The Peter Attia Drive - #194 - How fructose drives metabolic disease

00:00:00.000 Hey everyone, welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

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00:00:41.740 head over to peteratiyahmd.com forward slash subscribe. Now, without further delay,

00:00:47.800 here's today's episode. My guest this week is Rick Johnson. This will be a familiar name to a lot of

00:00:54.100 you as he was a previous guest back in January of 2020. And we recently re-released that episode.

00:00:58.920 in preparation for this interview, which was carried out in November of 2021. Rick has authored

00:01:04.840 over 700 scientific publications, as well as three books, the sugar fix in 2008, the fat switch in

00:01:10.480 2012, and his new book, nature wants us to be fat, which is out February 8th, 2022. Rick is a professor

00:01:18.940 of medicine and the chief of the renal division and hypertension at the university of Colorado,

00:01:24.160 where he conducts research exploring the role of fructose in the development of obesity,

00:01:27.920 metabolic syndrome, and kidney disease. Rick's initial episode was a really popular one,

00:01:33.480 despite the technical nature of it. And that coupled with a bunch of follow-up stuff is really

00:01:38.180 what prompted me to bring him back. In this episode, we talk about how the body can actually

00:01:42.280 generate fructose from glucose to novo, and the effect of circulating glucose and salt levels on

00:01:47.620 activating this conversion. That's a pretty novel concept. That's not something that I certainly

00:01:53.400 appreciated until very recently. We talk about the effects of fructose on weight gain by driving an

00:01:57.980 increase in food intake. We talk about the decline in metabolic flexibility associated with aging and

00:02:03.320 how factors such as sugar intake or menopause-associated hormone changes can alter the response to sugar

00:02:08.920 across a lifetime. We talk again about pharmaceutical therapies on the horizon for blocking fructose

00:02:13.780 metabolism and their potential use in treating metabolic syndrome. The impact of fructose metabolism

00:02:18.840 and uric acid on kidney function and blood pressure. And we conclude with a discussion on vasopressin,

00:02:24.260 a hormone that facilitates fructose's effect on weight gain and insulin resistance.

00:02:29.000 Again, a somewhat technical discussion, but I think Rick has a pretty good way of explaining

00:02:33.300 technical things in such a manner that even if you don't have a background in this biochemistry,

00:02:38.000 I think you can follow along really well. So without further delay,

00:02:40.480 please enjoy my conversation with Rick Johnson.

00:02:47.940 Hey, Rick. Good to see you again.

00:02:49.760 Great to see you too, Peter.

00:02:51.440 We had a lot of follow-up questions from our first podcast, which actually was probably about

00:02:56.340 two years ago. In addition to the other topics that I wanted to follow up on, we sort of asked

00:03:01.980 listeners, we're going to do another round two here. What do you have? So much of what we're going

00:03:06.400 to talk about today is a combination of things that I wanted to double click on coupled with that of

00:03:11.040 what others did. But I think a number of people have asked the question, hey, can you explain again,

00:03:17.160 why is it that fructose metabolism is kind of unique from a nutrient standpoint in terms of creating

00:03:24.120 this transient intracellular energy deficit? This is something that becomes very important

00:03:30.400 and we get into sort of the metabolic effects of fructose. Absolutely. So just to reiterate what

00:03:36.860 you're saying, all nutrients are there to produce energy. Any kind of food, we're using it to generate

00:03:44.420 energy or ATP in our body. But there's a cost to producing energy. And so some energy is used

00:03:51.860 to digest foods and some energy is used to metabolize foods. It's the idea, the old adage,

00:03:58.200 you have to spend money to make money. Now you're going to get that ATP back in spades if you just

00:04:03.220 stay with the program. That's absolutely truth. All right. So let's talk now about fructose. And

00:04:09.040 is fructose unique in what you're about to describe? Well, alcohol can also activate this process.

00:04:15.680 And so alcohol can cause rapid ATP depletion as well. But in terms of most nutrients, fructose is pretty

00:04:24.420 unique. Yes. Okay. So how does that work? Yes. So with fructose, the very first enzyme in fructose

00:04:31.800 metabolism is called fructokinase. And this is going to become an important enzyme to remember.

00:04:39.100 Its nickname is ketohexokinase or KHK. One of the key enzymes in fructose metabolism. It phosphorylates

00:04:47.860 fructose at the one position. So it's fructose one phosphate. That enzyme will literally phosphorylate

00:04:55.780 the fructose as soon as it sees it. Doesn't have any negative feedback. If ATP levels start to drop,

00:05:04.700 that's fine for the fructose metabolism. That's what fructose metabolism is aimed at doing.

00:05:11.020 And so if you have a large concentration of fructose, it's concentration dependent.

00:05:16.160 If the fructose concentration is very low, there won't be as much ATP depletion and it may actually

00:05:22.560 go undetected. If it's a lot of fructose present, the ATP depletion will be quite severe. So the degree

00:05:31.520 of ATP depletion varies with the concentration of fructose. And as we talked last time, the fructose

00:05:39.240 concentration relates to not just the amount of fructose, but how rapidly it's absorbed. So if

00:05:46.100 you drink liquid fructose, like a soft drink on an empty stomach, that liquid fructose can get

00:05:53.120 absorbed very quickly. And even more quickly, for example, with high fructose corn syrup,

00:05:58.760 there's some debate on this, but high fructose corn syrup, the fructose and glucose are already

00:06:03.040 separated. So it may be absorbed differently than sucrose where it's glucose and fructose bound

00:06:10.180 together, but they have to be degraded to the individual fructose and glucose in the gut before

00:06:17.280 they're absorbed. So if you drink liquid fructose, it will be absorbed very fast. And then the

00:06:23.700 concentration will be higher when it hits the liver. And the liver is one of the key sites that drives

00:06:30.460 this whole process. So what happens is when the fructose gets there, the fructokinase

00:06:36.320 phosphorylates it and the ATP levels acutely fall. But then there's a series of reactions that try to

00:06:46.100 help maintain the low ATP state. And that low ATP state is maintained primarily by a drop in

00:06:55.460 intracellular phosphate that accompanies this. And that activates this enzyme system that removes

00:07:03.200 the breakdown of ATP products. It removes it so that the ATP cannot be regenerated easily.

00:07:10.280 So the ATP levels fall. There's the accumulation of ADP and AMP. Adesine monophosphate is one of the key

00:07:20.620 ones. And then that is swept away. So normally AMP and ADP get reformed to make more ATP. They're really

00:07:29.300 important to make the ATP. If the AMP is removed, then it's hard to replenish the ATP because you've removed

00:07:37.580 a key building block for ATP. And that AMP is removed by an enzyme called AMP deaminase, which turns out to

00:07:46.960 be a very, very important enzyme in this pathway. And that breaks down the AMP stepwise until it produces

00:07:55.580 uric acid, which is the end product of purine metabolism. ATP basically has purines in it,

00:08:03.800 the adenine, and that gets broken down eventually to uric acid. And then the uric acid inside the cell

00:08:12.280 actually causes oxidative stress to the mitochondria. And the mitochondria are also really important in ATP

00:08:22.060 production. And the oxidative stress affects this several ways. First, it inhibits an enzyme called

00:08:29.840 aconitase, which is involved in the Krebs cycle and basically leads to citrate accumulation and the

00:08:37.600 stimulation of fat production. And it also blocks an enzyme called enol-CoA hydratase. And that enzyme's

00:08:45.880 involved in beta fatty acid oxidation. So it blocks the burning of fatty acids. And so what happens is

00:08:52.060 it reduces the production of ATP by blocking and shunts those components to make fat and to block the

00:09:02.560 burning of fat. So what it's trying to do is it's trying to stimulate fat storage. Uric acid also

00:09:08.760 inhibits this enzyme that's activated in starvation to help bring back it to raise energy levels called

00:09:15.600 AMP kinase, AMP activated protein kinase or AMP kinase. And by inhibiting that, it also blocks energy

00:09:23.840 production. So the whole thing is brilliant. I mean, it's a brilliant system to set the energy levels

00:09:32.180 down in a cell. And it mimics the condition of starvation. By reducing the energy in the cell,

00:09:40.540 it triggers an alarm signal. It's like a mayday. And that is what leads to a survival response,

00:09:50.440 makes the animal get hungry, thirsty, forage for food, try to store fat, try to store glycogen. It's

00:09:59.500 like an alarm signal saying, hey, you're going to be in trouble. And what we need to do is we need to

00:10:05.300 store energy as a means to help you because winter's coming. You're going to be without food.

00:10:13.540 You're going to have to travel 2,000 miles by air by flying to a place. And you're not going to be

00:10:20.680 able to eat or anything when you're flying over that ocean. It's a survival pathway.

00:10:26.200 All right. So let's go back and summarize that because there's obviously a lot you put out there.

00:10:31.400 So let's start from the beginning. Fructose enters a cell. By the way, is this typically a

00:10:37.800 hepatocyte? Is this a liver cell that is doing the lion's share of this metabolism? Or is it an

00:10:43.580 enterocyte, a gut epithelial cell? What type of cell is doing this type of metabolism typically?

00:10:49.500 One step back, fructose can be metabolized like glucose through some of the glucose enzymes. So

00:10:55.420 fructose can be metabolized by glucose enzymes, but it prefers to be metabolized by fructokinase.

00:11:03.180 We would say it has a higher affinity and will preferentially be metabolized by fructokinase

00:11:10.200 if the fructokinase is present. Normally, fructokinase is present a little bit in the gut.

00:11:19.360 It's in the gut, actually modest amounts, actually fairly modest amount. And it's also in the liver,

00:11:26.420 but it's also in the brain. It's in the islets of the pancreas. Very important because that's

00:11:32.480 where insulin and glucagon are produced. Some of it is in the white fat. Pheromone is in the kidney.

00:11:38.840 And then it has the ability to be induced, meaning that it's not normally present,

00:11:44.800 but it can be turned on. And one place that can be turned on is whenever there is like

00:11:50.800 injury, tissue injury, like a heart attack. It can be turned on and produced in the heart

00:11:59.300 following a heart attack, or it can be produced in the kidney further or be activated further

00:12:05.840 if you have kidney failure, like from a COVID infection. So it can be induced in sites,

00:12:12.480 and it's probably trying to provide some, quote, survival mechanisms in these sites. But what

00:12:19.600 happens is it tends to be over activated and end up causing worse injury rather than protection from

00:12:27.780 injury. And this has been a common issue when it's been studied in that it was probably originally

00:12:34.580 meant to be protective. But when it's turned on big time, and part of that is driven by our diet

00:12:40.920 and so forth, it can actually be injurious. So its main sites are the liver, the brain,

00:12:48.320 the islets, the kidney, and the intestine. Now, where it causes the energy depletion seems to be in

00:12:56.100 all those sites except the intestine. And the intestine, there's a tendency during the metabolism

00:13:03.240 to use up. There's work done by Dr. Josh Rabinowitz from Princeton, beautiful studies,

00:13:10.300 that has shown that the fructokinase in the gut, probably at high concentrations, you do get the

00:13:16.900 energy depletion. But when there's just small amounts of fructose, it actually tends to not

00:13:22.200 cause the energy depletion and to actually convert the fructose more along the lines towards glucose.

00:13:28.760 Fructose can be converted to glucose and glucose can be converted to fructose. The intestine tends

00:13:35.620 to be a shield that at low concentrations just helps remove the fructose without it being a problem.

00:13:43.060 And this is one reason why fruits, which have like four grams of fructose or vegetables,

00:13:49.900 have small amounts of fructose, like two to five grams. They don't cause the energy depletion

00:13:55.860 mainly because this intestinal fructokinase seems to inactivate small amounts. But if you

00:14:03.020 hit it with a large dose of fructose, the fructose gets through the intestine. It probably causes ATP

00:14:09.500 injury to the intestine. And we can talk about that because I've done some studies to show that it

00:14:14.960 causes gut leak. It may be responsible for anaphylaxis to certain foods, for example, food allergies. So

00:14:22.820 good story to talk about that. But most of the fructose ends up getting metabolized in the liver

00:14:28.880 and the liver seems to be the primary place that drives the metabolic syndrome and obesity and

00:14:36.900 diabetes. And if we knock out fructokinase just in the liver, we can protect animals from obesity and

00:14:44.920 diabetes and high blood pressure. So the liver is the king when it comes to metabolic syndrome.

00:14:50.320 The kidney is actually important for kidney disease and the brain is really important for diseases like

00:14:56.280 Alzheimer's and so forth that we can talk about. But yeah, fructose turns out to have been meant to

00:15:03.600 be this wonderful system for survival. But in our culture, with the amount of sugar and foods that

00:15:11.420 we are eating that either provide sugar or can be turned into fructose, this pathway has become hazardous.

00:15:19.240 Let me go back and make sure that folks are following along here, Rick. So as you pointed

00:15:24.080 out, the gut becomes the first place of contact. By definition, we're pretty much all eating things

00:15:28.820 through our mouth. They're going to wind their way through the stomach into the duodenum and into the

00:15:33.800 proximal part of what's called the jejunum. You have these epithelial cells that line the gut. And

00:15:40.240 as you're saying, at low doses of fructose, so if you're eating a piece of fruit or some vegetables,

00:15:47.360 which have some amounts of fructose in them, they can be absorbed there without creating that

00:15:53.600 phenomenon you've described. But when you override that system, when you expose the gut to

00:15:58.700 higher concentrations and presumably higher doses, so it is really a dose concentration problem,

00:16:03.740 which we'll come back to, it basically manages to get through the gut without the gut doing

00:16:08.880 the metabolism. And then it's going to enter the portal system. We didn't really explain that,

00:16:15.560 but the reason that it preferentially makes its way to the liver is that the venous system that drains

00:16:23.480 the gut has another very beautiful and unique to the body property, almost unique to the body.

