I think the other thing that may rouse some familiarity is that people will associate uric acid correctly with gout. But let's just take a step back and talk about what it is. So uric acid is a metabolite. It is the product of the breakdown of purines. So purines are certain types of DNA and RNA building blocks.

And as DNA and RNA are broken down, and in particular, these types of building blocks of DNA and RNA referred to as purines are broken down, one of the downstream byproducts of this is uric acid. Uric acid is also a metabolite of fructose. So again, people who have heard us talk about fructose on the podcast before...

very specifically with Rick Johnson, who I think has been on twice, if not at least once. We talk at length and in great detail about the biochemical pathway that leads from the metabolism of fructose to uric acid. Some people might even remember

I do write about it in Outlive, where I talk about a particular mutation in a gene for an enzyme that is quite unique to our species and some very adjacent species that actually allows us to have higher levels of uric acid than many of our related species.

ancestors. And I won't go into all the reasons why, but it might have to do with a survival advantage that was afforded to us specifically during a period of extreme cold in what is now Europe. So all of that to say uric acid, pretty interesting molecule. Most of our understanding of it, of course, is associated with pathology. And most of that pathology centers around gout. So when uric acid crystallizes, it can do so in joints.

And because it is quite inflammatory when it crystallizes, this inflammatory condition within the joints is what is clinically known as gout. And if you've ever had this, people listening will know it is incredibly painful. For reasons that are not entirely clear to me, and maybe they're clear to some, the great toe, the big toe, seems to be one of the joints where this occurs disproportionately.

And when patients get this, you can ride it out, but more commonly, you actually have to put them on pretty potent anti-inflammatory drugs. The other place where this shows up is in kidney stones. So while it's not the most common form of kidney stones, it's probably number two or number three. And so high levels of uric acid are also going to predispose to urate-based kidney stones. Finally, I would say, and we're going to go into this in more detail, hyperuricemia is

High levels of uric acid contribute to high blood pressure. And this has been demonstrated experimentally and it has been demonstrated through Mendelian randomization. We're going to talk a lot about Mendelian randomization today. And the reason for it is MR is a really valuable tool for establishing causality when you are studying a biomarker or a phenotype for which there is great genetic variation.

Mendelian randomization has helped us make sense, although I don't think we needed to make much more sense of the causality of LDL in atherosclerotic cardiovascular disease. So all the clinical literature on LDL makes it pretty clear that lowering LDL lowers cardiovascular disease.

But you could ask the question, well, do we know that lowering LDL is the cause of the reduction in risk? Or is it that giving medications that lower LDL lowers something else like inflammation and that's the driver? But when you do Mendelian randomization and you look at the genetic distribution of LDL cholesterol, you see that, in fact, there is causality.

And similarly, when you do that type of analysis with uric acid, you see that as uric acid levels go up, so too does blood pressure. As uric acid levels go down, so too does blood pressure. All of this, of course, is confounded by the fact that things that are bad for you tend to raise uric acid.

And that association is a little difficult to tease out causality. So for example, we know that patients with fatty liver disease and patients with type 2 diabetes usually have very high uric acid levels. And it's unclear exactly what the direction of causality is there. So probably a longer answer than you wanted, Nick, but given the nature of what we're talking about, it's probably worth giving a bit more of an expansive response.

If someone's looking at their uric acid levels, what are some factors that can increase their level of uric acid? Well, I sort of think of this as what are the modifiable things and what are the non-modifiable things? So let's just start with the non-modifiable. So sex is the biggest difference. On average, men have a uric acid level that is about 0.5 to 1 milligram per deciliter higher than women at a given age.

Now, that's based on the literature. If you asked me personally, like based on my experience and said, Peter, tell me what you think, I would have said it's easily one to two milligrams per deciliter higher, just based on what I see in patients. So in other words, the gap seems even larger to me than what is reported in the literature. But nevertheless, there's clearly a sex difference there. And the most obvious hypothesis is that it centers around estrogen and some of the downstream effects of estrogen.

It's also clear, by the way, that not only do women tend to have lower levels of uric acid, they also seem to be more susceptible to higher levels or to a given level of uric acid. In other words, they seem to be more likely to run into the trouble of a high uric acid than a man is at a given level. The other thing I alluded to this also above is genetics. The heritability of uric acid seems to be about 40%. In other words,

Nearly half of the value of your uric acid is determined genetically. And that means independent of just sex. Let's just say across men or across women. And again, that genetic variability, that heritability,

of uric acid is actually what allows us to determine the causality of uric acid in so many of these things that we care about. If there was no genetic variation to uric acid, it would be very difficult to do Mendelian randomization. The next thing that's not modifiable that plays a significant role in uric acid is age.

As we increase in age, we tend to increase in uric acid, although this effect is more pronounced in women than men. And it starts around the age of menopause, which again factors into the hypothesis I alluded to earlier, which is that estrogen probably plays a significant role in uric acid regulation, given that women are lower and then tend to have a big uptick when they get through menopause.

