#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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Summary
In this episode of the Ask Me Anything podcast, host Peter Atiyah is joined by Nick Stenson to discuss two topics: uric acid and protein deficiency, and why the Fanny Pack is a fashion faux pas.
Transcript
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Hey everyone, welcome to a sneak peek, ask me anything or AMA episode of the drive podcast.
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I'm your host, Peter Atiyah. At the end of this short episode, I'll explain how you can access
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the AMA episodes in full, along with a ton of other membership benefits we've created,
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or you can learn more now by going to peteratiyahmd.com forward slash subscribe.
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So without further delay, here's today's sneak peek of the ask me anything episode.
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Welcome to ask me anything episode number 62. I'm once again joined by my cohost, Nick Stenson.
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In today's episode, we're going to focus on two different topics, uric acid and protein.
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Now we've spoken about both of these in prior episodes, but today's conversation
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focuses on a different aspect of them. So when it comes to uric acid, we discuss how one should look
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at uric acid levels and what the relationship is between your uric acid level and various disease
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states, most notably, of course, cardiovascular disease. What we try to establish here is not
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the obvious correlation between high levels of uric acid and disease, but more the idea of causality.
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Because of course, if uric acid is causally related to cardiovascular disease, then lowering
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uric acid would indeed lower the risk of cardiovascular disease. We then move on to protein,
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which of course is a topic we've covered many times in the past, but here we talk about it in a
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different way, which is we ask the question and explore all of the literature that examines the
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relationship between protein and appetite and its impact on satiation. We discuss what happens
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when someone is not getting enough protein and what to understand about the relationship between
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protein deficiency and obesity. We discuss how much protein someone might need to avoid deficiency,
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which amino acids are important, and how one might compare protein sources. If you are a subscriber and
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want to watch the full video of this podcast, you can find it on the show notes page. And if you're
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not a subscriber, you can watch a sneak peek of the video on our YouTube page. So without further delay,
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I hope you enjoy AMA number 62. Peter, welcome to an AMA. How are you doing?
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I'm good. Thanks for having me back. By the way, you never comment when I say that. Thanks for having
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me back. Like it's such a stupid thing to say. I don't know why I say it. It's just natural probably
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for you, but yes, it's one of those, if you're not here, it's a lot different of an episode for sure.
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Well, speaking of that, there is something that I've been waiting to talk to you about,
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may or may not have been due to your fashion or lack of fashion choices. Does that help ring
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another bell? Fanny pack. Yes. Do you want to let people know what you were rocking and how big that
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thing was? Unless we're planning to do a dedicated AMA on the utility of the fanny pack. I don't know
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that we want to go down this rabbit hole. Are you worried that you have to justify it with a full
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90 minute podcast to why you should be wearing that in the first place?
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Well, I mean, north of 25,000 people voted in disfavor of the fanny pack, which look,
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I would bet that the same number of people who think that the fanny pack is a faux pas are probably
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equal in proportion, not necessarily the same people, but equal in proportion to the number of people who
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think HRT causes breast cancer or TRT causes prostate cancer. And so it requires deep, thorough,
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nuanced discussion to explain the merits of certain approaches. And I think the fanny pack is no
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exception. That was quite a leap that you made there, which I didn't see coming. The biggest argument
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against the fanny pack that I saw was a photo where you had the big old fanny pack on and your phone in
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your pocket. So what's the point of the fanny pack if the phone's not even going in there?
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That was one photo. For the most part, the phone is in the fanny pack. I think in that moment,
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the phone out of habit was just placed back in my pocket.
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I mean, there is a slight friction to the fanny pack because you have to undo the zipper to put
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it in and then put it back in. And if you think I'm going to use this phone again in five seconds,
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sometimes it's just easier to put it in your pocket.
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All right. Well, I was very amazed at how many times the fanny pack showed up on
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social media that I'm not even paying attention to, but somehow you are, and you keep sending me
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these pictures of me with a fanny pack all over the place.