00:16:30.940 It occurs in one other place, but where the superior mesenteric vein, inferior mesenteric vein,

00:16:37.280 join the splenic vein, these things become the portal vein. And you now have a vein that becomes

00:16:44.060 an inflowing conduit to the liver. So now that's why the liver plays, as you said,

00:16:49.080 such an important role in metabolism. It has two incoming blood supplies, the arterial supply,

00:16:56.040 which supplies its oxygen, and its venous incoming supply, which supplies these nutrients

00:17:01.640 on first pass from the gut. Now they get into the liver. And the first thing that happens is we need

00:17:10.060 to phosphorylate fructose. And by definition, we're already in a high fructose state because we've

00:17:16.120 already exceeded the gut's capacity to metabolize this. And so now it's basically a free for all with

00:17:22.680 unlimited fructose becoming fructose one phosphate. And we're generating in the cell lots of ADP. So we

00:17:33.400 need, we start with ATP, which has three phosphates. We rip off a phosphate to put it on our fructose in

00:17:40.280 the number one carbon position. That leaves us with ADP, adenosine diphosphate. It's shy of one

00:17:46.000 phosphate. That reaction doesn't slow down. ADP further gives up a phosphate becoming AMP,

00:17:52.840 adenosine monophosphate. The ADP and AMP are being shunted elsewhere in the further degradation

00:18:00.860 of their adenosine component. And that's being turned into uric acid. Uric acid being the final

00:18:09.260 breakdown product of adenosine. You're doing two things, which is you're taking away the base that

00:18:16.620 you could rephosphorylate to repopulate ATP. You're running more and more fructose through this.

00:18:23.060 And if that weren't enough, the uric acid goes on to be metabolized into other molecules that

00:18:33.180 both increase the substrate for de novo lipogenesis in the form of citrate and also create other

00:18:42.720 molecules that inhibit the process of beta oxidation, which is the process by which we break down fatty

00:18:49.780 acids to make ATP. Do I have that right so far? You're right on the money. It's a fantastic review.

00:18:57.140 The only thing I would correct is that when the uric acid is generated, it actually doesn't further

00:19:03.380 break down. I mean, it does break down a little bit, but the way it works is it stimulates oxidative

00:19:10.260 stress in the mitochondria. And it does that by stimulating a specific enzyme called NADPH oxidase,

00:19:17.000 which I hadn't mentioned. And that enzyme produces oxidative stress and it actually translocates

00:19:23.720 that enzyme to the mitochondria. So the enzyme not only is activated, but it's moves into the

00:19:30.520 mitochondria. That oxidative stress then inhibits different enzymes and that lead to fat synthesis and

00:19:40.280 blocks of fatty acid oxidation. So the uric acid accumulates in the cell and you can measure the

00:19:47.800 uric acid and the levels go up in the cell. And it's the uric acid turning on these processes

00:19:54.440 that seems to really drive this whole mechanism. One can view it, Peter, like there's two pathways for

00:20:02.760 fructose metabolism. One is the caloric pathway. Fructose gets metabolized to CO2 and water.

00:20:09.720 In that sense, the caloric pathway, it's sort of similar to glucose, but unlike glucose that triggers

00:20:16.920 another pathway, an ATP degradation pathway, and that is not considered a caloric pathway. It's not part of

00:20:26.200 the calories. What it's doing is it's activating metabolic processes that lead to the development of

00:20:33.160 diabetes, obesity, hypertension, and all these things are driven by this side chain reaction. So it's not

00:20:41.320 the calories of fructose that are driving obesity. It's not the calories from fructose. It's the fact

00:20:49.480 that fructose lowers the energy and keeps the energy levels low. And this is due to this runaway

00:20:57.320 renegade enzyme fructokinase that just takes all the ATP again to phosphorylate the fructose as it's seasoned.

00:21:06.600 A couple things I would say there. One is going back to the why. This is an amazingly engineered system

00:21:14.360 in a food-scarce environment because every one of those things that you said, which is

00:21:21.240 an enzyme that is by definition not telling the organism to stop eating, it's not signaling

00:21:29.880 that we have enough energy. It's signaling the exact opposite, which is the more of this you eat,

00:21:34.920 the more of this we want you to get. And it's turning off your ability to oxidize fat and turning

00:21:41.240 on your ability to store and make more fat out of the byproduct here. Those are really incredible,

00:21:49.080 valuable adaptations without which we wouldn't be having this discussion because we wouldn't exist.

00:21:53.000 Exactly. So it's like a very fundamental mechanism that developed in nature. It's like a process that

00:22:01.800 is so key for survival that all animals use this pathway. And what's interesting is that one of the

00:22:10.280 breakthroughs was the discovery that it's not just the fructose we eat, but that the body can make

00:22:17.480 fructose. And when the body makes enough fructose, it can activate this pathway. When we were originally

00:22:25.400 studying this, we said to ourselves, okay, it looks like it's fructose is the problem. And so if we just

00:22:31.240 go on a low fructose diet, maybe this is how low carb diets work because low carb diets would be low

00:22:37.880 fructose diets. And we were originally thinking, yeah, this is the pathway that's activated. So

00:22:44.280 let's just go on a low fructose diet. I actually wrote a book, the sugar fix back in 2008, because

00:22:49.960 I thought that was the solution, just go on a low fructose diet. But the problem is that the body can

00:22:56.840 make fructose. And it turns out that the favorite way it makes fructose is through high glucose levels.

00:23:08.360 High glucose, the classic is diabetes, is a high glucose state. In diabetes, it's been known for

00:23:15.960 decades that there's the enzyme that gets turned on in high glucose states called the polyol pathway.

00:23:23.960 And that enzyme can convert glucose to sorbitol, and sorbitol then gets converted to fructose. By

00:23:32.520 the way, sorbitol is considered one of the artificial sugars. So be aware, it actually gets turned into

00:23:38.040 fructose in the body. Glucose gets converted to sorbitol, which converts to fructose, and that occurs

00:23:45.000 under high glucose conditions. Say more about what that means, Rick. Does that mean

00:23:50.360 under high plasma glucose conditions? We always were thinking high plasma

00:23:55.800 glucose conditions. But then we thought to ourselves, actually, it's not the plasma that's

00:24:01.880 so important. It's what's going on in the liver that's so important. So high glycogen conditions?

00:24:07.960 When glucose gets to the liver. Now remember that when we eat carbs, we're generating glucose.

00:24:14.920 And so, you know, if you eat broccoli, you're going to generate some glucose because it's a vegetable

00:24:21.320 that has carbohydrates in it. But it doesn't produce a lot of glucose. So the glucose concentrations in the

00:24:28.760 liver and the blood don't go up with broccoli. But if you eat bread or rice or potatoes, chips, cereals,

00:24:38.440 these are what we call high glycemic foods, which means that they have a fair amount of

00:24:45.080 starch that gets broken down to glucose in the gut. So when you eat bread, you actually generate

00:24:52.680 a fair amount of glucose. And if you have like continuous glucose monitor or things like that,

00:24:57.800 you can actually see a rise in your blood glucose when you eat bread or rice or potatoes,

00:25:04.200 it will go up. And it's also going up in your liver.

00:25:07.640 And do we know what the difference is in the portal vein? So if you're wearing a continuous

00:25:12.360 glucose monitor and it's showing before you eat, your glucose is 90 milligrams per deciliter. And

00:25:18.920 after you eat, it's 150 milligrams per deciliter. Do you have a sense of how high it is in the portal

00:25:24.920 vein at that peak level?

00:25:26.840 We have not done those studies, but it would be very, very helpful to understand because

00:25:32.600 there is what we call first pass effect where food, when it goes through the liver, the liver uses up

00:25:38.840 some of it before it gets into the blood. So a lot of the glucose that enters the liver is quickly

00:25:45.240 sequestered in the liver cells and metabolized. And some of it passes through. Glucose in our blood

00:25:51.480 is like the tip of the iceberg. There's the glucose levels in the liver are likely higher.

00:25:57.560 Now, this enzyme that converts glucose to fructose is normally when we're born,

00:26:03.720 it's very little of it's in the liver, but it gets induced over time. And I would love to develop

00:26:11.480 an assay for looking at peripheral blood, for example, to see if you've turned on your

00:26:18.760 aldose reductase is the name of the enzyme, whether or not that enzyme is elevated in your

00:26:24.120 liver or not. Because if it is, bread is going to be much more fattening than if you don't have

00:26:31.160 that enzyme. Where would you be measuring that, Rick? Do you think measuring that in the,

00:26:36.120 literally in the plasma, would there be enough of it there? Or is this something that's particularly

00:26:40.280 inducible in the liver? Well, it's inducible in the liver, but you can measure. So sorbitol

00:26:46.120 is kind of a good marker of the activation of this pathway. Is this the enzyme that turns

00:26:51.880 glucose into sorbitol or sorbitol into fructose? Yeah. The rate limiting enzyme is the enzyme that

00:26:57.400 converts glucose to sorbitol. And that enzyme is called aldose reductase. And it's normally low in

00:27:05.960 the liver, but it gets induced and it can be induced by high glucose. It's induced by high uric acid. So

00:27:13.240 there's a positive feedback system because fructose is metabolized. When fructose is metabolized,

00:27:19.080 you generate uric acid. Uric acid then goes back and tries to turn on the enzymes that can lead to

00:27:25.160 more fructose metabolism. What's the evidence for those two claims? What's the evidence that glucose

00:27:32.600 and uric acid both induce the enzyme that turns glucose into sorbitol? Is there human data for that

00:27:40.280 or is that all in mice? High glucose activating aldose reductase has been shown in humans, as well as in

00:27:49.080 animals, as well as in cell culture. And it was the very basis for the original concerns about this

00:27:56.840 pathway being important in diabetic complications. This has been known for 50 years, but the uric acid

00:28:04.760 as a stimulus for aldose reductase was published by our group based on animal studies and cell culture

00:28:12.520 studies. But it was not based on human studies. So it would have to be shown in humans. But I believe

00:28:19.080 it's very likely true based upon the animal data, the cell culture data. And at what levels of uric acid

00:28:26.200 does it start to become clinically relevant? Meaning, do you get enough sorbitol production

00:28:33.640 that it leads to meaningful amounts of fructose generated de novo? Most of our studies, when we do

00:28:40.520 it, when we go from a normal uric acid to a high uric acid in a laboratory rat, the levels of high versus

00:28:48.520 low are different in humans. But they seem to translate when we've done studies like in human cells versus

00:28:54.680 rat cells. The correlation is beautiful. So generally speaking, I would say levels of

00:29:01.640 uric acid that might turn on this pathway are probably be over seven milligrams per deciliter

00:29:07.320 in a human. And certainly that's what you see in metabolic syndrome. What's very common in our studies,

00:29:13.320 when we gave glucose to animals, my theory was that that would not cause obesity because glucose will

00:29:21.080 maintain the ATP levels, blah, blah, blah. The fructose is activating this metabolic syndrome

00:29:27.400 through dropping ATP levels. I did not think that glucose would really cause obesity. When we gave it,

00:29:36.440 we found that the mice over time became very, very fat and insulin resistant. And I was a little

00:29:42.440 depressed, but I was hoping that we would find that the glucose was being converted to fructose.

00:29:48.600 When we looked in the livers, we found that about maybe as much as 25% of the glucose was being

00:29:54.040 converted to fructose in this laboratory mice. I want to make sure we understand the conditions

00:29:59.080 of which this experiments are being done. Are these animals being force-fed glucose? And if so,

00:30:05.320 how much of a caloric surplus are they experiencing? And what other macronutrients are factoring into this?

00:30:12.040 I mean, are they literally just eating pure starch? So the way we did this experiment was we gave glucose

00:30:18.440 in the drinking water. So it was like 10% glucose in the drinking water, and we gave it to laboratory

00:30:24.520 mice. Which strains? I would have to look it up. The C57, I think it's called. This strain's

00:30:31.560 propensity for obesity is how much compared to the wild type behaves how here? So the wild type

00:30:39.000 mice, the control mice, they get fat when you give them fructose in the water. They get fat when you

00:30:44.280 give them glucose in the water. It's pretty significant. But it takes weeks to months really

00:30:50.200 to see the effects of glucose or fructose to cause obesity. It goes through a period of time,

00:30:57.080 several months. And what happens is, initially, when you give glucose or fructose in the drinking

00:31:03.320 water, the animals like it. So they drink a lot more water than they normally, and they're getting

00:31:08.280 a fair amount of caloric intake from the water, from the drinking water, because it has sugar in it.

00:31:14.520 So what are the control animals drinking? Just access to the same chow, but no glucose in the water?

00:31:20.360 Right. Or we can do things like give artificial sugars. We have done that, like give Splenda,

00:31:25.400 where they'll drink increased amounts of water, similar to glucose or fructose, but they're getting

00:31:31.640 an artificial sugar. And what happens is that when an animal is getting calories in its water,

00:31:38.840 it will reduce how much food it eats. And that's a normal process, and it's true for sugar as well.

00:31:44.760 It's true for table sugar, it's true for fructose, and it's true for glucose. But what happens is,

00:31:51.160 over a period of a month or so, suddenly they start eating more and more despite still drinking a lot.

00:31:59.560 They end up being in a high caloric state. When we look at that, it's because they start developing

00:32:06.440 leptin resistance. And the leptin resistance, leptin is a hormone produced in the fat cells that

00:32:14.200 tells the brain that it's full. When leptin levels go up, say, you know, you've eaten enough,

00:32:20.600 it's what they call a satiety signal. It says, okay, you've eaten enough.

00:32:24.200 Doesn't it work more in the reverse? I mean, isn't it really more that low levels of leptin

00:32:30.520 tell you that you are low in your fat stores? But if you don't look at leptin receptor deficient

00:32:37.240 animals, I didn't realize that high leptin had a satiety component. Otherwise,

00:32:43.320 injections of leptin would curb appetite, but I don't think they do in normal mice.

