#194 - How fructose drives metabolic disease | Rick Johnson, M.D.

Hey everyone.

Welcome to the Drive Podcast. I'm your host Peter Attia. This podcast, my website and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in depth content. If you want to take your knowledge of this space to the next level, at the end of this episode I'll explain what those benefits are. Or if you want to learn more now, head over to peterattiamd.com subscribe Now without further delay. Here's today's episode. My guest this week is Rick Johnson. This will be a familiar name to a lot of you as he was a previous guest back in January of 2020 and we recently re released that episode in preparation for this interview which was carried out in November of 2021. Rick has authored over 700 scientific publications as well as three books, the Sugar Fix in 2008, the Fat Switch in 2012 and his new book Nature Wants Us to Be Fat, which is out February 8, 2022. Rick is a professor of medicine and the Chief of the Renal Division and Hypertension at the University of Colorado, where he conducts research exploring the role of fructose in the development of obesity, metabolic syndrome and kidney disease. Rick's initial episode was a really popular one, despite the technical nature of it, and that coupled with a bunch of follow up stuff is really what prompted me to bring him back. In this episode we talk about how the body can actually generate fructose from glucose de novo and the effect of circulating glucose and salt levels on activating this conversion. That's a pretty novel concept. That's not something that I certainly appreciated until very recently. Talk about the effects of fructose on weight gain by driving an increase in food intake. Talk about the decline in metabolic flexibility associated with aging and how factors such as sugar intake or menopause associated hormone changes can alter the response to sugar across a lifetime. We talk again about pharmaceutical therapies on the horizon for blocking fructose metabolism and their potential use in treating metabolic syndrome, the impact of fructose metabolism and uric acid on kidney function blood pressure and we conclude with a discussion on vasopressin, a hormone that facilitates fructose's effect on weight gain and insulin resistance. Again, a somewhat technical discussion, but I think Rick has a pretty good way of explaining technical things in such a manner that even if you don't have a background in this biochemistry, I think you can follow along really well. So without further delay, please enjoy my conversation with Rick Johnson.

Hey, Rick, good to see you again.

Great to see you too, Peter.

We had a lot of follow up questions from our first podcast, which actually was probably about two years ago. In addition to the other topics that I wanted to follow up on, we sort of asked listeners, we're going to do another round two here. What do you have? So, so much of what we're going to talk about today is a combination of things that I wanted to double click on, coupled with that of what others did. But I think a number of people have asked the question, hey, can you explain again, why is it that fructose metabolism is kind of unique from a nutrient standpoint in terms of creating this transient intracellular energy deficit? This is something that becomes very important and we get into sort of the metabolic effects of fructose.

Absolutely. So just to reiterate what you're saying, all nutrients are there to produce energy. Any kind of food, we're using it to generate energy or ATP in our body. But there's a cost to producing energy. And so some energy is used to digest foods and some energy is used to metabolize foods.

It's the idea, the old adage, you have to spend money to make money. Now you're going to get that ATP back in spades if you just stay with the program.

That's absolutely truth.

All right, so let's talk now about fructose. And is fructose unique in what you're about to describe?

Well, alcohol can also activate this process. And so alcohol can cause rapid ATP depletion as well. But in terms of most nutrients, fructose is pretty unique. Yes.

Okay, so how does that work?