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I mean, it was shocking how much it made the rounds and a little alarming as well, but that's
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all right. We'll save it for another podcast. But for this AMA, we're going to touch on two different
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topics. The first is one we've spoken about before, but it's been a really long time. And actually,
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since then, a lot of new information has come out and that's on uric acid, which is a blood-based
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biomarker. A lot of times when people think about uric acid, they naturally go to gout.
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However, we'll cover it as it relates to diseases, metrics that you look at for yourself and your
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patients. And then from there, we'll go into protein, obviously a topic we've covered in great
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detail. But for this conversation, we're going to cover a piece that we haven't before. And it's
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something we get asked about a lot, which is the relationship between protein and appetite.
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And so I think we'll cover some pretty interesting effects of protein and how they're unique to
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protein compared to other macronutrients on appetite, energy expenditure, and what that means
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for protein intake, weight control, and how different types of proteins compare within that.
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So I think it should be a pretty interesting conversation. But with that said, anything else
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No, I think this is a really interesting couple of topics that are also somewhat adjacent in
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terms of the relationship between protein and uric acid, which obviously we'll discuss.
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Yeah. And also, I assume you had a lot of protein in your fanny pack in those photos. Is that correct?
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I did. That's one of the beauties of the fanny pack is you can transport protein.
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There you go. You should have led with that. And I think people would have been a little more
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understanding. All right. Well, I think it'd be helpful to start off on the uric acid, just
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reminding people briefly, what is uric acid? Why should people even care about this metric?
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Great question. Look, I think uric acid is probably something that many people have seen on a blood
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test. It's not something that is commonly ordered, but it wouldn't surprise me if people have at least
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seen it once or twice on a blood test. And I think the other thing that may rouse some familiarity is
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that people will associate uric acid correctly with gout. But let's just take a step back and talk
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about what it is. So uric acid is a metabolite. It is the product of the breakdown of purines.
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So purines are certain types of DNA and RNA building blocks. And as DNA and RNA are broken down,
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and in particular, these types of building blocks of DNA and RNA referred to as purines are broken
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down. One of the downstream byproducts of this is uric acid. Uric acid is also a metabolite of
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fructose. So again, people who have heard us talk about fructose on the podcast before,
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very specifically with Rick Johnson, who I think has been on twice, if not at least once,
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we talk at length and in great detail about the biochemical pathway that leads from the metabolism
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of fructose to uric acid. Some people might even remember, I do write about it in Outlive,
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where I talk about a particular mutation in a gene for an enzyme that is quite unique to our species
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and some very adjacent species that actually allows us to have higher levels of uric acid than many of
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our related species ancestors. And I won't go into all the reasons why, but it might have to do with a
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survival advantage that was afforded to us specifically during a period of extreme cold
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in what is now Europe. So all of that to say uric acid, pretty interesting molecule. Most of our
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understanding of it, of course, is associated with pathology and most of that pathology centers around
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gout. So when uric acid crystallizes, it can do so in joints. And because it is quite inflammatory when
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it crystallizes, this inflammatory condition within the joints is what is clinically known as gout. And if
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you've ever had this, people listening will know it is incredibly painful. For reasons that are not
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entirely clear to me, and maybe they're clear to some, the great toe, the big toe, seems to be one of
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the joints where this occurs disproportionately. And when patients get this, you can ride it out,
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but more commonly, you actually have to put them on pretty potent anti-inflammatory drugs.
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The other place where this shows up is in kidney stones. So while it's not the most common form of
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kidney stones, it's probably number two or number three. And so high levels of uric acid are also
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going to predispose to urate-based kidney stones. Finally, I would say, and we're going to go into
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this in more detail, hyperuricemia, high levels of uric acid contribute to high blood pressure.