00:32:47.960 In normal mice, if you inject an animal with leptin, they will reduce their food intake

00:32:53.000 immediately within hours, and they'll reduce it by 30%. So normally, leptin does signal satiety.

00:33:01.880 If you inject animals with leptin, they will eat less.

00:33:05.560 But why does this not work in humans?

00:33:07.480 Because people, when you become overweight, you become resistant to leptin. And the leptin

00:33:14.440 resistance is at the hypothalamic level. So people who are overweight almost always have

00:33:20.280 very high leptin levels, and the leptin is not signaling, is not working. We call this leptin

00:33:27.160 resistance. It turns out that leptin resistance is how fructose causes animals to eat more.

00:33:34.760 Because when you give animals fructose, it takes like a month, but eventually the animals become

00:33:40.360 resistant to leptin, then you can inject them with leptin and they continue to eat. So the way we

00:33:45.640 test them is to actually inject them with leptin. So we do those experiments. Normally,

00:33:50.840 animals are sensitive to leptin. And if you inject leptin, they'll reduce their intake. If they're born

00:33:57.240 with low leptin, they're going to be hungry and they're going to eat more. And if they become

00:34:02.360 resistant to leptin, they can have a high leptin level, but they will not respond to it. And so they'll eat

00:34:08.760 more. You diagnose leptin resistance based on the response to a leptin injection.

00:34:14.440 Correct. And we do that in all of our studies. And then we also look for the evidence of leptin

00:34:20.360 resistance by studying the hypothalamus because there's a characteristic change that occurs that

00:34:26.920 you can look for with leptin resistance. We also test for that. What is that change?

00:34:32.920 It's, I think, STAT5 phosphorylation. I'd have to look it up again, but we do it. So that helps

00:34:39.640 determine if the animal is leptin resistant. And what's the mechanism of this, Rick? What causes

00:34:45.480 leptin resistance? Well, it's not fully known, but there's some evidence from some groups that

00:34:51.000 it might be due to uric acid. And you can kind of induce a leptin resistant state by, I think,

00:34:57.800 injecting uric acid in brains of animals. There's a group from China that they showed that it caused

00:35:03.320 leptin resistance, but they definitely showed that it can cause inflammation in the hypothalamus. And

00:35:08.840 the inflammation in the hypothalamus is thought to be the driver for leptin resistance.

00:35:14.760 Going back to the experiment, when we give glucose to animals, initially they reduce their chow intake.

00:35:21.000 Over time, they started increasing their chow intake. They become very fat. They become insulin

00:35:27.160 resistant. They develop all features of metabolic syndrome. And when we look in their livers, they're

00:35:33.080 making fructose and they've turned on this enzyme. This polyol pathway is high. And so they are

00:35:41.720 gaining weight and becoming fat related to fructose production. And to prove that it was the fructose,

00:35:48.520 we gave glucose to animals that lack fructokinase. These are genetically manipulated mice

00:35:56.200 where we've removed the gene or knocked out the gene for fructokinase. And so what happens is these

00:36:02.920 animals cannot metabolize fructose through this ATP depletion pathway. When we give them glucose,

00:36:10.040 they can drink the glucose. They gain some weight and fat, probably related to the effects of insulin.

00:36:17.000 But because glucose stimulates insulin, and insulin can decrease fat breakdown in the peripheral fat.

00:36:24.520 But what happens is these animals do not develop insulin resistance. They do not develop fatty liver.

00:36:32.840 They're really protected from the metabolic syndrome and they gain much less weight and have less fat.

00:36:39.240 And just to be clear, Rick, these are absolutely isocaloric, these two animals?

00:36:44.680 Yeah, it's very close. It looks identical. Yeah, it's super close.

00:36:49.960 Can you do this and pair feed the animals so that you have a fructokinase knockout pair fed with a wild

00:36:58.280 type and they're otherwise getting the same glucose in the water and the same chow and they're pair fed to

00:37:04.840 match? Yeah, well, we do a lot of pair feeding studies. In this case, the animals are drinking basically

00:37:10.600 the same amount of glucose. I mean, I think that it's within 5% or 3% difference. I mean,

00:37:17.160 it's very, very similar. And what's the difference in body weight or body fat at the end of this?

00:37:23.080 Oh, it's remarkable. It's remarkable. What percent is the difference?

00:37:27.800 I have to go back to the study. Now, we did it two different ways and we

00:37:33.080 did get slightly different results. So when we gave just glucose alone, the animals gained a little

00:37:39.320 bit of weight. They drank a lot of glucose. They still gained weight a little bit compared to a mouse

00:37:45.960 that didn't get glucose, even when the fructokinase was knocked out. But it was probably significantly more

00:37:52.600 weight gain than a mouse that got glucose. A mouse that just gets glucose alone really gains weight.

00:37:59.320 A mouse that gets glucose in which they cannot metabolize fructose, it's dramatically less,

00:38:05.320 but it's still a little bit more than normal. Again, to make sure I understand this,

00:38:09.400 both animals are only getting glucose and they're getting it in liquid form and solid form, though-

00:38:15.480 There's also chow. Right. One animal has a functional fructokinase,

00:38:20.600 one does not. Now, it's interesting that both animals presumably can make the same amount of

00:38:27.720 fructose. Correct. Because you're not impairing the conversion of glucose to sorbitol to fructose.

00:38:34.360 You're just impairing in one animal, the conversion of fructose to fructo-1-phosphate,

00:38:40.280 and therefore the metabolism of fructose. That whole pathway we discussed at the outset.

00:38:44.120 Yes, that's correct. So their fructose levels are still high in the fructokinase knockout,

00:38:49.240 it's just they can't metabolize it. Yes. So are they experiencing fructose

00:38:53.800 urea? Where is the excess fructose going in that animal? They do have fructose urea.

00:39:00.520 Where I'm going with this, Rick, is I'm trying to understand from an energy balance perspective,

00:39:04.760 what accounts for this difference? Is it that the fructokinase knockout is peeing out the excess

00:39:11.800 energy and that explains the difference in weight? Or is the energy expenditure different in these

00:39:19.480 animals? And that explains the weight. What happens is when you block fructokinase,

00:39:26.840 animals regulate their weight, regulate their caloric intake. So as I mentioned, if you give

00:39:33.320 fructose and glucose to animals, initially they reduce their chow so that they maintain the normal

00:39:40.440 weight. But after the leptin resistance kicks in, they start eating more chow than they need. And so they

00:39:48.440 go into a positive energy balance where they're eating a lot more than they normally do.

00:39:54.040 And this is associated with weight gain. When you give glucose to an animal that is a fructokinase

00:40:01.240 knockout, what happens is it continues to keep its chow low. So even though it's drinking a lot of

00:40:08.600 glucose, the chow stays low so that the overall energy intake is only very mildly increased.

00:40:15.800 So I misunderstood. I thought these animals were isocaloric across the board, but they're not.

00:40:20.920 The fructokinase knockout is eating less. Yes. They get the same exact amount of glucose.

00:40:27.080 They're drinking the same volumes of glucose. Right. But they're eating different amounts of chow.

00:40:31.240 They're eating. Exactly. The chow contains everything, fat, protein, and glucose. Yes.

00:40:36.680 But we have done, and in that experiment, we did do an isocaloric experiment too, where we

00:40:42.520 compared mice that were getting glucose and eating chow. We did a lot of animals. So we did paired them up

00:40:51.640 where the animals were actually eating the same total amount of calories. And when you do that,

00:40:57.400 you still see a very dramatic difference in things like fatty liver and insulin resistance.

00:41:04.440 Just to make sure you understand, you're saying when you do pair feed the animals

00:41:07.960 so that you have fructokinase knockouts and wild types. Again, I think the whole liquid versus chow

00:41:14.520 thing complicates this experiment. Let's just keep it simple. If you just are feeding them isocaloric

00:41:20.680 amounts of food that contain glucose, protein, fat, your hypothesis would be that the fructokinase

00:41:28.680 knockouts would be protected from the negative effects of fructose, both the fructose that they're

00:41:34.840 eating directly and the fructose that they will make from glucose in the event that they do so.

00:41:39.800 So just to really simplify it, what we've identified is that fructose stimulates obesity and metabolic

00:41:47.800 syndrome. And it does it through two major ways. One way is by encouraging an animal to eat more

00:41:55.880 and it basically stimulates hunger and stimulates food intake. Part of that is through the brain and

00:42:01.880 part of that is through this leptin resistance, which is also kind of a brain effect. And so the

00:42:07.240 animals eat more and they also drop their resting energy metabolism. So they're both metabolizing less

00:42:15.640 and they're eating more and that causes the weight gain. And what's the relative contribution of

00:42:21.320 those? This is very important to me because look, I think Rick, there are a lot of people out there

00:42:26.520 vociferously that calorie for calorie, they're all the same. It doesn't matter if you're eating a

00:42:33.240 calorie of glucose, a calorie of fructose, a calorie of fatty acid. If you can regulate the intake,

00:42:41.400 it's all the same. So when you look at what you just said, which is fructose ingestion can lead to

00:42:49.400 weight gain through two mechanisms. One, it can drive you to eat more. So on the intake side of

00:42:55.480 the ledger, it's causing you to eat more, but it can also lower your energy expenditure. And I assume

00:43:02.200 that could be both deliberate and non deliberate. It could reduce, if that's true, resting energy

00:43:08.280 expenditure. And it could presumably even reduce drive, energetic drive, which would be spontaneous

00:43:15.480 energy expenditure. What's the contribution of these? No. So actually that is still the first

00:43:21.400 mechanism. The first mechanism is it makes you gain weight by increasing energy intake and dropping

00:43:29.400 energy metabolism. What happens is a lot of weight gain from sugar is because you are eating more and

00:43:39.720 exercising less. Moving less. Yeah. Moving less, less resting energy metabolism. Can you quantify those

00:43:46.360 two? How much is the increase in intake? The way you would do this, I think in animals would be

00:43:51.240 because you're letting them eat ad libitum. In this case, you'd have to let them eat ad lib.

00:43:54.840 You could quantify the difference in energy intake and you could say, does that difference explain the

00:44:01.480 weight gain fully? If it does, then none of it has to do with the decline of energy expenditure.

00:44:06.520 If it doesn't, you would see what the gap is. Right. Let me explain that. Most weight gain from sugar

00:44:13.880 is due to eating more. Some weight gain is due to a decrease in energy metabolism. And if you do

00:44:22.440 isocaloric diet, so all the animals, the controls and the sugar fed animals are eating the exact same

00:44:30.440 amount. Weight gain, there's basically minimal difference in weight gain in the short term.

00:44:36.920 If you go for two months, if you give sugar versus starch after two months in animals, there's very little

00:44:45.720 difference in weight gain. There's a little bit of weight gain because of the decreased energy metabolism

00:44:50.600 in the fructose group, but it can be hard to show. And the high fructose corn syrup industry loves this.

00:44:57.960 So they say, hey, the problem is people are eating too much, but if you control for how much sugar

00:45:04.600 you're eating and we do isochloric studies and we look at short term studies, there's no difference in

00:45:10.600 weight gain. And they publish this like in the Annals of Internal Medicine and they say sugar's safe,

00:45:15.320 but they miss the point that the sugar is actually causing hunger. And by forcing an isochloric diet,

00:45:23.800 the people are hungry, but they're not able to eat because they're not allowed to eat. And so if you

00:45:30.680 do a short term study like several weeks to months, you can't show a difference in weight gain. If you

00:45:37.000 went longer, like a year, you probably would show a difference in weight gain because of the difference in

00:45:42.280 energy metabolism. Yeah. Just to put some numbers to that, if feeding somebody a high fructose isocaloric

00:45:49.080 diet compared to a high glucose diet, if the high fructose group was driven to eat an extra 300

00:45:56.120 calories per day while simultaneously experiencing a reduction of energy expenditure of 25 calories per day,

00:46:03.720 the increase in the drive to eat 300 calories a day would be readily apparent. Again, this is very back of

00:46:11.720 the envelope math. No, no, you're totally right. And this is overly simplifying things because it

00:46:16.760 doesn't work out to be quite this straightforward a math, but by the numbers I gave every 12 days,

00:46:23.960 you could gain a pound on the intake side, but it would take months to show a gain of a pound on the

00:46:33.720 energy expenditure side. You're absolutely right. And the other problem is like in the

00:46:38.280 industry, they'll compare fructose to glucose, but we know that

00:46:41.720 some of the glucose is being converted to fructose. So it's really not a fair comparison,

00:46:46.760 but there's another major mechanism. And the other major mechanism is that even if you pair feed animals

00:46:56.360 so that they're eating the exact same amount, yes, there may not be a difference in weight gain

00:47:02.760 because they're all eating the exact same number of calories. And even though these guys are

00:47:07.560 left in resistant, they can't eat what they want to eat. So presumably they're less happy.

00:47:13.640 Yes, they're less happy. They're hungry. They're like feeling they're on a diet. But even when you

00:47:20.040 control the exact same diet, all the other metabolic effects of fructose are still going on.

00:47:26.600 They're still becoming insulin resistant. They're still getting fatty liver. They're still getting

00:47:31.640 hypertension. And you can see this beautifully in animals. It's very easy. I've seen clinical evidence

00:47:39.240 of this in people too. A great example, and I may have told this story last time when we were on,

00:47:45.640 but we were doing a pair feeding study of 40% sugar versus starch. And so the animals were

00:47:52.920 getting the exact same amount of food. And pair feeding means you take a group of animals,

00:47:58.200 let's say you have 10 animals in this group and 10 animals in this group, they have to eat the same

00:48:02.680 amount of food each day. And what that means is that the animal that eats the least amount of food,

00:48:08.600 all the other animals have to eat that least amount of food. So if you have one guy who's got a

00:48:14.360 problem and isn't eating a lot, all the animals are forced to do that. So we were doing this study,

00:48:19.800 Carlos Roncalo and our group was doing the study just to look at pair feeding. And he did not know

00:48:26.360 that one of the animals had cancer and that animal was eating hardly anything.