Yeah, so with fructose, the very first enzyme in fructose metabolism is called fructokinase. And this is going to become an important enzyme to remember. Its nickname is ketohexokinase or khk, one of the key enzymes in fructose metabolism. It phosphorylates fructose at the 1 position, so it's fructose 1 phosphate. That enzyme will literally phosphorylate the fructose as soon as it sees it doesn't have any negative feedback. If ATP levels start to drop, that's fine for the fructose metabolism. That's what fructose metabolism is aimed at doing. And so if you have a large concentration of fructose, it's concentration dependent. If the fructose concentration is very low, there won't be as much ATP depletion and it may actually go undetected. If it's a lot of fructose present, the ATP depletion will be quite severe. So the degree of ATP depletion varies with the concentration of fructose. And as we talked last time, the fructose concentration relates to not just the amount of fructose, but how rapidly it's absorbed. So if you drink liquid fructose, like a soft drink on an empty stomach, that liquid fructose can get absorbed very quickly and even more quickly. For example, with high fructose corn syrup, there's some debate on this. But high fructose corn syrup, the fructose and glucose are already separated so that it may be absorbed differently than sucrose, where it's glucose and fructose bound together, but they broken and they have to be degraded to the individual fructose and glucose in the gut before they're absorbed. So if you drink liquid fructose, it will be absorbed very fast and then the concentration will be higher when it hits the liver. And the liver is of the key sites that drives this whole process. So what happens is when the fructose gets there, the fructokinase phosphorylates it, and the ATP levels acutely fall. But then there's a series of reactions that try to help maintain the low ATP state. And that low ATP state is maintained primarily by a drop in intracellular phosphate that accompanies this. And that activates this enzyme system that removes the breakdown of ATP products. It removes it so that the ATP cannot be regenerated easily. So the ATP levels fall. There's the accumulation of ADP and amp. Atosine monophosphate is one of the key ones.

And.

And then that is swept away. So normally AMP and ADP get reformed to make more ATP. They're really important to make the ATP. If the AMP is removed, then it's hard to replenish the ATP because you've removed a key building block for ATP. And that AMP is removed by an enzyme called AMP deaminase, which turns out to be a very, very important enzyme in this pathway. And that breaks down the amp stepwise, until it produces uric acid, which is the end product of purine metabolism. ATP basically has purines in it, the adenine, and that gets broken down eventually to uric acid. And then the uric acid inside the cell actually causes oxidative stress to the mitochondria and the mitochondria are also really important in ATP production. And the oxidative stress affects this several ways. First, it inhibits an enzyme called aconitase, which is involved in the Krebs cycle and basically leads to citrate accumulation and the stimulation of fat production. And it also blocks an enzyme called enol COA hydratase. And that enzyme's involved in beta fatty acid oxidation. So it blocks the burning of fatty acids. And so what happens is it reduces the production of ATP by blocking and shunts those components to make fat and to block the burning effect. So what it's trying to do is it's trying to stimulate fat storage. Uric acid also inhibits this enzyme that it's activated in starvation to help bring back to raise energy levels, called AMP kinase, AMP activated protein kinase or AMP kinase. And by inhibiting that, it also blocks energy production. So the whole thing is brilliant. I mean, it's a brilliant system to set the energy levels down in a cell. And it mimics the. The condition of starvation by reducing the energy in the cell. It triggers an alarm signal. It's like a mayday. And that is what leads to a survival response. Makes the animal get hungry, thirsty, forage for food, try to store fat, try to store glycogen. It's like an alarm signal saying, hey, you're going to be in trouble. And what we need to do is we need to store energy as a means to help you, because winter's coming, you're going to be without food. You're going to have to travel 2000 miles by air by flying to a place, and you're not going to be able to eat or anything when you're flying over that ocean. It's a survival pathway.

All right, so let's go back and summarize that, because there's obviously a lot you put out there. So let's start from the beginning. Fructose enters a cell. By the way, is this typically a hepatocyte? Is this a liver cell that is doing the lion's share of this metabolism? Or is it an enterocyte, a gut epithelial cell? What type of cell is doing this type of metabolism?