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And this has been demonstrated experimentally, and it has been demonstrated through Mendelian
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randomization. We're going to talk a lot about Mendelian randomization today. And the reason for it is
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MR is a really valuable tool for establishing causality when you are studying a biomarker or
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a phenotype for which there is great genetic variation. Mendelian randomization has helped us
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make sense, although I don't think we needed to make much more sense of the causality of LDL
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in atherosclerotic cardiovascular disease. So all the clinical literature on LDL makes it pretty clear
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that lowering LDL lowers cardiovascular disease. But you could ask the question, well, do we know
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that lowering LDL is the cause of the reduction in risk, or is it that giving medications that lower
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LDL lowers something else like inflammation, and that's the driver? But when you do Mendelian
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randomization and you look at the genetic distribution of LDL cholesterol, you see that,
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in fact, there is causality. And similarly, when you do that type of analysis with uric acid,
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you see that as uric acid levels go up, so too does blood pressure. As uric acid levels go down,
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so too does blood pressure. All of this, of course, is confounded by the fact that things that are bad
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for you tend to raise uric acid. And that association is a little difficult to tease out causality.
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So for example, we know that patients with fatty liver disease and patients with type 2 diabetes
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usually have very high uric acid levels. And it's unclear exactly what the direction of causality is
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there. So probably a longer answer than you wanted, Nick, but given the nature of what we're talking
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about, it's probably worth giving a bit more of an expansive response. If someone's looking at their
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uric acid levels, what are some factors that can increase their level of uric acid?
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Well, I sort of think of this as what are the modifiable things and what are the non-modifiable
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things? So let's just start with the non-modifiable. So sex is the biggest difference. On average,
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men have a uric acid level that is about 0.5 to 1 milligram per deciliter higher than women at a
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given age. Now that's based on the literature. If you asked me personally, like based on my experience
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and said, Peter, tell me what you think, I would have said it's easily one to two milligrams per
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deciliter higher, just based on what I see in patients. So in other words, the gap seems even
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larger to me than what is reported in the literature. But nevertheless, there's clearly a sex difference
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there. And the most obvious hypothesis is that it centers around estrogen and some of the downstream
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effects of estrogen. It's also clear, by the way, that not only do women tend to have lower levels
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of uric acid, they also seem to be more susceptible to higher levels or to a given level of uric acid.
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In other words, they seem to be more likely to run into the trouble of a high uric acid than a man
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is at a given level. The other thing I alluded to this also above is genetics. The heritability
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of uric acid seems to be about 40%. In other words, nearly half of the value of your uric acid
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is determined genetically. And that means independent of just sex, let's just say across
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men or across women. And again, that genetic variability, that heritability of uric acid is
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actually what allows us to determine the causality of uric acid in so many of these things that we
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care about. If there was no genetic variation to uric acid, it would be very difficult to do Mendelian
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randomization. The next thing that's not modifiable that plays a significant role in uric acid is age.
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As we increase in age, we tend to increase in uric acid, although this effect is more pronounced in
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women than men. And it starts around the age of menopause, which again factors into the hypothesis I
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alluded to earlier, which is that estrogen probably plays a significant role in uric acid regulation,
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given that women are lower and then tend to have a big uptick when they get through menopause.
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Actually, there's a pretty cool figure that might be worth showing for folks if they want to see
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the relationship between uric acid in men, women, and then what happens around menopause. So
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Nick, if you can just pull that up, this is a figure that really speaks for itself here.
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Obviously, the blue line represents men and the red line represents women. And you can see
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that the blue line, well, first of all, it's always higher than the red line and the rate of increase
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is modest and steady. Conversely, the red line stays largely flat until the mid forties and then
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really increases at a rate that exceeds even the rate at which the males increase. And this continues
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throughout life. But to note, even at the age of 80, which is where these data stop, women are still
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considerably lower than men. And so you kind of laid out those are the things that people really
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don't have control over. What do we know about factors that can cause uric acid to raise that
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people may have control over? A lot of discussion on this topic points towards nutrition because
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epidemiologic data tell us that average serum uric acid levels have been increasing pretty substantially
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over the past century. So in addition to all of the things that we've talked about, the sex
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differences, the age progression, if you just look at the population level of uric acid, it is going up.