00:48:31.560 So we had an experiment that went for four months in which all the animals are eating like hardly

00:48:37.560 anything. They're all eating the exact same food. They are on a severe diet, but one group was on a 40%

00:48:43.880 sugar diet and the other was on a starch diet. Everything was equal. They're eating the exact

00:48:49.640 same amount. At the end of the four months, the sugar fed animals tended to be higher weight,

00:48:56.360 but it wasn't significant, but it was from that resting metabolism from the fact that they had a

00:49:02.040 lower energy metabolism. And it looked like it would have been significant if we'd gone a little bit

00:49:05.880 longer. How long did you go?

00:49:07.480 Four months, I believe.

00:49:09.080 Just to put that in perspective and give a sense of magnitude, four months in mice is about 10% of

00:49:17.720 their life. It's about 15% of their life. They lived two and a half years.

00:49:23.080 Okay. Yeah, yeah, yeah. So that's like 15 years in a human. That would suggest, by the way,

00:49:28.040 that at least in a calorie controlled state, excess fructose does not alter energy expenditure in any

00:49:35.640 clinically relevant manner. If after 15 years, which is effectively what that was in humans,

00:49:40.760 if after 15 years there was no difference in weight between the groups despite one mainlining

00:49:46.200 fructose and one not, you would say, at least in the context of low calorie intake, which is what

00:49:52.040 they were, energy expenditure is not a driver of adiposity. I think over decades it is.

00:49:59.160 That's one and a half decades. That's a long time.

00:50:02.200 Maybe as much as a half a pound a year, I would say, could be from this, half a pound to a pound,

00:50:07.720 perhaps. Just depends on the individual. But you're right. Probably by its, you know,

00:50:13.800 we can't completely separate it from the increased food intake that accompanies this in people,

00:50:19.560 because we're not pair feeding. But you might be right. But the other thing that happened is these

00:50:24.920 animals that got sugar, every one of them became diabetic. Every one of them had severe fatty liver.

00:50:32.280 I mean, it was a very dramatic difference from the starch fed animals. The islets of the pancreas

00:50:37.880 were showing changes of type two diabetes as well. And so I think what we've shown and we've shown it

00:50:44.200 multiple times is that there are many, many effects that are independent of calories from fructose. And

00:50:50.520 it's due to this energy depletion pathway. One of the consequences of this energy depletion

00:50:56.760 is that it stimulates food intake. And so part of obesity really is eating more and exercising or

00:51:04.680 moving less. I mean, that really is true. It's just that it's not so much behavioral driven. It's not

00:51:11.080 your fault. You are activating biologic pathways in your body. It's a biology. Certainly, advertisement

00:51:20.840 encourages you to go to movies and be more sedentary. There's lots of things that are pushing

00:51:27.320 that and people are serving bigger plates of food, but maybe they're serving bigger plates of food because

00:51:32.520 they know that you're going to leave hungry if you don't have that extra food because you are

00:51:38.120 becoming leptin resistant and you're eating more as part of this problem.

00:51:43.880 So is it safe to say that neither of these animals were overweight at the end of this study,

00:51:48.760 but one of them became very skinny fat, you know, to use the term that we now describe for the lean,

00:51:55.640 metabolically unhealthy phenotype?

00:51:57.960 Yes, you're right. These people exist out there, calorically restrict themselves,

00:52:03.480 but are still eating the wrong foods.

00:52:05.720 So if you had done that study long enough, Rick, which by the way, it's an elegant study that you sort

00:52:11.400 of did accidentally, it would be interesting to see if there was a survival difference.

00:52:15.960 I think that this whole pathway is very important in aging.

00:52:20.200 Well, it's hard to imagine it's not. It's one of those studies where I feel like if you can devote

00:52:24.760 the resources to do the experiment for two and a half years and say, look, we're going to go after

00:52:30.200 the Holy Grail outcome, which is all cause mortality. And again, I'd like the way that

00:52:35.160 these animals were calorically restricted because it gets you away from obesity is the problem.

00:52:43.080 I've always felt that obesity is a passenger that comes along for the ride, but it's the metabolic

00:52:48.200 derangement that lies under obesity. That's highly correlated with obesity, but is quite separate

00:52:54.760 from obesity. That's the root cause of our mortality. And this would be an experimental

00:53:00.040 way to demonstrate that, that I think would be, again, not beyond the realm of doing.

00:53:05.880 I've actually proposed to do that study. I'll tell you some things that really

00:53:10.200 suggest that this is important in aging. The first thing to talk about is that there have been studies

00:53:17.800 done in fruit flies, looking at the effects of sugar on aging. Sort of interesting, the fruit fly

00:53:25.720 actually is eating fruit. I mean, that's what they like. They are always on some fructose,

00:53:33.800 but they're not getting highly concentrated fructose because the fruit also has lots of other things

00:53:39.800 in it, fiber and other things that they're probably getting, the flavanols and everything in there that

00:53:45.960 some of them neutralize some of the effects of sugar. But if you give a fruit fly sucrose or table

00:53:53.720 sugar, which is really fructose and glucose together, a liquid sucrose, they'll love it.

00:54:00.360 And there are studies showing that they will develop obesity, believe it or not. So you'll have obese

00:54:06.200 insulin resistant flies and they die early. And also when they die, they die from complications related to

00:54:14.200 uric acid production, which is really interesting. They develop equivalently kidney failure for their

00:54:20.520 equivalent of their kidney. I'm going to wait and see the mice data on that.

00:54:24.360 Yeah, yeah. Now I'm going to move to the mice. We were interested in whether or not

00:54:29.480 mice that lacked fructose metabolism might live longer than normal mice. And we happened to have

00:54:37.640 some that we were keeping around and they were on a normal mouse chow diet that is very low

00:54:44.120 in fructose. So these animals are eating almost no fructose. It's like less than three percent of

00:54:49.880 their chow. How much glucose on their chow? They get a fair amount of starch and protein

00:54:56.440 in the chow. They are getting a fair amount of carbohydrate. What are the approximate macros of the

00:55:02.920 three? I would have to look it up. I can't tell you at the moment, but standard chow, which is

00:55:08.600 basically... But it's a very low sugar chow. It's a low sugar chow. We took them out to like

00:55:15.000 a little bit over two years and we found that they had stayed lean compared to the control mice. They

00:55:22.680 were more lean. And when an animal age develops kidney disease... Sorry, was that statistically

00:55:28.680 significantly lean? Yes. Tended to have normal blood pressure or lower blood pressure than the

00:55:35.800 control animals. How do you measure blood pressure in the mice? You put a cuff on their tail. It's

00:55:42.520 called a tail cuff and you can measure the systolic pressure. What's a typical mouse blood pressure?

00:55:48.920 It's very similar to ours. It's like 100 to 120. Yeah. And so if they were statistically significantly

00:55:57.160 leaner than the non-fructokinase wild types, could you document how much less they were eating?

00:56:03.960 We did not actually measure that. Oh my God. That's like the single most important piece of

00:56:09.560 information you'd want. Yeah, exactly. In retrospect, it is very important to know. It's hard to do that

00:56:15.320 over a two-year period. It's a lot of laboratory time. But anyway, what was striking, and I just bring

00:56:22.200 this up, is that normal mouse showed aging changes in the kidney. And all mice and rats and humans,

00:56:28.520 we all get aging changes in our kidney. But the fructokinase knockout had no aging changes in their

00:56:35.400 kidney. It was very exciting. And how much of that do you think was due to blood pressure differences?

00:56:42.280 Was the blood pressure basically the same in these animals? They were pretty normal. It tended to be a

00:56:46.760 little bit lower in the fructokinase knockout. But we did do a study and showed that if you give them

00:56:53.080 salt, normal animals would show a much more rise in blood pressure than these animals,

00:56:58.520 than the fructokinase knockout. So there is a difference in response to salt,

00:57:03.240 which has also been reported with aging. People become more sensitive to the effects of salt with

00:57:08.360 aging. But baseline blood pressure was not really different. So what do you hypothesize was the

00:57:14.200 difference between the kidney function in these two animals? The dramatic thing is that the

00:57:19.880 fructokinase knockout were protected from aging associated changes to the kidney. And so it suggests

00:57:26.520 that endogenous fructose production is maybe more important than we think, and that it could have a

00:57:34.440 role in the aging process. How can we quantify endogenous fructose production? Well, there is a

00:57:40.600 way it can be done. There was recently a study that looked at labeling fructose and giving it to

00:57:48.840 people and they were able to, maybe it was giving a label glucose and measuring the label on the

00:57:54.200 fructose. But there is a study that shows that when you give a soft drink, you increase the production

00:58:00.120 of fructose by threefold, three to fourfold. Over the amount of fructose that's in the soft drink?

00:58:06.920 No, compared to what a person normally makes. So we're always making some fructose in our body.

00:58:13.560 I'm trying to figure out like a quantifier. So I'll give you an example, right? If I have a patient with

00:58:17.580 fatty liver disease, the first thing I do is restrict fructose and alcohol. We stop all alcohol

00:58:24.340 and we drop fructose dramatically to typically five to 10 grams per day, which basically means

00:58:32.540 vegetables and a handful of berries if they must have some fruit. But it's basically a minimal fruit

00:58:39.980 diet and no alcohol. And that's step one. We don't start with caloric restriction. We don't start

00:58:46.460 manipulating other macros, carbohydrate restricting or anything like that. We just take alcohol out of

00:58:51.420 the picture and basically get fructose out of the diet. That usually improves NAFLD in most people.

00:58:59.500 And by the way, that may or may not accompany weight loss. So that's the interesting thing

00:59:04.300 there is you don't have to lose a staggering amount of weight to reverse NAFLD under the

00:59:10.140 conditions I just described. It's so true. You often do lose weight with that intervention

00:59:16.380 because generally the people who have acquired NAFLD are also in a state of positive energy balance.

00:59:23.340 So it is a little bit difficult to disentangle that. And as I'm sure you're aware, a number of

00:59:27.820 studies, David Ludwig's group, Rob Lustig, Miriam Voss, a number of people have looked at this.

00:59:34.620 And one of the challenges that all of these investigators have had is maintaining the weight

00:59:39.500 of the fructose restricted group. In other words, you almost have to force feed them extra glucose

00:59:45.100 to try to keep their weight on par with the control group to disentangle this. Now, I haven't

00:59:49.500 looked at this literature in a year. So it might be that there's a new study out there that has

00:59:54.140 managed to overcome that obstacle, which is to say they've managed to pair feed the humans such that

01:00:00.620 you can maintain weight while reversing NAFLD. Are you aware of such studies in humans?

01:00:06.780 I think Rob Lustig did an isochloric fructose restriction and did see an improvement in fatty liver.

01:00:13.340 Did the weight stay the same? I think that there was still some weight loss, but I'm not sure.

01:00:18.860 The observation that fructose could be a cause of fatty liver was actually first reported by our

01:00:24.460 group way back when. Non-alcoholic fatty liver disease was first being recognized as an epidemic.

01:00:30.700 We became interested in the possibility that fructose could be playing a role. And with Manal Abdul-Malik

01:00:37.260 at the University of Florida, we did a study on patients and found that they were drinking large

01:00:42.300 amounts of soft drinks, that they had high uric acid levels. And we even looked at liver biopsies and

01:00:48.540 found an increased expression of fructokinase. By what amount? Oh, it was like three to four fold

01:00:55.260 increase and ended up publishing that. And then I started putting people on low fructose diets for

01:01:01.660 fatty liver in addition to alcohol. It really does work. In fact, one of the people in my lab

01:01:07.580 had a son who had developed fatty liver, was skinny, but had fatty liver, but it turned out he was

01:01:12.220 drinking soft drinks almost every day. Just cutting that out was enough. That was one of the

01:01:17.900 precipitants for me to write that first book. The dramatic effects we could see in some people

01:01:23.500 with fructose restriction. But now we know that it isn't just the fructose you drink,

01:01:29.180 it's the fructose you make. I kind of got off track there and I apologize. That's really where

01:01:33.420 I wanted to go with that observation, which was, do we know what the average American consumes in terms

01:01:38.460 of fructose per day? First, about 15 to 20% of the diet is from sugar and sugar is half fructose and

01:01:45.900 half glucose. So 10% of the diet is for 10 to 15% because we also are getting fructose from fruits

01:01:51.980 and other foods besides added sugars. Sugar in the diet can vary. Some people are eating as much as 25%

01:01:59.500 of their diet is sugar. So people can be eating as much as 15, even 20% of their diet is fructose.

01:02:05.820 Let's just do the math and say conservatively, it's not hard to eat 100 grams of fructose a day.

01:02:13.820 400 calories of fructose could represent 15% of your caloric intake.

01:02:20.460 Absolutely correct.

01:02:21.740 Okay. So if you take the average American walking around eating, let's just give a range,

01:02:27.660 75 to 100 grams of fructose, that's their exogenous consumption of fructose. And that individual

01:02:34.620 who we assume is a little bit insulin resistant, maybe a little bit leptin resistant, but not off

01:02:40.860 the charts, what would you expect their endogenous production to be? How much are they adding to that

01:02:47.820 till? I would suspect a fair amount. I know you want a quantitative amount.

01:02:54.620 Directionally, are we talking 10% of that amount, 50% of that amount, 100% of that amount? What zip code?

01:03:00.220 It would be a guess, but I would say 25 to 50% of more from endogenous production.

01:03:07.820 And that's based on animal data?

01:03:10.060 Based on our animal data. Now there's three major sources of fructose that we can make.

