The Peter Attia Drive - #313 - AMA #62： Protein's impact on appetite and weight management, and uric acid's link to disease and how to manage levels

00:00:00.000 Hey everyone, welcome to a sneak peek, ask me anything or AMA episode of the drive podcast.

00:00:15.820 I'm your host, Peter Atiyah. At the end of this short episode, I'll explain how you can access

00:00:20.280 the AMA episodes in full, along with a ton of other membership benefits we've created,

00:00:24.900 or you can learn more now by going to peteratiyahmd.com forward slash subscribe.

00:00:30.600 So without further delay, here's today's sneak peek of the ask me anything episode.

00:00:39.000 Welcome to ask me anything episode number 62. I'm once again joined by my cohost, Nick Stenson.

00:00:45.820 In today's episode, we're going to focus on two different topics, uric acid and protein.

00:00:51.040 Now we've spoken about both of these in prior episodes, but today's conversation

00:00:54.940 focuses on a different aspect of them. So when it comes to uric acid, we discuss how one should look

00:01:02.780 at uric acid levels and what the relationship is between your uric acid level and various disease

00:01:09.180 states, most notably, of course, cardiovascular disease. What we try to establish here is not

00:01:14.560 the obvious correlation between high levels of uric acid and disease, but more the idea of causality.

00:01:20.960 Because of course, if uric acid is causally related to cardiovascular disease, then lowering

00:01:26.800 uric acid would indeed lower the risk of cardiovascular disease. We then move on to protein,

00:01:32.500 which of course is a topic we've covered many times in the past, but here we talk about it in a

00:01:36.580 different way, which is we ask the question and explore all of the literature that examines the

00:01:42.860 relationship between protein and appetite and its impact on satiation. We discuss what happens

00:01:48.340 when someone is not getting enough protein and what to understand about the relationship between

00:01:52.520 protein deficiency and obesity. We discuss how much protein someone might need to avoid deficiency,

00:01:57.800 which amino acids are important, and how one might compare protein sources. If you are a subscriber and

00:02:03.920 want to watch the full video of this podcast, you can find it on the show notes page. And if you're

00:02:08.260 not a subscriber, you can watch a sneak peek of the video on our YouTube page. So without further delay,

00:02:12.880 I hope you enjoy AMA number 62. Peter, welcome to an AMA. How are you doing?

00:02:23.060 I'm good. Thanks for having me back. By the way, you never comment when I say that. Thanks for having

00:02:27.380 me back. Like it's such a stupid thing to say. I don't know why I say it. It's just natural probably 0.99

00:02:33.900 for you, but yes, it's one of those, if you're not here, it's a lot different of an episode for sure.

00:02:39.700 Well, speaking of that, there is something that I've been waiting to talk to you about,

00:02:42.880 may or may not have been due to your fashion or lack of fashion choices. Does that help ring

00:02:49.500 another bell? Fanny pack. Yes. Do you want to let people know what you were rocking and how big that

00:02:56.520 thing was? Unless we're planning to do a dedicated AMA on the utility of the fanny pack. I don't know

00:03:03.780 that we want to go down this rabbit hole. Are you worried that you have to justify it with a full

00:03:08.860 90 minute podcast to why you should be wearing that in the first place?

00:03:13.560 Well, I mean, north of 25,000 people voted in disfavor of the fanny pack, which look,

00:03:23.280 I would bet that the same number of people who think that the fanny pack is a faux pas are probably

00:03:29.080 equal in proportion, not necessarily the same people, but equal in proportion to the number of people who

00:03:33.200 think HRT causes breast cancer or TRT causes prostate cancer. And so it requires deep, thorough,

00:03:41.860 nuanced discussion to explain the merits of certain approaches. And I think the fanny pack is no

00:03:47.280 exception. That was quite a leap that you made there, which I didn't see coming. The biggest argument

00:03:53.580 against the fanny pack that I saw was a photo where you had the big old fanny pack on and your phone in

00:04:02.440 your pocket. So what's the point of the fanny pack if the phone's not even going in there?