Typically, one step back. Fructose can be metabolized like glucose through some of the glucose enzymes. So fructose can be metabolized by glucose enzymes, but it prefers to be metabolized by fructokinase. We would say it has a higher affinity and will preferentially be metabolized by fructokinase if the Fructokinase is present. Normally, fructokinase is present a little bit in the gut. It's in the gut, actually modest amounts, actually fairly modest amount. And it's also in the liver, but it's also in the brain. It's in the islets of the pancreas. Very important because that's where insulin and glucagon are produced. Some of it is in the white fat, pheromone is in the kidney. And then it has the ability to be induced, meaning that it's not normally present, but it can be turned on. And one place that can be turned on is whenever there is like injury, tissue injury, like a heart attack, it can be turned on and produced in the heart following a heart attack, or it can be produced in the kidney further or be activated further if you have kidney failure, like from a COVID infection. So it can be induced in sites and it's probably trying to provide some quote, survival mechanisms in these sites. But what happens is it tends to be over activated and end up causing worse injury rather than protection from injury. And this has been a common issue when it's been studied in that it was probably originally meant to be protective. But when it's turned on big time, and part of that is driven by our diet and so forth, it can actually be injurious. So its main sites are the liver, the brain, the islets, the kidney and the intestine. Now where it causes the energy depletion seems to be in all those sites except the intestine. In the intestine, there's a tendency during the metabolism to use up. There's work done by Dr. Josh Rabinowitz from Princeton, beautiful studies that has shown that the fructokinase in the gut, probably at high concentrations you do get the energy depletion. But when they're just small amounts of fructose, it actually tends to not cause the energy depletion and to actually convert the fructose more along the lines towards glucose. Fructose can be converted to glucose and glucose can be converted to fructose. The intestine tends to be a shield that at low concentrations just helps remove the fructose without it being a problem. And this is one reason why fruits, which have like 4 grams of fructose, or vegetables have small amounts of fructose, like 2 to 5 grams. They don't cause the energy depletion, mainly because this intestinal fructokinase seems to inactivate small amounts. But if you hit it with a large dose of fructose. The fructose gets through the intestine. It probably causes ATP injury to the intestine. And we can talk about that because I've done some studies to show that it causes gut leak. It may be responsible for anaphylaxis to certain foods, for example, food allergies. So good story to talk about that. But most of the fructose ends up getting metabolized in the liver. And the liver seems to be the primary place that drives the metabolic syndrome and obesity and diabetes. And if we knock out fructokinase just in the liver, we can protect animals from obesity and diabetes and high blood pressure. So the liver is the king when it comes to metabolic syndrome. The kidney is actually important for kidney disease, and the brain is really important for diseases like Alzheimer's and so forth that we can talk about. But, yeah, fructose turns out to have been meant to be this wonderful system for survival. But. But in our culture, with the amount of sugar and foods that we are eating that either provide sugar or can be turned into fructose, this pathway has become hazardous.

Let me go back and make sure that folks are following along here. Rick. So, as you pointed out, the gut becomes the first place of contact. By definition, we're pretty much all eating things through our mouth. They're going to wind their way through the stomach, into the duodenum and into the proximal part of what's called the jejunum. You have these epithelial cells that line the gut. And as you're saying, at low doses of fructose, so if you're eating a piece of fruit or some vegetables which have some amounts of fructose in them, they can be absorbed there without creating that phenomenon you've described. But when you override that system, when you expose the gut to higher concentrations and presumably higher doses. So this is really a dose concentration problem, which we'll come back to. It basically manages to get through the gut without the gut doing the metabolism. And then it's going to enter the portal system. We didn't really explain that, but the reason that it preferentially makes its way to the liver is that the venous system that drains the gut has another very beautiful and unique to the body property, almost unique to the body. It occurs in one other place, but where the superior mesenteric vein, inferior mesenteric vein, join the splenic vein, these things become the portal vein, and you now have a vein that becomes an inflowing conduit to the liver. So now, that's why the liver plays, as you said, such an important role in metabolism. It has two incoming blood supplies, the arterial supply, which supplies its oxygen, and its venous incoming supply, which supplies these nutrients on first pass from the gut. Now they get into the liver and the first thing that happens is we need to phosphorylate fructose and by definition, we're already in a high fructose state because we've already exceeded the gut's capacity to metabolize this. And so now it's basically a free for all, with unlimited fructose becoming fructose, one phosphate. And we're generating in the cell lots of adp. So we start with ATP, which has three phosphates. We rip off a phosphate to put it on our fructose in the number one carbon position. That leaves us with adp, adenosine diphosphate. It's shy of one phosphate. That reaction doesn't slow down. ADP further gives up a phosphate, becoming amp, adenosine monophosphate. The ADP and AMP are being shunted elsewhere in the further degradation of their adenosine component, and that's being turned into uric acid. Uric acid being the final breakdown product of adenosine. You're doing two things, which is you're taking away the base that you could rephosphorylate to repopulate ATP. You're running more and more fructose through this. And if that weren't enough, the uric acid goes on to be metabolized into other molecules that both increase the substrate for de novo lipogenesis in the form of citrate, and also create other molecules that inhibit the process of beta oxidation, which is the process by which we break down fatty acids to make ATP. Do I have that right so far?