01:03:16.540 And we've only talked about one of them. The first one is high glycemic carbs, rice, potatoes, bread,

01:03:24.460 chips. We think maybe a quarter of that can be turned into fructose. And I think that that's

01:03:31.100 playing a major role in metabolic syndrome. So what happens is when you're young and you don't have this

01:03:38.700 polyol enzyme pathway activated, eating things like potatoes and french fries may not cause

01:03:45.260 so much weight gain. You may feel you're invincible, but as this pathway gets activated and

01:03:51.820 aldose reductase starts being highly expressed in the liver, then potatoes and bread may cause much

01:03:58.380 more weight gain. And we think it's because of this fructose conversion because we actually did another

01:04:05.020 study, Peter, where we gave soft drinks, a high fructose corn syrup to animals, and they got really fat

01:04:12.620 and insulin resistant. But if we blocked fructokinase, we completely blocked development of metabolic

01:04:19.740 syndrome. So with soft drinks really was all fructose, even though there's a lot of glucose in there.

01:04:26.540 We saw a little bit of weight gain with glucose alone, but when we give high fructose corn syrup,

01:04:32.140 it was pretty much all from the fructose that was causing them to gain weight and to get metabolic

01:04:37.180 syndrome. Rick, before we go to the other two sources of substrate for making fructose,

01:04:44.780 you mentioned almost in passing that when you're young, you can tolerate lots of high glycemic foods.

01:04:50.380 I think anyone listening to this can relate to that or probably 90% of people can relate to that. I know

01:04:54.620 I certainly can. What is it about just aging that alters our sensitivity or vulnerability,

01:05:03.740 maybe as a more accurate word, to glucose? Throw another wrinkle at you because we've had a lot

01:05:09.180 of questions about this from women. What is it about menopause that for many women also seems to,

01:05:15.740 almost overnight or certainly within the span of about a year, also alter the sensitivity or

01:05:22.220 vulnerability that one has to glucose and by extension fructose? There's three or four different

01:05:29.820 reasons. And so let me just go through the list real quick. The very first one is that when we're

01:05:35.820 young, we tend to have very healthy mitochondria where a lot of kids are active and we keep the

01:05:42.380 mitochondria healthy. And the way that this fructose works is it has to cause oxidative stress

01:05:50.140 to the mitochondria to activate these pathways. But if you have really, really powerful mitochondria,

01:05:56.060 you won't show these metabolic effects as easily because they're more resistant

01:06:00.620 to the effects of fructose. And you can still see this in super athletes. They have fantastic

01:06:05.500 mitochondria. They, many of them feel like they can drink a lot of sugar and that they are immune.

01:06:11.260 And it's because they have really, really healthy mitochondria.

01:06:15.420 Tell me more about what that means. What does healthy mitochondria mean? We talk about this,

01:06:19.420 but give people a sense of what a healthy mitochondria does that an unhealthy one does not do.

01:06:24.380 And why is mitochondrial dysfunction viewed as one of the hallmarks of aging?

01:06:29.740 So your mitochondria are one of your major places where you make energy. And in fact, it's the

01:06:35.660 high output energy producer. So it's producing the ATP that we need to drive everything we do.

01:06:44.540 Over many years, the mitochondria get less good at making the energy because of damage,

01:06:50.380 recurrent damage. And it's thought that oxidative stress to the mitochondria can cause this damage.

01:07:00.460 And so when you want to try to store fat, mitochondrial oxidative stress is part of the

01:07:07.020 requirement to store fat. And fructose works to store fat by stimulating mitochondrial

01:07:14.380 oxidative stress. And initially that is a reversible, very easily reversible mechanism.

01:07:20.220 The oxidative stress goes on, inhibits these enzymes, and it leads to fat production and so

01:07:26.700 forth. So it's a survival pathway. But what happens is if you keep stimulating mitochondrial

01:07:32.860 oxidative stress, and it's been shown with fructose, for example, the mitochondria start to decrease

01:07:39.820 and the mitochondrial change, they become smaller and less efficient. And what happens is the mitochondrial

01:07:47.340 function starts to reduce the number. And so you have less mitochondria. And when that happens,

01:07:53.660 you make less ATP. It's associated with feeling more fatigued, more tired. If you have lower ATP levels in

01:08:00.460 your muscle, it's associated with muscle fatigue. Your natural gait will slow down as your mitochondrial

01:08:07.100 function decreases. And it's all associated with aging.

01:08:11.020 How do you quantify this in animals? So if you were to take a four-month-old mouse versus a two-and-a-half-year-old

01:08:16.860 mouse and you did muscle biopsies, obviously there's a quantitative assessment that you would do. You would

01:08:22.620 say per gram of muscle, there's this many mitochondria versus this. They're this big versus that big. How are you

01:08:29.820 assessing ATP output? And how are you quantifying the functionality on a per unit of mitochondria basis?

01:08:36.780 Well, first off, you can measure the mitochondria themselves by looking at electron microscopy. You

01:08:43.180 can measure it indirectly with a PCR technique, looking at mitochondrial DNA divided by nuclear

01:08:49.820 DNA. You can measure ATP levels in the tissues. There's all kinds of ways to do it. What we do know

01:08:57.500 is that mitochondrial function tends to decrease as we get older. There's a very good evidence that

01:09:03.820 recurrent chronic oxidative stress to the mitochondria is involved in this. We think that

01:09:10.220 fat storage is associated with mitochondrial oxidative stress. So if you're continually

01:09:14.700 stimulating these pathways with fructose, that may actually wear down the mitochondria. We did do a study

01:09:21.580 in Newman's where we put people on a low fructose diet and showed that we could increase mitochondrial

01:09:27.420 biogenesis in people within 30 days. And we had a very dramatic increase in mitochondrial production.

01:09:35.420 Fasting is thought to increase mitochondria probably the same way. And actually, even caloric restriction,

01:09:42.300 the concept that caloric restriction can promote aging is probably through this pathway. Reduce aging

01:09:49.180 by reducing mitochondrial oxidative stress. Think about this. When you're eating, whenever you're storing fat,

01:09:55.580 it seems to involve some mitochondrial oxidative stress. And so if you eat less food, you're going

01:10:01.420 to have less oxidative stress of the mitochondria and you'll have less fat stores. But what will happen

01:10:07.420 is you will live longer. So in an animal, they always want to have some extra fat on board because they're

01:10:13.420 living in the wild. They don't know if there's going to be a food shortage suddenly or not. So they want to

01:10:18.300 try to maintain a little bit extra fat. So if you take animals and you put them on 70% of their normal

01:10:25.580 caloric intake, their fat stores are very minimal. They have less oxidative stress to their mitochondria

01:10:31.340 and they're going to live longer. The mitochondria are going to stay healthier. But if you take those

01:10:36.220 animals and you put them in the wild, and remember when they're in a lab, they're being fed a certain

01:10:42.460 amount of food every day. So they're safe. You put them out in the wild, now they have no fat stores.

01:10:47.580 And the first big crisis suddenly kills half of them because they can't survive because they don't

01:10:53.500 have enough energy stores. So animals in the wild want to have a little bit of extra fat.

01:10:58.780 It seems that we do too. I mean, the obesity paradox is hard to ignore

01:11:03.500 that low levels of obesity actually seem protective.

01:11:07.340 Absolutely. So if you have cancer or heart failure or any kind of chronic disease,

01:11:12.460 you'll actually live longer if your fat stores, if you have a BMI of like 27,

01:11:18.380 that's going to do better than a BMI of 20 when you have a chronic illness.

01:11:22.460 Dr. Even 28 is going to do better than 24 as you age based on the overall data, which is,

01:11:29.020 again, quite a paradox. Dr. Yes. It's because of that need to

01:11:32.300 have a little bit of fat stores. If we get back to the original question, which is, you know,

01:11:37.900 why is it that when I'm young, I can eat bread and there's no problem? One is that our mitochondria

01:11:43.900 are healthier at that point. And we have what we call metabolic flexibility. We can metabolize things

01:11:50.300 very easily. Everything's kind of young, but over time, the more sugar we eat, the more we get better

01:11:58.060 at metabolizing it. So normally in the beginning, when we eat sugar, the transporter for fructose in our

01:12:04.940 gut is expressed at low levels and animals that get fructose when they're young tend not to absorb

01:12:11.020 it as well. But the more we get exposed to sugar, the better we get at absorbing it. We turn on the

01:12:17.500 enzymes and the transporters that allow us to absorb fructose more readily. So if you give an animal

01:12:23.900 sugar for a month, for example, you'll upregulate all these pathways and maybe you can stop the sugar

01:12:30.540 for one day. And then if you give them a bolus of sugar, they get a very dramatic activation of

01:12:36.780 this switch. And, you know, the fall in energy is very dramatic compared to a normal animal that's

01:12:42.540 not been exposed to sugar that gets a single dose. And that's because we turn on these pathways. So we

01:12:49.500 turn on the ability to metabolize sugar. So we did a study in children where we gave them a dose of

01:12:56.060 fructose and we had lean children. We had children that were obese and we had children that were obese

01:13:02.460 that had biopsy proven fatty liver. When we gave them a dose of fructose, the lean people only absorbed

01:13:10.620 about 70% of the fructose and they metabolized it slowly. And this was a liquid bolus?

01:13:15.900 Yes. How much?

01:13:17.420 It's like one gram per kilogram body weight, as I recall. I would have to go back to the paper.

01:13:22.940 A pretty good dose.

01:13:24.700 Yeah, they got a good dose of fructose and they absorbed it only partially. Then we looked at the

01:13:30.620 kids that were obese and they absorbed much more fructose and they metabolized it a little bit

01:13:36.380 faster, but they still didn't absorb it all. And then we gave the fructose to the kids that had fatty

01:13:42.140 liver and obesity and they absorbed 100% of it and they metabolized it faster. We think it's because of

01:13:49.260 prior exposure to sugar and so forth. It's possible there could be genetic differences,

01:13:55.180 but the bottom line is in animals, the more sugar you give them, the more they'll absorb it. And we

01:13:59.980 think that this carries over to people as well. Likewise, and actually there's other data in humans

01:14:05.500 to support this. So that's a second mechanism. And then the third mechanism is this polyol pathway

01:14:11.420 also gets turned on over time. By the time you have metabolic syndrome, you probably have this enzyme

01:14:18.300 turned on because you're have a high uric acid. And as I mentioned that that can activate this pathway

01:14:24.380 too. So now you're able to convert glucose to fructose. So let's say you're overweight. You say,

01:14:30.700 okay, I know it's sugar. I'm going to cut out sugar. I'm going to cut out the fructose. And then you go,

01:14:35.660 hey, I'm still gaining weight. And it's probably because your body's now making a lot of fructose.

01:14:41.500 And it's from those high glycemic carbs. And that's like your number one

01:14:45.500 food that converts, that is used to generate fructose. And so those are your main mechanisms

01:14:52.940 that make you more resistant or more sensitive to fructose over time. And what about menopause?

01:14:59.420 What effect do you think that has? Estrogen increases uric acid excretion. So young women

01:15:05.820 tend to have lower uric. A very low uric acid. Lower uric acid compared to men. But when you go

01:15:12.300 through menopause and estrogen levels fall, uric acids increase and suddenly post-menopausally,

01:15:19.100 women have the same, suddenly develop obesity, diabetes, heart disease, more like males. Pre-menopausal

01:15:28.140 estrogen is providing some protection. You can certainly overwhelm it by eating a lot of sugar,

01:15:34.220 of course, and so forth. But menopause, I believe it's related to this change in uric acid.

01:15:40.780 And not anything to do with fructokinase or insulin or other hormones?

01:15:47.740 Fructose metabolism will be upregulated by uric acid. So when uric acid goes up,

01:15:54.620 not only does it turn on the polyol pathway, but it actually upregulates fructokinase as well. So

01:16:01.660 we've shown in animals that when you raise uric acid, you raise fructokinase. And you also amplify

01:16:08.380 the effects of sugar. And how direct is the relationship between uric acid and aldose reductase?

01:16:13.980 It's pretty direct. Meaning if you give a person allopurinol and you knock their uric acid from

01:16:23.100 seven to four and make no other change, do you reduce the conversion of glucose to sorbitol?

01:16:31.180 We have not actually done that experiment. It's a great experiment, Peter.

01:16:34.620 Let's get on it. Let's get on it.

01:16:38.700 It's a good study. Before we leave this subject and go on to the next thing I want to talk about,

01:16:44.700 which is blood pressure, kidney function, I want to go back to something to make this more practical

01:16:52.060 for people, which is what do people need to be wary of? I mean, I think the other question that

01:16:57.980 emerges from a discussion like this for many people is, oh my God, do I need to not eat any fructose?

01:17:04.620 This means I can't have any fruit. Tomatoes have fructose in them. By God,

01:17:08.700 I can't have tomatoes. So how do we provide some insight to people so that they can figure out

01:17:16.500 how to adjust the dose of something that, something that, by the way, is ubiquitous,

01:17:23.820 completely ubiquitous. So if you want to go on a zero fructose diet, boy, you're going to have a

01:17:28.680 hard time. Yeah, no, it's not going to work. How do people get a sense if they're consuming too

01:17:33.060 much fructose? Okay. So the very first thing I would recommend, Peter, would be to really try

01:17:38.920 not to drink liquids that have a lot of sugar in it. So immediately get rid of soft drinks

01:17:44.360 and fruit juices. I would drink minimal because there's a fair amount of fructose in that and it

01:17:50.240 can kind of overwhelm the system. Sports drinks are sort of interesting. Some sports drinks are

01:17:56.240 relatively low in fructose. So maybe they're two to four percent fructose with four percent glucose

01:18:02.520 or six percent glucose. Let's explain to people what that means, right? So a six percent glucose

01:18:07.720 drink means there is 60 grams of glucose per liter. Yeah. So soft drinks are like 11 percent.