00:04:09.480 That was one photo. For the most part, the phone is in the fanny pack. I think in that moment,

00:04:15.680 the phone out of habit was just placed back in my pocket.

00:04:18.860 It was just a weak, weak moment on your part.

00:04:22.400 I mean, there is a slight friction to the fanny pack because you have to undo the zipper to put

00:04:26.560 it in and then put it back in. And if you think I'm going to use this phone again in five seconds,

00:04:30.940 sometimes it's just easier to put it in your pocket.

00:04:33.740 All right. Well, I was very amazed at how many times the fanny pack showed up on

00:04:39.840 social media that I'm not even paying attention to, but somehow you are, and you keep sending me

00:04:46.140 these pictures of me with a fanny pack all over the place.

00:04:50.320 I mean, it was shocking how much it made the rounds and a little alarming as well, but that's

00:04:56.780 all right. We'll save it for another podcast. But for this AMA, we're going to touch on two different

00:05:02.220 topics. The first is one we've spoken about before, but it's been a really long time. And actually,

00:05:06.980 since then, a lot of new information has come out and that's on uric acid, which is a blood-based

00:05:11.780 biomarker. A lot of times when people think about uric acid, they naturally go to gout.

00:05:16.920 However, we'll cover it as it relates to diseases, metrics that you look at for yourself and your

00:05:22.200 patients. And then from there, we'll go into protein, obviously a topic we've covered in great

00:05:27.980 detail. But for this conversation, we're going to cover a piece that we haven't before. And it's

00:05:32.200 something we get asked about a lot, which is the relationship between protein and appetite.

00:05:36.880 And so I think we'll cover some pretty interesting effects of protein and how they're unique to

00:05:42.640 protein compared to other macronutrients on appetite, energy expenditure, and what that means

00:05:48.120 for protein intake, weight control, and how different types of proteins compare within that.

00:05:54.060 So I think it should be a pretty interesting conversation. But with that said, anything else

00:05:58.920 you want to add before we get started?

00:06:01.740 No, I think this is a really interesting couple of topics that are also somewhat adjacent in

00:06:06.820 terms of the relationship between protein and uric acid, which obviously we'll discuss.

00:06:10.600 Yeah. And also, I assume you had a lot of protein in your fanny pack in those photos. Is that correct?

00:06:15.980 I did. That's one of the beauties of the fanny pack is you can transport protein. 0.98

00:06:21.260 There you go. You should have led with that. And I think people would have been a little more

00:06:24.180 understanding. All right. Well, I think it'd be helpful to start off on the uric acid, just

00:06:29.880 reminding people briefly, what is uric acid? Why should people even care about this metric?

00:06:36.820 Great question. Look, I think uric acid is probably something that many people have seen on a blood

00:06:42.220 test. It's not something that is commonly ordered, but it wouldn't surprise me if people have at least

00:06:48.180 seen it once or twice on a blood test. And I think the other thing that may rouse some familiarity is

00:06:54.140 that people will associate uric acid correctly with gout. But let's just take a step back and talk

00:06:59.280 about what it is. So uric acid is a metabolite. It is the product of the breakdown of purines.

00:07:06.280 So purines are certain types of DNA and RNA building blocks. And as DNA and RNA are broken down,

00:07:15.340 and in particular, these types of building blocks of DNA and RNA referred to as purines are broken

00:07:20.080 down. One of the downstream byproducts of this is uric acid. Uric acid is also a metabolite of

00:07:26.420 fructose. So again, people who have heard us talk about fructose on the podcast before,

00:07:32.280 very specifically with Rick Johnson, who I think has been on twice, if not at least once,

00:07:36.980 we talk at length and in great detail about the biochemical pathway that leads from the metabolism

00:07:43.160 of fructose to uric acid. Some people might even remember, I do write about it in Outlive,

00:07:49.480 where I talk about a particular mutation in a gene for an enzyme that is quite unique to our species