Actually, there's a pretty cool figure that might be worth showing for folks if they want to see the relationship between uric acid in men, women, and then what happens around menopause. So Nick, if you can just pull that up, this is a figure that really speaks for itself here. Obviously the blue line represents men and the red line represents women. And you can see that the blue line, well, first of all, it's always higher than the red line and the rate of increase is modest and steady.

Conversely, the red line stays largely flat until the mid 40s and then really increases at a rate that exceeds even the rate at which the males increase. And this continues throughout life. But to note, even at the age of 80, which is where these data stop, women are still considerably lower than men.

And so you kind of laid out those are the things that people really don't have control over. What do we know about factors that can cause uric acid to raise that people may have control over? A lot of discussion on this topic points towards nutrition because

And epidemiologic data tell us that average serum uric acid levels have been increasing pretty substantially over the past century. So in addition to all of the things that we've talked about, the sex differences, the age progression, if you just look at the population level of uric acid, it is going up. And therefore, the obvious question is, is it going up for the same reasons that certain other things are going up, such as obesity and metabolic syndrome? And if so, what

What is it about those things that's increasing uric acid? Well, given that fructose is one of the things that drives uric acid production, at least transiently,

The question is, does chronic consumption of high amounts of fructose, presumably in liquid form more than solid form, play a role in this? Does it play a role directly or does it play a role indirectly? What does that mean? Well, directly would mean, does fructose consumption, which is known to unequivocally increase uric acid levels transiently, does enough fructose consumption lead to chronic elevation of uric acid? That I think is an unknown question.

An alternative explanation is that high levels of fructose consumption are driving more eating. So we talked a lot about that with Rick Johnson. What is it about fructose consumption?

and intracellular energy levels that lead to more consumption of food and therefore obesity. And is that the driver through energy balance? So there have been bi-directional Mendelian randomization studies that have been done, and they have suggested that higher levels of adiposity can cause hyperuricemia. So in other words, that would explain that

Obesity and energy imbalance is a driver of elevated uric acid and not the other way around. By the way, that's done by looking at genes that are known to increase fat mass, such as the FTO gene, MC4R gene, and other genes that are

clearly associated causally with obesity. There are certain medications that can do this. So diuretics, which are very common in the treatment of high blood pressure, and even low dose aspirin can do this. We talked about obviously the dietary effects of fructose, but we shouldn't negate the dietary consumption of foods that are very high in purines. So a

Foods that are very high in DNA, meat and believe it or not, beer is quite high in DNA. Why? Because beer contains a lot of yeast and the yeast obviously has genetic material in it. So high amounts of alcohol, though, again, I think disproportionately beer over other types of alcohol.

high amounts of very dense foods. By foods, I mean foods that are dense in DNA, so sardines, things of that nature, red meat. These are things that are going to also increase the production of uric acid. Now,

I'll tell you about another funny example, Nick, of something that I learned many years ago when I was in ketosis, which is that being in ketosis, either nutritionally or through starvation, will increase uric acid levels and can do so quite dramatically. And the reason for that is the primary ketone that is produced during either of those states, nutritional ketosis or starvation ketosis, i.e. fasting, is something called beta-hydroxybutyrate. And beta-hydroxybutyrate

competes with uric acid in the kidney for the same transporter that is going to excrete either uric acid or BHB. So when BHB is out-competing uric acid vis-a-vis impairing this tubular secretion in the kidney, uric acid is going to go up. And so the first time I learned that was when I was deep in nutritional ketosis and I actually got gout.

And this was probably 12 years ago because I didn't fit the phenotype of gout. At the time, I was just really lean, really healthy, smoking and joking in my ketosis. It took me like two weeks to figure out why my toe hurt so much that I couldn't do a flip turn in the pool and put any weight on that foot as I pushed off. I mean, that's how bad it was.

Of course, I would go on to learn exactly what happened. And then in subsequent years, as I would fast, I would always make sure I was taking allopurinol or something. But I did confirm that during some significant fasts, my uric acid would rise from say five to nine or 10 as my ketone levels approached four and five millimole. So those are some of the things that are modifiable and obviously unmodifiable.

One other thing that's, by the way, kind of interesting is anaerobic exercise. Heavy, heavy bouts of anaerobic exercise can also increase uric acid transiently. It might be that this goes away over time, but we're not entirely clear why. The hypothesis is that heavy bouts of anaerobic exercise cause depletion of muscle ATP and that the energy needs of the muscle obviously can't be met exclusively by glycolysis.

We basically experience the buildup of ATP degradation byproducts in the muscle. And in particular, one of those is IMP, which is converted into uric acid. So I think what's interesting is that there seems to be an adaptation to that. And I'm also not convinced that there's anything pathologic about that. So that's just more of an interesting aside, not like, oh, don't do intense anaerobic activity.

You mentioned kind of earlier a few times the relationship between uric acid and blood pressure, and we know about blood pressure's role in cardiovascular disease. What do we know about uric acid as it potentially relates to the risk of cardiovascular disease? Thank you for listening to today's sneak peek AMA episode of The Drive. If you're interested in hearing the complete version of this AMA, you'll want to become a premium member.

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