01:18:14.220 They have like six percent fructose and five percent glucose. And that really is bad stuff. Soft drinks

01:18:21.180 should, I think they should be banned. Right. So that's like 110 grams of total sugar per liter.

01:18:28.820 Huge amount. Teaspoons and teaspoons. Teaspoons. So soft drinks are really bad. Sports drinks were

01:18:36.200 developed originally by Bob Cade and the invention of Gatorade. People who are exercising a lot are losing

01:18:43.880 salt, lots of salt in their sweat. They're burning up glucose and some of them were getting hypoglycemic.

01:18:50.680 on the fields. And sports drinks were really meant to help replenish the electrolytes and to fix the

01:18:59.300 glucose problem and to provide glucose as fuel for the muscle during these heavy exercise bouts. We

01:19:06.420 often use a lot of glucose during exercise. The original sports drinks were glucose rich and had a lot of

01:19:14.100 salt and water, of course. And then there were some studies that showed that oxidation of glucose could

01:19:20.620 be facilitated by having a little bit of fructose in the drink. Having a small amount of fructose

01:19:25.960 actually accelerated glucose uptake. It's working in the gut primarily. And actually your performance

01:19:32.540 was increased by having small amounts of fructose, like one to two percent, maybe three percent fructose.

01:19:38.380 And the optimal glucose in sports drinks was found to be around five or six percent.

01:19:42.800 Now, some sports drinks actually have more fructose in it because it tastes better.

01:19:48.140 And so that's a problem, a little bit of a problem. If you're out there exercising, if you're using it

01:19:53.860 for what it's meant for, which is a sport, I think sports drinks for the most part are fine. But if you're

01:20:00.240 drinking sports drinks in front of a TV watching a movie and you're drinking a lot of this stuff,

01:20:06.580 it probably is not good. I want to go back to the juices. If I take oranges and I squeeze them into

01:20:16.100 my little juice squeezer and I ratchet it down and I just make concentrated orange juice, what is the

01:20:21.620 concentration of glucose and fructose in freshly squeezed orange juice? Pretty significant. It's

01:20:26.720 probably about two-thirds of a soft drink. If you made it with apple juice, apple juice is so sweet,

01:20:32.940 it's equivalent to a soft drink. And so you can get a lot of sugar from juice, unfortunately. So

01:20:39.920 the Pediatric Society a long time ago realized that juice has so much fructose that it was being

01:20:46.000 associated with obesity in children. So they made recommendations to limit fruit juice to like

01:20:52.380 six ounces or less for older children and like four ounces or so for really small children. And I think

01:20:59.460 that we should even limit it more. And fruit juice is, I think, a real problem in children because of

01:21:06.860 all the sweetness of sugar that's in it. Natural fruits are different. So natural fruits have like

01:21:13.340 much less fructose in an individual fruit. When you make fruit juice, it's multiple fruits that are put

01:21:18.760 in there. Eat like an orange and it has like six grams of fructose. That's news to me. I didn't realize

01:21:24.960 an orange would only have six grams of fructose. That's surprisingly low. I mean, we're talking

01:21:29.560 about a real orange here, not like a little Christmas orange, right? Like a real orange

01:21:32.940 would only have six grams of fructose? I believe it's like six to eight grams. I don't think it's

01:21:37.920 over eight grams. It's closer to six grams, I believe. And equal amount of glucose? Yeah,

01:21:43.100 it has some glucose in it too, for sure. But I think there's about six grams of fructose in an orange.

01:21:48.420 So if that's the case, outside of someone maybe with NAFLD, you'd have a hard time making the case

01:21:54.960 to not eat an orange. Yeah, I think that natural fruits are fine.

01:21:59.420 Including like fake fruits, like grapes? I call grapes fake fruits.

01:22:03.840 There are certain fruits that are high in sugar. Mangoes, figs, oh my God, they're very,

01:22:09.960 very enriched in fructose. Figs are probably something that we should avoid.

01:22:13.980 Right. Figs, dates. Oh, dates, yes. Mangoes are high. Apples and pears,

01:22:21.520 plums, they tend to be fairly high, like around nine, 10 grams. I think oranges are around six

01:22:27.380 grams. Bananas are fairly high glycemic. They have a fair amount of fructose, but

01:22:32.160 it's probably in the range of six to eight grams. I think what we'll do in the show notes is we'll

01:22:37.660 have our team pull together a table of- Yeah, I have a great table.

01:22:42.200 Typical sizes. This is actually news to me. I would have guessed fruits would have a little

01:22:46.860 bit more, but it'll be good to know that. Most fruits are between three grams and nine

01:22:52.380 to 10 grams max. And most fruits are around four to six grams. Some fruits have much less sugar,

01:22:59.140 like kiwi, like berries, strawberries, blueberries. They're very healthy. People should be encouraged

01:23:05.280 to eat those. And we actually did a study. We gave people a low sugar diet where it was low in refined

01:23:13.340 sugar, low in high fructose corn syrup. One group got natural fruit and the other group,

01:23:20.740 we restricted that too. So it was either a low fructose diet that was low fructose in all aspects.

01:23:26.120 The other was low sugar, low fructose, but you're allowed natural fruits. So that actually was sort of

01:23:31.720 a modest total fructose intake. And when we did that, we found equivalent improvement in metabolic

01:23:38.260 syndrome. The presence of natural fruit did not block the ability of the low sugar diet to improve

01:23:46.320 metabolic syndrome. So the takeaway here is don't drink it and don't consume added sugar. And I think

01:23:53.260 this is a difficult thing for people to differentiate. So added sugar is when a food has sucrose or high

01:24:01.840 fructose corn syrup are typically the most common agents that are added. It's literally added to the

01:24:07.140 food. So if you go out and get a jar of pasta sauce, they added sugar to it. Yes, absolutely.

01:24:13.440 That's not the sugar that you're seeing from the tomatoes that go into making that. It's the

01:24:18.300 deliberate addition of sucrose or high fructose corn syrup to make it taste sweeter.

01:24:22.420 And remember that the intestine does act as a shield for up to like five or four to six grams

01:24:28.620 of fructose. So if you eat four or five grams of fructose in a fruit, the intestine is going to

01:24:33.820 protect you. In addition, you have fiber in a natural fruit and that slows the absorption.

01:24:39.960 So the concentration of fructose that gets to the liver is lower. So there's less ATP depletion.

01:24:45.420 Now, what about dry versus not dry? So if you take the equivalent of apple chips versus

01:24:52.080 apples, but you take equal amounts of the actual calories. So it's just obviously one is a lot

01:24:58.120 bigger because it's got more water and things in it. What's the difference in how we metabolize

01:25:02.380 that? The trouble with dry fruit is that it still has all the fructose, but a lot of the good things

01:25:08.240 are removed. So that's the problem. Dry fruit is sort of like candy. So it's not just the loss of water

01:25:15.840 that's problematic there. Right. And things like vitamin C tends to be low in dry fruit and stuff.

01:25:21.600 Why is that? I guess vitamin C is water soluble. Is that why? Maybe that's it.

01:25:25.880 I always thought the issue was more that you lose the satiating benefit of the water. It's hard to eat

01:25:32.160 more than two apples in one sitting. It's not hard to eat more than 10 apples worth of apple chips in

01:25:37.980 one sitting. So I really thought it was more of just a regulation of quantity.

01:25:42.200 It's probably the amount you're eating. You know, I certainly have read that dried fruits do not

01:25:46.920 contain as much of the good nutrients, but we should probably check this before we put it on

01:25:53.360 your show. This is something we should fact check. We'll have the show notes. We'll assess that.

01:25:58.540 Yeah. I'm not a hundred percent certain about the vitamin C issue. And I would hate to actually be

01:26:04.540 quoted if I'm wrong on that. But it's been said, Peter, that dried fruits are thought to be primarily

01:26:10.860 devoid of the good components that are in fruit. And we know that there are many other good components

01:26:17.520 in fruit besides fiber. There's potassium and flavanols, and there's a substance called

01:26:24.080 epicatechin that's in a lot of fruit that actually can block some of the effects of fructose. And

01:26:29.940 other things like luteolin and mangosteen and some of these things also seem to block the effects of

01:26:36.380 fructose. Astol and different flavanols. So last question I have before we leave at least fructose

01:26:43.920 from this standpoint is we talk about fructokinase knockouts in the lab. I'm sure most people listening

01:26:50.940 to this, if they're like me, are thinking two thoughts. One, how do I knock out my fructokinase?

01:26:56.520 And maybe more interestingly, how much polymorphism exists in the fructokinase gene in humans that

01:27:07.140 might account for differences in fructose tolerance. So while I don't think there are too

01:27:12.660 many people born who have no fructokinase and therefore would seem completely immune to the

01:27:19.200 effects of fructose, I would have to believe that there's a distribution across which people exist

01:27:25.100 and where they have higher versus lower natural either quantity or activity of this enzyme. Has

01:27:31.000 that been documented? Well, first off, there is a condition called essential fructosuria. This is a

01:27:38.160 hereditary condition in which you do not have fructokinase. Right. So you pee all your fructose

01:27:43.860 out. Yeah. Well, you pee about 10% of the fructose you eat goes out through the urine and the rest is

01:27:51.420 metabolized by the glucose enzymes because some of the glucose enzymes can metabolize fructose.

01:27:57.380 And to date, no one has ever been reported with type 2 diabetes with this condition. No one has ever

01:28:04.440 been reported to have obesity. It seems that it's associated with normal lifespan or maybe even

01:28:11.080 prolonged lifespan. But certainly with normal lifespan, I'm in connection with a small kindred of a family

01:28:18.240 that has this condition. And interestingly, they can eat all the sugar they want, but they tend to

01:28:24.440 prefer other kinds of foods. They don't have a taste affinity for sugar? They tend to prefer salty foods

01:28:30.180 to sugary foods. Okay. So last question on that then is basically what is the hope for a pharmacologic

01:28:38.520 agent that could block fructokinase as a treatment for obesity, type 2 diabetes, NAFLD?

01:28:46.000 Disclosure, I have a small company. We're trying to develop fructokinase inhibitors for the treatment

01:28:52.920 of metabolic syndrome and other conditions associated with fructose. But there are also several large pharma

01:29:00.160 that are actively working on making fructokinase inhibitors. Eli Lilly, for example, is one that's

01:29:07.620 actively trying to make fructokinase inhibitors. And so I think it's a very exciting future if we

01:29:14.840 could develop these inhibitors. Look like they hold great promise. You know, in animal studies,

01:29:19.760 they can block sugar-induced obesity and diabetes and fatty liver. So there's a lot of promise with

01:29:26.320 these. These agents already exist? Because I always thought in animal studies, you were doing it

01:29:31.360 genetically. No, we have developed fructokinase inhibitors in our laboratory, but there's also

01:29:37.480 Eli Lilly and Pfizer made fructokinase inhibitors. And Pfizer actually had a success in a phase 2 trial

01:29:46.980 where it reduced fatty liver pretty significantly and improved insulin resistance.

01:29:52.620 And so where is that Pfizer drug today? Is it in phase 3?

01:29:56.080 Sadly, Pfizer recently stopped progressing with this despite a positive phase 2 result. I'm not sure

01:30:05.120 what the reason was. They have another drug they're developing for fatty liver that also had very

01:30:11.860 positive results. And it may be that they're focusing on one versus the other. But I don't know

01:30:19.460 exactly why Pfizer stopped developing their drug. Eli Lilly is, I believe, doing phase 1 trials right now

01:30:28.200 with theirs. So the Pfizer thing is kind of a mystery. And you may not want to discuss it at this point

01:30:34.900 since we don't really know. I love discussing stuff for which we don't know the answer.

01:30:38.780 I'm totally fine with that. So yeah, Pfizer just decided to not proceed.

01:30:45.000 And there was no toxicity that you were aware of in the phase 2?

01:30:47.880 No. And what was reported, it looked very promising.

01:30:50.860 Okay. So let's talk a little bit about blood pressure. It seems to play a very important role

01:30:56.080 in really all of the major chronic diseases except for cancer. And if there's a role in cancer,

01:31:02.780 I don't know what it is, but who knows? Maybe somebody knows that. But certainly when we come

01:31:06.340 to neurodegenerative disease, cardiovascular disease, cerebrovascular disease, and renal disease,

01:31:12.820 which are really the main pillars of death, hypertension seems to work against you.

01:31:18.540 So what is it about everything that we've spoken about that ties into hypertension?

01:31:25.000 Yeah. So high blood pressure, which is sometimes called primary or essential hypertension,

01:31:31.240 is extraordinarily common in our country. And throughout the world, maybe one third of adults

01:31:37.180 have high blood pressure. How is it defined today?

01:31:40.060 In most places of the world, it's defined as a blood pressure greater than 140 over 90.

01:31:45.600 140 over 90 or higher. But in this country, recently was redefined as being greater than

01:31:53.020 130 over 80. I think that for the majority of the world, the definition is 140 over 90.

01:31:59.560 And from a physiologic perspective, where do you fit on that spectrum? I mean, you're the

01:32:04.900 nephrologist. So you take care of the organ that is arguably the most sensitive to blood pressure.

01:32:11.240 You could make a case that even more than the heart and the brain, the kidney is the first place that

01:32:17.120 damage shows up. I don't know if you would agree with that. Is that a true statement?

01:32:21.040 There's actually three main sites where high blood pressure really causes problems. And the first one

01:32:26.780 is stroke. It's the major cause of stroke. It's also the major cause of heart failure. And it's one of

01:32:33.980 the two major causes of kidney disease. And so those are the three main pressure related conditions where

01:32:40.580 pressure is driving. The higher the pressure, the higher the risk for stroke, heart failure, and kidney

01:32:46.660 disease. The studies show that the greatest risk for stroke, heart failure, and kidney disease are when the blood

01:32:55.360 pressure is like 160 to 180 systolic is kind of the turning point where when it's above that level,

01:33:03.080 there's a really a dramatic increased risk for these conditions. But it's been known for a long time

01:33:09.700 that there's been tendency for a linear relationship between blood pressure and stroke and blood pressure

01:33:17.120 and heart failure going all the way down to 120 over 80. So there are a lot of people that would like to

01:33:23.200 say that 120 over 80 or 130 over 80 should be our cutoff because it's really a linear relationship.