00:07:58.120 and some very adjacent species that actually allows us to have higher levels of uric acid than many of

00:08:05.320 our related species ancestors. And I won't go into all the reasons why, but it might have to do with a

00:08:11.520 survival advantage that was afforded to us specifically during a period of extreme cold

00:08:17.620 in what is now Europe. So all of that to say uric acid, pretty interesting molecule. Most of our

00:08:24.380 understanding of it, of course, is associated with pathology and most of that pathology centers around

00:08:28.800 gout. So when uric acid crystallizes, it can do so in joints. And because it is quite inflammatory when

00:08:37.280 it crystallizes, this inflammatory condition within the joints is what is clinically known as gout. And if

00:08:43.220 you've ever had this, people listening will know it is incredibly painful. For reasons that are not

00:08:48.680 entirely clear to me, and maybe they're clear to some, the great toe, the big toe, seems to be one of

00:08:55.700 the joints where this occurs disproportionately. And when patients get this, you can ride it out,

00:09:01.780 but more commonly, you actually have to put them on pretty potent anti-inflammatory drugs.

00:09:06.560 The other place where this shows up is in kidney stones. So while it's not the most common form of

00:09:11.420 kidney stones, it's probably number two or number three. And so high levels of uric acid are also

00:09:16.960 going to predispose to urate-based kidney stones. Finally, I would say, and we're going to go into

00:09:22.820 this in more detail, hyperuricemia, high levels of uric acid contribute to high blood pressure.

00:09:29.140 And this has been demonstrated experimentally, and it has been demonstrated through Mendelian

00:09:33.700 randomization. We're going to talk a lot about Mendelian randomization today. And the reason for it is

00:09:40.140 MR is a really valuable tool for establishing causality when you are studying a biomarker or

00:09:50.400 a phenotype for which there is great genetic variation. Mendelian randomization has helped us

00:09:56.880 make sense, although I don't think we needed to make much more sense of the causality of LDL

00:10:01.920 in atherosclerotic cardiovascular disease. So all the clinical literature on LDL makes it pretty clear

00:10:09.240 that lowering LDL lowers cardiovascular disease. But you could ask the question, well, do we know

00:10:15.640 that lowering LDL is the cause of the reduction in risk, or is it that giving medications that lower

00:10:21.760 LDL lowers something else like inflammation, and that's the driver? But when you do Mendelian

00:10:27.220 randomization and you look at the genetic distribution of LDL cholesterol, you see that,

00:10:33.480 in fact, there is causality. And similarly, when you do that type of analysis with uric acid,

00:10:38.280 you see that as uric acid levels go up, so too does blood pressure. As uric acid levels go down,

00:10:46.620 so too does blood pressure. All of this, of course, is confounded by the fact that things that are bad

00:10:53.840 for you tend to raise uric acid. And that association is a little difficult to tease out causality.

00:11:01.740 So for example, we know that patients with fatty liver disease and patients with type 2 diabetes

00:11:06.440 usually have very high uric acid levels. And it's unclear exactly what the direction of causality is

00:11:15.440 there. So probably a longer answer than you wanted, Nick, but given the nature of what we're talking

00:11:20.840 about, it's probably worth giving a bit more of an expansive response. If someone's looking at their

00:11:25.680 uric acid levels, what are some factors that can increase their level of uric acid?

00:11:31.200 Well, I sort of think of this as what are the modifiable things and what are the non-modifiable

00:11:36.760 things? So let's just start with the non-modifiable. So sex is the biggest difference. On average,

00:11:43.260 men have a uric acid level that is about 0.5 to 1 milligram per deciliter higher than women at a

00:11:50.340 given age. Now that's based on the literature. If you asked me personally, like based on my experience

00:11:55.540 and said, Peter, tell me what you think, I would have said it's easily one to two milligrams per

00:12:01.320 deciliter higher, just based on what I see in patients. So in other words, the gap seems even

00:12:05.800 larger to me than what is reported in the literature. But nevertheless, there's clearly a sex difference

00:12:11.960 there. And the most obvious hypothesis is that it centers around estrogen and some of the downstream

00:12:17.100 effects of estrogen. It's also clear, by the way, that not only do women tend to have lower levels

00:12:22.220 of uric acid, they also seem to be more susceptible to higher levels or to a given level of uric acid.