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And therefore, the obvious question is, is it going up for the same reasons that certain other things
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are going up, such as obesity and metabolic syndrome? And if so, what is it about those things
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that's increasing uric acid? Well, given that fructose is one of the things that drives uric acid
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production, at least transiently, the question is, does chronic consumption of high amounts of
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fructose, presumably in liquid form more than solid form, play a role in this? Does it play a role directly
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or does it play a role indirectly? What does that mean? Well, directly would mean, does fructose
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consumption, which is known to an unequivocally increase uric acid levels transiently, does enough
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fructose consumption lead to chronic elevation of uric acid? That I think is an unknown question.
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An alternative explanation is that high levels of fructose consumption are driving more eating.
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So we talked a lot about that with Rick Johnson. What is it about fructose consumption and intracellular
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energy levels that lead to more consumption of food and therefore obesity? And is that the driver
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through energy balance? So there have been bi-directional Mendelian randomization studies
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that have been done, and they have suggested that higher levels of adiposity can cause hyperuricemia.
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So in other words, that would explain that obesity and energy imbalance is a driver of elevated
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uric acid and not the other way around. By the way, that's done by looking at genes that are known
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to increase fat mass, such as the FTO gene, MC4R gene, and other genes that are clearly associated
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causally with obesity. There are certain medications that can do this. So diuretics, which are very common
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in the treatment of high blood pressure, and even low-dose aspirin can do this. We talked about,
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obviously, the dietary effects of fructose, but we shouldn't negate the dietary consumption
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of foods that are very high in purines. So foods that are very high in DNA, meat, and believe it or
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not, beer is quite high in DNA. Why? Because beer contains a lot of yeast, and the yeast obviously
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has genetic material in it. So high amounts of alcohol, though again, I think disproportionately beer
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over other types of alcohol, high amounts of very dense foods. By foods, I mean foods that are dense in
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DNA, so sardines, things of that nature, red meat. These are things that are going to also increase
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the production of uric acid. Now, I'll tell you about another funny example, Nick, of something that
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I learned many years ago when I was in ketosis, which is that being in ketosis, either nutritionally
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or through starvation, will increase uric acid levels and can do so quite dramatically. And the reason
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for that is the primary ketone that is produced during either of those states, nutritional ketosis
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or starvation ketosis, i.e. fasting, is something called beta-hydroxybutyrate. And beta-hydroxybutyrate
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competes with uric acid in the kidney for the same transporter that is going to excrete either uric acid
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or BHB. So when BHB is out-competing uric acid vis-a-vis impairing this tubular secretion in the
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kidney, uric acid is going to go up. And so the first time I learned that was when I was deep in
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nutritional ketosis and I actually got gout. And this was probably 12 years ago because I didn't fit
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the phenotype of gout. At the time, I was just really lean, really healthy, smoking and joking in
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my ketosis. It took me like two weeks to figure out why my toe hurt so much that I couldn't do a flip
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turn in the pool and put any weight on that foot as I pushed off. I mean, that's how bad it was.
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Of course, I would go on to learn exactly what happened. And then in subsequent years, as I would
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fast, I would always make sure I was taking allopurinol or something. But I did confirm that
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during some significant fast, my uric acid would rise from say five to nine or 10 as my ketone levels
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approached four and five millimole. So those are some of the things that are modifiable and obviously
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play a role. One other thing that's, by the way, kind of interesting is anaerobic exercise. Heavy,
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heavy bouts of anaerobic exercise can also increase uric acid transiently. It might be that this goes away
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over time, but we're not entirely clear why. The hypothesis is that heavy bouts of anaerobic
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exercise cause depletion of muscle ATP and that the energy needs of the muscle obviously can't be
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met exclusively by glycolysis. So we basically experience the buildup of ATP degradation byproducts
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in the muscle. And in particular, one of those is IMP, which is converted into uric acid. So I think
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what's interesting is that there seems to be an adaptation to that. And I'm also not convinced
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that there's anything pathologic about that. So that's just more of an interesting aside, not like,
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oh, don't do intense anaerobic activity. You mentioned kind of earlier a few times,
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the relationship between uric acid and blood pressure. And we know about blood pressure's
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role in cardiovascular disease. What do we know about uric acid as it potentially
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