01:33:30.640 But most studies done around 1900 showed that less than 5% of the population had blood pressures of

01:33:38.200 over 140 over 90. Based upon the normal Gaussian curve of the population back then, probably about 140 over

01:33:46.060 90 was the cutoff for what was thought to be high. I'm a believer that 140 over 90 is a good

01:33:52.180 mark for where we should be viewing hypertension as a condition that really should involve active

01:33:59.360 management. So Rick, does that imply that if somebody has a blood pressure of 135 over 85, which

01:34:06.460 would be below the cutoff that you're saying you would deem the time to act of 140 over 90, at 135 over

01:34:13.700 85, you could roll around at that blood pressure indefinitely without any damage to the kidney?

01:34:19.780 Yes, exactly. So they're relatively minimal risk with a blood pressure 135 over 85. In epidemiology

01:34:28.520 studies over many years, you can show that, you know, 120 over 80 is superior to 135 over 85.

01:34:34.860 And the reason I bring this up, Rick, is not to be a pain, but it's to talk about what our standards

01:34:40.940 are really about. I'm not a nephrologist, but boy, am I a freak when it comes to managing GFR in my

01:34:48.400 patients? Why? Because I want people to live to a hundred. That's an aspiration. Most people aren't

01:34:55.980 going to, but we make that the aspiration. If I'm talking to a 40 year old patient and their GFR

01:35:03.200 is 85. Well, most people would say that's normal, but I want that 40 year old not to live to 80.

01:35:12.280 I want her to live to a hundred, which means I can't treat her like a 40 year old. I have to treat

01:35:20.320 her like a 20 year old. I have to time shift her back to say, I need her kidneys to survive another

01:35:28.640 60 years. So based on epidemiologic data, I can't treat her as a 40 year old and her GFR of 87 is not

01:35:38.320 good enough. I want her GFR to be 107 because I need to know that at a hundred, her GFR is still

01:35:46.660 40. So that's why I push back on this idea. I really want to understand this. If we're in the

01:35:52.720 business of trying to get people's kidneys to have a GFR above 40 at the age of a hundred, do we have to

01:35:59.720 revise our standards on hypertension? It's a wonderful comment that you make there. And I think that the

01:36:07.420 answer is we would prefer blood pressure of 120 over 80, but if it's 135 over 85 to put someone on a

01:36:16.980 medication that they'll have to take for the next 60 years, I'm not sure that that's the best way to

01:36:24.220 go. I think that doing nutritional and exercise related maneuvers when you're 135 or 85 should be

01:36:31.840 the way to go. And we can fix it by diet, by reducing salt and picking healthier foods and

01:36:39.000 exercising. But the trouble with, when you get to 140 over 90, if you can't lower your blood pressure

01:36:46.400 by dietary means, you really probably should go on an anti-hypertensive because it will provide

01:36:53.920 anti-hypertension over time. But when your blood pressure is like 135 over 85, I haven't seen any

01:37:01.300 evidence that anti-hypertensives really provide long-term benefit to that group. I do think that

01:37:08.560 dietary measures, though, make sense. And I agree with your general idea, the idea that optimize health

01:37:16.220 as best as we can, and that's your best chance to maintain health for the longest you can.

01:37:22.460 So I like that idea. You're right on. But I don't know if we should be doing interventions.

01:37:28.280 The trouble with defining blood pressure hypertension at a lower level is it implies that

01:37:33.520 anti-hypertensive should be used at those lower levels. And I don't think that the evidence is

01:37:39.400 strong enough to warrant that. Yeah. But unfortunately, the absence of evidence is not the evidence of

01:37:45.860 absence. In other words, the challenge we would have in doing that trial, which by the way, I'm not

01:37:51.200 advocating for that. I agree that I think most of the time a person's walking around at 135 over 85,

01:37:56.400 you can fix it without medication. But it's an important point here because it's the same

01:38:01.460 problem that we face when we try to think about this through the lens of cardiovascular disease,

01:38:07.700 which is, is a 30-year-old with an ApoB of 100 worse off than a 30-year-old with an ApoB of 70?

01:38:17.940 There's no study that can answer that question because if you study a 30-year-old for the next

01:38:24.100 five years, ApoB of 70 versus hell, 170, you cannot see a difference over that period of time. You would

01:38:33.480 have to study those people over their lifetimes. Now, I believe there would wholeheartedly be a

01:38:37.720 difference in that population. Unquestionably, the 30-year-old with the higher ApoB, all things

01:38:43.880 equal, is going to have higher cardiovascular risk, just as the epidemiology would suggest the

01:38:49.340 person whose blood pressure is 135 over 85 relative to 120 over 80 is going to have lower renal function

01:38:55.840 at the end of their life. So just because we can't do this study, because we can't, right? If you

01:39:01.320 looked at comparing 135 to 85 to 120 over 80 over five years, you're not going to see enough of a

01:39:06.560 difference. So it creates a bit of a problem with how you create guidelines, but it shouldn't confuse

01:39:12.260 the underlying physiology. Yeah, I totally agree with you on the physiology part. I think if you use

01:39:17.840 these more stringent definitions of hypertension, then suddenly a very large number of adults have

01:39:25.040 hypertension. And if you then say that they need treatment for it in terms of like an antihypertensive,

01:39:31.080 then you're talking about probably the majority of the population. Well, or they need treatment via

01:39:36.840 reduced insulin resistance. Yes, I think that's the way to go. Reduced metabolic syndrome is the

01:39:42.880 treatment for which, frankly, drugs aren't great at reducing metabolic syndrome. I'll leave it at that.

01:39:48.300 Let's talk about the role that fructose, sodium play on hypertension through the lens of uric acid,

01:39:57.760 vasopressin, fluid retention, whatever the effectors are. Absolutely. So blood pressure,

01:40:05.040 I've had a very long-standing interest in the mechanisms driving high blood pressure. The way

01:40:10.600 we kind of tracked it back, and I'm going to kind of track it back in the way that our work kind of

01:40:15.220 uncovered it. The first issue was that it's known that salt is important in blood pressure and that

01:40:22.040 animals that are sensitive to high blood pressure, you can make blood pressure a lot worse by giving

01:40:27.880 them salt. And studies from 1900 showed that if you took people with high blood pressure and you put

01:40:33.860 them on a salt restriction, that you can lower blood pressure. So it's been known for a long time that

01:40:39.140 salt is very important in blood pressure. This has led to recommendations to restrict salt in people

01:40:45.520 with high blood pressure. Not everybody is sensitive to salt. A lot of people, when they're young,

01:40:50.000 can eat all the salt they want, and they don't seem to have so much of a problem. But as we get older,

01:40:56.720 we become more and more sensitive to the effects of salt and blood pressure. And you can show that as

01:41:01.760 we get older, when you give salt, blood pressure rises, tends to rise more. So the question is,

01:41:07.860 why is that? And for years, it was thought that the problem is that the kidneys and people with high

01:41:13.700 blood pressure can't excrete salt as easily or as well as normal people. And so that there was

01:41:19.980 some defect in the kidney that could cause that. To make a long story short, we spent over a decade

01:41:26.260 studying this. And we discovered that people with high blood pressure have inflammation in their

01:41:32.040 kidneys. They have low-grade inflammation in their kidneys. And it's due to T-cells and macrophages. And

01:41:38.500 they tend to be in the main part of the kidney where the tubules are and around the little blood

01:41:44.060 vessels. We were able to prove that the inflammation was actually maintaining the kidney in a state where

01:41:51.800 it couldn't get rid of salt very well. And it did this by basically creating reduced blood flow to

01:41:58.080 the kidneys. So in people with high blood pressure, they all have reduced blood flow to their kidney.

01:42:03.120 When you reduce the blood flow, you affect the ability of the kidney to excrete salt,

01:42:07.440 and you start to retain salt. When we discovered this and others also followed this by noting this

01:42:14.320 association, it really emphasized the fact that high blood pressure is an inflammatory disease that

01:42:20.600 is driven by inflammation. But then the question is, what was driving the inflammation? And what we found

01:42:26.220 was that there are many things that can cause inflammation to the kidneys. There's drugs like

01:42:31.720 things that are very vasoconstrictive, cocaine, for example, and other things that constrict the renal

01:42:37.900 arteries or activation of the renin angiotensin system, for example, can cause ischemia to the kidneys and

01:42:45.780 bring in this inflammation. But one thing that seems to drive it is a high uric acid. When we found this, we did

01:42:52.860 some studies in adolescents, and we found that these adolescents who are overweight, many of them had a high

01:42:59.060 uric acid, and they were discovered to have high blood pressure. Did some studies, and we found that

01:43:03.820 when we raised uric acid in animals that they developed high blood pressure. And so we thought

01:43:08.540 maybe the uric acid could be playing a role in blood pressure in humans. And so we did a study done by Dan

01:43:14.960 Feig, published it in JAMA. And what we did is we randomized adolescents with high blood pressure to drugs to

01:43:23.060 lower uric acid or not. And these were kids with newly discovered hypertension. They'd never been on any

01:43:28.940 kind of drug at all. We put them on allopurinol, which is a drug that can lower uric acid. And we

01:43:35.320 had a remarkable 90% of them normalize their blood pressure when they lowered their uric acid levels.

01:43:41.960 Was this the study in, I want to say, 09, 74 men who were placed on a high fructose diet and then given

01:43:51.200 allopurinol or not? Or is that a different study? That was a different study. So this was a study in

01:43:56.860 adolescence. They were like 14 or 15-year-old kids. They were randomized to allopurinol. We had a big

01:44:03.000 effect. How much blood pressure reduction did you see in the allopurinol group? The blood pressure

01:44:07.360 completely normalized. What was the starting point? It was mainly done by ambulatory blood pressure,

01:44:13.720 but also clinic blood pressure. It was like a five, I would say five to eight millimeter drop.

01:44:19.560 So they didn't really have high blood pressure to begin with. High for teenagers, but...

01:44:23.680 Yeah. They were all defined as having high blood pressure. They weren't like 160 over 90 or...

01:44:29.440 But they weren't even 140, right? How do we define a teenager's blood pressure?

01:44:33.840 There are standards of what is considered high. I'd have to go back to look exactly at what it was.

01:44:39.020 But that 2009 study where they were given 200 grams of fructose, so a lot of fructose,

01:44:46.520 with and without allopurinol, I think it was seven millimeters of mercury systolically,

01:44:52.480 five diastolically. Do we think that that's clinically significant?

01:44:56.280 That's clinically significant for sure. I mean, when blood pressure goes up that much,

01:45:01.260 that is definitely associated with increased cardiovascular events over time. It's thought

01:45:05.880 to be clinically significant when you can lower diastolic by more than like three millimeters and

01:45:10.560 when you can lower your systolic by more than four or five millimeters.

01:45:15.780 How high did you induce the blood pressure in the group that was not getting allopurinol?

01:45:20.160 Their blood pressures all went up quite significantly. We'd need to go back and look,

01:45:25.160 but I know that 25% of them developed metabolic syndrome de novo. It was mainly because of the rise

01:45:31.780 in blood pressure. Yeah. We'd have to go back to look at the actual numbers. I've written about 800 papers,

01:45:39.020 a lot of papers to remember all the specific details. And what do we think is the mechanism?

01:45:46.000 Do we think it is all operating through the inflammation in the kidney? That's the most

01:45:52.000 sensitive pressure sensing aspect of the body? More complicated than that. So we know that to

01:45:57.180 have chronically elevated blood pressure, you have to have this inflammation in the kidney.

01:46:02.460 And we know that that inflammation in the kidney was associated with a high uric acid.

01:46:06.920 The uric acid is also raising blood pressure directly through effects on blood vessels. For

01:46:13.480 example, it will inhibit nitric oxide. It will stimulate oxidative stress as we talked about.

01:46:19.500 The elevated blood pressure will inhibit nitric oxide synthase or the uric acid will?

01:46:24.420 Uric acid will reduce endothelial nitric oxide.

01:46:28.220 Through the inhibition of NOS or what mechanism?

01:46:31.120 It does it through multiple mechanisms. One is it removes nitric oxide directly by binding to it.

01:46:39.080 Another is it decreases the uptake of L-arginine, which is used to make nitric oxide. There's some

01:46:46.160 models that seems to be blocking the endothelial nitric oxide synthase. It's working through multiple

01:46:52.640 mechanisms. Have you looked at symmetric and asymmetric dimethyl arginine levels as well?

01:46:58.400 There's some association between these elevated levels and decreased renal function, and it's also

01:47:03.860 believed to work through the inhibition of nitric oxide synthase.

01:47:09.140 High blood pressure is a very complicated problem. And we think that it's initiated by eating foods high

01:47:17.340 in salt and foods high in sugar. And if you give sugar to animals, blood pressure goes up acutely.

01:47:24.620 And if you give sugar or fructose to humans, blood pressure goes up within minutes.

01:47:31.300 How much? Like if you drink a Coke, how much does your blood pressure go up?

01:47:35.080 Three to four millimeters with a 20 ounce Coke.

01:47:38.620 To push back on that for a second, when I exercise, my blood pressure goes up 40 millimeters of

01:47:44.400 mercury. And acutely, that's not problematic because, I mean, everything about exercise acutely

01:47:51.480 is very dangerous. Blood pressure goes up. Inflammation goes up. Hepatic glucose goes up.