00:12:28.480 In other words, they seem to be more likely to run into the trouble of a high uric acid than a man

00:12:35.160 is at a given level. The other thing I alluded to this also above is genetics. The heritability

00:12:40.400 of uric acid seems to be about 40%. In other words, nearly half of the value of your uric acid

00:12:48.420 is determined genetically. And that means independent of just sex, let's just say across

00:12:53.980 men or across women. And again, that genetic variability, that heritability of uric acid is

00:13:00.520 actually what allows us to determine the causality of uric acid in so many of these things that we

00:13:08.640 care about. If there was no genetic variation to uric acid, it would be very difficult to do Mendelian

00:13:14.160 randomization. The next thing that's not modifiable that plays a significant role in uric acid is age.

00:13:21.660 As we increase in age, we tend to increase in uric acid, although this effect is more pronounced in

00:13:28.860 women than men. And it starts around the age of menopause, which again factors into the hypothesis I

00:13:35.180 alluded to earlier, which is that estrogen probably plays a significant role in uric acid regulation,

00:13:42.580 given that women are lower and then tend to have a big uptick when they get through menopause. 1.00

00:13:48.240 Actually, there's a pretty cool figure that might be worth showing for folks if they want to see

00:13:52.380 the relationship between uric acid in men, women, and then what happens around menopause. So

00:13:57.120 Nick, if you can just pull that up, this is a figure that really speaks for itself here.

00:14:02.120 Obviously, the blue line represents men and the red line represents women. And you can see

00:14:08.540 that the blue line, well, first of all, it's always higher than the red line and the rate of increase

00:14:14.640 is modest and steady. Conversely, the red line stays largely flat until the mid forties and then

00:14:23.460 really increases at a rate that exceeds even the rate at which the males increase. And this continues

00:14:30.840 throughout life. But to note, even at the age of 80, which is where these data stop, women are still 0.99

00:14:37.200 considerably lower than men. And so you kind of laid out those are the things that people really 0.92

00:14:43.300 don't have control over. What do we know about factors that can cause uric acid to raise that

00:14:49.140 people may have control over? A lot of discussion on this topic points towards nutrition because

00:14:55.420 epidemiologic data tell us that average serum uric acid levels have been increasing pretty substantially

00:15:02.260 over the past century. So in addition to all of the things that we've talked about, the sex

00:15:07.080 differences, the age progression, if you just look at the population level of uric acid, it is going up.

00:15:13.900 And therefore, the obvious question is, is it going up for the same reasons that certain other things

00:15:19.840 are going up, such as obesity and metabolic syndrome? And if so, what is it about those things

00:15:26.640 that's increasing uric acid? Well, given that fructose is one of the things that drives uric acid

00:15:35.720 production, at least transiently, the question is, does chronic consumption of high amounts of

00:15:42.940 fructose, presumably in liquid form more than solid form, play a role in this? Does it play a role directly

00:15:49.460 or does it play a role indirectly? What does that mean? Well, directly would mean, does fructose

00:15:54.720 consumption, which is known to an unequivocally increase uric acid levels transiently, does enough

00:16:02.300 fructose consumption lead to chronic elevation of uric acid? That I think is an unknown question.

00:16:07.560 An alternative explanation is that high levels of fructose consumption are driving more eating.

00:16:14.000 So we talked a lot about that with Rick Johnson. What is it about fructose consumption and intracellular

00:16:18.900 energy levels that lead to more consumption of food and therefore obesity? And is that the driver

00:16:26.480 through energy balance? So there have been bi-directional Mendelian randomization studies

00:16:31.920 that have been done, and they have suggested that higher levels of adiposity can cause hyperuricemia.