01:47:56.160 I mean, if you analyzed a person physiologically in exercise, heart rate variability is down,

01:48:01.200 heart rate's up, blood pressure's up. Like you name a physiologic profile, it got worse.

01:48:05.280 Their question is what's the chronic effect of it, right? Because chronically exercise reduces all

01:48:10.740 of those things, though acutely during the bout of exercise, it makes them worse.

01:48:15.220 I'm always a little bit worried when we talk about, hey, you know, you drink a Coke and this

01:48:19.420 happens acutely without understanding what it's doing chronically, if that makes sense.

01:48:23.860 You're absolutely right. So let's go back to sugar. So sugar is linked epidemiologically with

01:48:31.720 the development of hypertension. There are studies out there where people have put overweight people

01:48:38.120 on low sugar diets and blood pressure comes down. And there's evidence that the fructose component

01:48:44.980 is what's driving the blood pressure response because acutely, if you give fructose, blood pressure

01:48:50.780 goes up in a person. If you give glucose, it acutely does not. So fructose has something it does that

01:48:58.480 raises blood pressure. And our group discovered that when you give a salty diet to animals, that they

01:49:08.440 actually start producing fructose in their bodies. So salty foods turned out to be another way

01:49:13.660 to stimulate fructose production. And when you give salt chronically to animals, they get high blood

01:49:21.700 pressure, they get hypertrophy of their heart, and they also develop metabolic syndrome. They actually

01:49:28.680 develop obesity, insulin resistance, and everything. That may seem surprising because we don't think of

01:49:35.780 salt as driving obesity. It's non-caloric, but actually there's data in humans that high-salt diet

01:49:42.700 also increases the risk for obesity and insulin resistance besides hypertension.

01:49:47.840 What's the mechanism?

01:49:49.260 So the mechanism is that salt, when you eat salt, the salt concentration in your blood goes up. And when

01:49:56.580 the salt concentration in your blood goes up, it activates the polyol pathway. It turns on this enzyme

01:50:03.800 to make fructose.

01:50:05.440 Which one? The aldose reductase?

01:50:07.980 Yes, it turns on aldose reductase, and that helps convert glucose to fructose. And so when you

01:50:16.700 eat potato chips, the chips provide the glucose, and the salt stimulates the enzyme to convert the glucose

01:50:26.300 to fructose. So French fries are particularly fattening because they have the salt and the carbs,

01:50:33.800 that together really turn on this pathway to make fructose.

01:50:38.360 And how strong is the evidence for that in humans, that serum sodium concentration activates

01:50:44.180 aldose reductase?

01:50:45.700 Very high. That data is very strong. The data in humans that increased serum osmolality activates

01:50:52.020 this pathway, or increased salt concentration in the blood can activate the aldose reductase pathways

01:50:57.920 is very strong in humans. It's very strong in all organisms.

01:51:02.580 Is it the salt, or is it the osmolality?

01:51:04.940 It's the osmolality.

01:51:06.400 So that's why elevated glucose could also do it.

01:51:09.340 Correct.

01:51:10.060 If you have someone with type 2 diabetes, and their glucose concentration is 140 milligrams per

01:51:14.460 deciliter, that's a huge osmolar load. So even if they have normal salt concentration,

01:51:19.920 that could be activating it. What is it about osmolality that activates this enzyme?

01:51:24.640 In the promoter region of the enzyme, there's an osmosensitive region that gets activated.

01:51:31.980 It's a transcription factor called Tony BP, and that activates aldose reductase,

01:51:38.280 and that converts glucose to fructose. And it's a major mechanism that animals use when they get

01:51:45.600 dehydrated. Interestingly, that dehydration, or the increase in salt, when you eat salty foods,

01:51:53.860 when you get thirsty, it means the salt concentration in your blood is high. When you

01:51:59.240 eat salt, the salt concentration in your blood goes up, you get thirsty, and you start making

01:52:04.020 fructose in your body from the glucose you've been eating. And then that fructose appears to be enough

01:52:11.180 that over time, it's actually driving the metabolic syndrome, as well as sugar. So salt and sugar both

01:52:18.640 activate the pathway. When we give salt to animals, it takes them a longer time to gain weight than sugar.

01:52:25.180 Sugar is pretty quick. But when you give salt, it takes a few more months before the animals really

01:52:31.300 get overweight. And we've done epidemiologic studies in humans. And when salt intake is high,

01:52:37.600 it increases the risk for fatty liver and diabetes. For example, in Japanese adults was this one study we

01:52:44.600 did. It increases the risk for blood pressure. It's the salt concentration that's the greatest risk

01:52:50.740 factor for high blood pressure. It's not the amount of salt you eat, how salty the food is, and how much

01:52:56.660 salt it goes up in your blood. So for example, if you drink a lot of water, and so the salt concentration

01:53:03.600 doesn't go up, then the effect of salt to raise blood pressure is blunted. So we did a study in humans

01:53:09.540 where we gave salty soup with or without water. And if we gave enough water to prevent the salt

01:53:15.600 concentration to go up, we could prevent the rise in blood pressure. We know that this osmolal pathway,

01:53:22.260 that salt increases the salt concentration in the blood, that activates this pathway. And if we give

01:53:28.380 salt to animals that cannot metabolize fructose, what we find is they eat the same amount of salt,

01:53:34.020 they get that salt concentration goes up in their blood the same, but they don't gain weight,

01:53:40.400 they don't become obese, and they don't become hypertensive. So that this hypertension and that

01:53:46.060 left ventricular hypertrophy and all these things that are happening are driven in a lot by the

01:53:51.940 conversion of glucose to fructose in the body from the salt. So the salt and sugar work together,

01:53:59.100 and then it's what they're doing to actually drive the blood pressure response and obesity.

01:54:06.100 Now, interestingly, when salt concentrations go up in the blood, so does vasopressin. And vasopressin

01:54:12.980 is a hormone that's produced in the brain that helps to conserve water. And so when you eat salt,

01:54:20.800 or if you eat sugar, vasopressin levels go up in the blood, and the vasopressin is released from the

01:54:27.660 brain goes up in the blood, and it helps hold on to water to try to help you conserve water. But what

01:54:34.660 we've recently found is that the vasopressin is also helping the fructose to drive fat. When you eat

01:54:42.020 fructose, or you eat salt, the fructose that's produced from the salt stimulates vasopressin. And

01:54:49.040 the vasopressin actually binds to a specific receptor called the V1B receptor. And that actually

01:54:56.000 is important in driving obesity. And if you block that receptor, you can block the effects of sugar

01:55:02.720 to cause obesity, metabolic syndrome, and so forth. How is that demonstrated?

01:55:07.580 So we took animals where we knocked out the different vasopressin receptors, and there's a

01:55:13.500 vasopressin receptor called 1B. No one has known what the function of that receptor was.

01:55:18.940 I mean, really, it's been a receptor that's had no real known function. And when we blocked that

01:55:25.460 receptor, we had a remarkable finding. The animals could eat all the sugar they want, or they could

01:55:30.780 eat salt, but they won't get obese because the obesity pathway is driven through that receptor.

01:55:38.700 Exactly how the receptor works, we don't fully know. It stimulates a hormone called ACTH that

01:55:45.480 stimulates cortisol, steroids. It also stimulates the islets to produce glucagon, which counters the

01:55:52.460 effects of insulin. And it also works to upregulate the fructose pathways in the liver.

01:56:00.340 Where is this receptor found? Is it only central?

01:56:03.000 It's central, but it's also in the adrenal gland, and it's also in the islet. In obesity,

01:56:07.800 it seems to be expressed in the liver.

01:56:09.560 How does this effect compare to the fructokinase knockouts? So if you took the fructokinase

01:56:16.040 knockout mice and compared it to the mouse that has normal fructokinase, but just has this receptor

01:56:22.640 blocked, and you give them the same amount of fructose, glucose, salt, et cetera, which one is

01:56:29.440 more resistant to the obese phenotype? So the fructokinase knockout tends not to want to eat

01:56:35.720 sugar. They tend to not like fructose. You have to kind of force them to eat the fructose,

01:56:41.880 but even if you force them to eat the fructose, they'll never get fat. The V1B receptor knockout

01:56:47.480 like fructose. They'll eat a lot of sugar. They won't get fat.

01:56:52.360 How are they disposing of their fructose?

01:56:54.500 They're totally regulating total caloric intake. So although they eat more fructose,

01:57:00.500 they'll eat less chow. So they maintain their energy balance.

01:57:03.880 But how do they not turn into skinny fat mice who are lean because their overall energy balance is

01:57:10.360 fine, but they still get fatty liver disease and they still get diabetes?

01:57:14.440 They do not get that. They don't get fatty liver. They don't get insulin resistant.

01:57:18.580 They stay normal.

01:57:20.360 That's counterintuitive, right? Because you'd think that, remember the energy restricted

01:57:24.720 high fructose animals, they were lean, but they were inside fat. They had visceral fat. They had

01:57:31.060 liver fat. They had hypertension. So remember that the metabolic syndrome is driven through

01:57:35.700 the energy depletion pathway. The actual caloric pathway is still intact. What we know is that it's

01:57:43.380 down-regulating fructokinase. This is probably the key point. The V1B receptor knockout have less,

01:57:51.920 they don't have as much fructokinase. They're turning it off. They're reducing the amount.

01:57:56.300 Normally when you eat sugar, the fructokinase levels get higher and higher. They get turned

01:58:02.440 on by sugar. And the V1B knockout doesn't do that. So the fructokinase stays at a low level. So my guess

01:58:10.680 is that some of the fructose is being metabolized by other enzymes like glucose, glucokinase and stuff.

01:58:18.120 What happens is they eat normal amounts and they stay normal weight. And they don't develop metabolic

01:58:24.220 syndrome, but they don't turn up their fructokinase. Well, Rick, this has been an amazing

01:58:31.120 discussion. We've managed to go a lot deeper into things that I think we already covered in some

01:58:35.120 depth in the first podcast, but I've certainly learned a lot more in the interval of just two

01:58:39.480 years. And I believe it or not, I think we got through many of the questions that people wanted

01:58:45.200 to go deeper into. So again, thank you very much for providing your wisdom as always. And we'll make sure

01:58:51.100 that the show notes are littered with a lot of the references that we spoke about. And in fact,

01:58:56.820 some of the things that we didn't know, we'll make sure we track down.

01:59:00.440 Yes. Some of the fact checking. Thank you so much, Peter. It's great seeing you.

01:59:04.240 I hope you can mention the book, Nature Wants Us to Be Fat.

01:59:08.100 I will mention it in the intro, but pulled it up again. So we'll talk about that. Yeah. So the book is

01:59:12.860 called Nature Wants Us to Be Fat. And by the time this podcast comes out, it will already be on bookshelves.

01:59:19.540 And I think the book, which is the follow-up to The Fat Switch, really goes into a lot of the stuff

01:59:26.900 that we talked about today. It goes into this next level of insight around fructose metabolism,

01:59:33.340 uric acid, byproduct of that, and the sequelae of that. And do you mention also the vasopressin

01:59:39.100 link and stuff in there as well? Yeah, that's in the book. The one thing that we might want to

01:59:44.380 point out that's a very important finding is that when we studied the fructose survival pathway,

01:59:50.820 we found that the fat produced was not just being used as a caloric source, but it was being used as

01:59:58.100 a source for water. Because when fat is metabolized... When it's oxidized, it generates a ton of water.

02:00:03.620 It generates water. So animals in the wild, when they store fat, they're actually storing it not

02:00:10.520 just for calories, but for water. So the hibernating bear will use the fat as a source

02:00:16.100 of water while they're hibernating. And they must have very high vasopressin when they're hibernating.

02:00:21.300 Actually, while they're storing fat, vasopressin levels are high, but vasopressin levels plummet

02:00:27.100 during hibernation. So that seems to allow them to burn the fat.

02:00:30.860 Well, that's interesting. Does that mean that a hibernating bear is basically peeing itself

02:00:35.140 constantly? They are making some urine, but their bladders stay permeable, and so they reabsorb some

02:00:40.840 of their urine. But I don't think they're making large amounts of urine. It's probably because of

02:00:45.420 the low metabolism, because they drop their temperature and their body metabolism, so they're

02:00:50.780 generating less urine. But their vasopressin levels typically are turned off during hibernation.

02:00:55.580 And animals in the desert often have fat, like in their tails, or the camel has a hump, because they

02:01:02.600 don't want the fat on their body, because that would increase the insulation and increase the body

02:01:07.480 temperature. But they want to use the fat as a source of water. And they live in these environments.

02:01:13.000 They do have very high vasopressin levels. And big breakthrough was to realize that vasopressin's not

02:01:19.220 just holding onto water by reducing the volume of urine, but it's also holding onto water by

02:01:26.420 stimulating fat. And the way it stimulates fat is through this V1B receptor. We know as this V1B

02:01:33.440 receptor increases cortisol. Of course, high cortisol levels can lead to Cushing syndrome,

02:01:39.660 where you develop kind of metabolic syndrome. So we think that's part of it. And it also stimulates

02:01:45.320 glucagon, which raises glucose, counters some of the effects of insulin, so it creates an insulin

02:01:50.780 resistant state. But also because the fructokinase in the liver seems to go increase in the setting

02:01:58.980 where the V1B receptor is activated. And that may help produce more energy depletion by increasing the

02:02:07.580 enzyme so that it can really metabolize the fructose as fast as it can. So I think that that's the

02:02:14.220 mechanism. And animals that have the V1B receptor knocked out like sugar, they like salt, but they

02:02:22.800 cannot metabolize the fructose very well. They seem to be protected from obesity.

02:02:30.160 Congrats on the upcoming book. And thank you again for all your insights today.

02:02:35.280 Thank you, Peter. It was great being on your show.

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The Peter Attia Drive - February 07, 2022

#194 - How fructose drives metabolic disease ｜ Rick Johnson, M.D.

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