00:16:38.740 So in other words, that would explain that obesity and energy imbalance is a driver of elevated

00:16:44.640 uric acid and not the other way around. By the way, that's done by looking at genes that are known

00:16:50.200 to increase fat mass, such as the FTO gene, MC4R gene, and other genes that are clearly associated

00:16:57.460 causally with obesity. There are certain medications that can do this. So diuretics, which are very common

00:17:03.420 in the treatment of high blood pressure, and even low-dose aspirin can do this. We talked about,

00:17:08.620 obviously, the dietary effects of fructose, but we shouldn't negate the dietary consumption

00:17:13.440 of foods that are very high in purines. So foods that are very high in DNA, meat, and believe it or

00:17:21.040 not, beer is quite high in DNA. Why? Because beer contains a lot of yeast, and the yeast obviously

00:17:27.880 has genetic material in it. So high amounts of alcohol, though again, I think disproportionately beer

00:17:33.600 over other types of alcohol, high amounts of very dense foods. By foods, I mean foods that are dense in

00:17:39.400 DNA, so sardines, things of that nature, red meat. These are things that are going to also increase

00:17:45.660 the production of uric acid. Now, I'll tell you about another funny example, Nick, of something that

00:17:50.940 I learned many years ago when I was in ketosis, which is that being in ketosis, either nutritionally

00:17:58.000 or through starvation, will increase uric acid levels and can do so quite dramatically. And the reason

00:18:03.860 for that is the primary ketone that is produced during either of those states, nutritional ketosis

00:18:10.220 or starvation ketosis, i.e. fasting, is something called beta-hydroxybutyrate. And beta-hydroxybutyrate

00:18:16.360 competes with uric acid in the kidney for the same transporter that is going to excrete either uric acid

00:18:24.980 or BHB. So when BHB is out-competing uric acid vis-a-vis impairing this tubular secretion in the

00:18:33.160 kidney, uric acid is going to go up. And so the first time I learned that was when I was deep in

00:18:38.920 nutritional ketosis and I actually got gout. And this was probably 12 years ago because I didn't fit

00:18:46.660 the phenotype of gout. At the time, I was just really lean, really healthy, smoking and joking in

00:18:51.820 my ketosis. It took me like two weeks to figure out why my toe hurt so much that I couldn't do a flip

00:19:00.480 turn in the pool and put any weight on that foot as I pushed off. I mean, that's how bad it was.

00:19:05.580 Of course, I would go on to learn exactly what happened. And then in subsequent years, as I would

00:19:10.540 fast, I would always make sure I was taking allopurinol or something. But I did confirm that

00:19:15.840 during some significant fast, my uric acid would rise from say five to nine or 10 as my ketone levels

00:19:23.460 approached four and five millimole. So those are some of the things that are modifiable and obviously

00:19:30.860 play a role. One other thing that's, by the way, kind of interesting is anaerobic exercise. Heavy,

00:19:37.140 heavy bouts of anaerobic exercise can also increase uric acid transiently. It might be that this goes away

00:19:44.200 over time, but we're not entirely clear why. The hypothesis is that heavy bouts of anaerobic

00:19:49.520 exercise cause depletion of muscle ATP and that the energy needs of the muscle obviously can't be

00:19:56.100 met exclusively by glycolysis. So we basically experience the buildup of ATP degradation byproducts

00:20:04.140 in the muscle. And in particular, one of those is IMP, which is converted into uric acid. So I think

00:20:11.780 what's interesting is that there seems to be an adaptation to that. And I'm also not convinced

00:20:15.780 that there's anything pathologic about that. So that's just more of an interesting aside, not like,

00:20:19.800 oh, don't do intense anaerobic activity. You mentioned kind of earlier a few times,

00:20:24.520 the relationship between uric acid and blood pressure. And we know about blood pressure's

00:20:29.540 role in cardiovascular disease. What do we know about uric acid as it potentially

00:20:35.060 relates to the risk of cardiovascular disease?

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The Peter Attia Drive - August 12, 2024

#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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