You're right on the money. It's a fantastic review. The only thing I would correct is that when the uric acid is generated, it actually doesn't further break down. I mean, it does break down a little bit, but the way it works is it stimulates oxidative stress in the mitochondria. And it does that by stimulating a specific enzyme called NADPH oxidase, which I hadn't mentioned. And that enzyme produces oxidative stress and it actually translocates that enzyme to the mitochondria. So the enzyme not only is activated, but it moves into the mitochondria. That oxidative stress then inhibits different enzymes that lead to fat synthesis and blocks of fatty acid oxidation. So the uric acid accumulates in the cell and you can measure the uric acid and the levels go up in the cell and it's the uric acid turning on these processes that seems to really drive this whole mechanism. One can view it, Peter, like there's two pathways for fructose metabolism. One is the caloric pathway. Fructose gets metabolized to CO2 and water. In that sense, the caloric pathway, it's sort of similar to glucose. But unlike glucose, that triggers another pathway, an ATP degradation pathway. And that is not considered a caloric pathway. It's not part of the calories. What it's doing is it's activating metabolic processes that lead to the development of diabetes, obesity, hypertension. And all these things are driven by this side chain reaction. So it's not the calories of fructose that are driving obesity. It's not the calories from fructose, it's the fact that fructose lowers the energy and keeps the energy levels low. And this is due to this runaway renegade enzyme, fructokinase, that just takes all the ATP it can to phosphorylate the fructose as it's seasoned.

A couple things I would say there one is going back to the why this is an amazingly engineered system in a food scarce environment. Because every one of those things that you said, which is an enzyme that is by definition not telling the organism to stop eating, it's not signaling that we have enough energy, it's signaling the exact opposite, which is the more of this you eat, the more of this we want you to get. And it's turning off your ability to oxidize fat and turning on your ability to store and make more fat out of the byproduct here. Those are really incredible, valuable adaptations without which we wouldn't be having this discussion because we wouldn't exist.

Exactly. So it's like a very fundamental mechanism that developed in nature. It's like a process that is so key for survival that all animals use this pathway. And what's interesting is that one of the breakthroughs was the discovery that it's not just the fructose we eat eat, but that the body can make fructose and when the body makes enough fructose, it can activate this pathway. When we were originally studying this, we said to ourselves, okay, it looks like it's fructose is the problem. And so if we just go on a low fructose diet, maybe this is how low carb diets work. Because low carb diets would be low fructose diets. And we were originally thinking, yeah, this is the pathway that's activated, so let's just go on a low fructose diet. I actually wrote a book, the Sugar fix, back in 2008, because I thought that was the solution. Just go on a low fructose diet. But the problem is that the body can make fructose, and it turns out that the favorite way it makes fructose is through high glucose levels. High glucose, the classic is diabetes, is a high glucose state. In diabetes, it's been known for decades that there's an enzyme that gets turned on in high glucose states called the polyol pathway. And that enzyme can convert glucose to sorbitol. And sorbitol then gets converted to fructose. By the way, sorbitol is considered one of the artificial sugars, so be aware, it actually gets turned into fructose. In the body, glucose gets converted to sorbitol, which converts to fructose, and that occurs under high glucose conditions.

Say more about what that means, Rick. Does that mean under high plasma glucose conditions?

We always were thinking high plasma glucose conditions, but then we thought to ourselves, actually, it's not the plasma that's so important. It's what's going on in the liver that's so important.

So high glycogen conditions when glucose gets to the liver.

Now, remember that when we eat carbs, we're generating glucose. And so, you know, if you eat broccoli, you're going to generate some glucose because it's a vegetable that has carbohydrates in it, but it doesn't produce a lot of glucose. So the glucose concentrations in the liver and the blood don't go up with broccoli. But if you eat bread or rice or potatoes, chips, cereals, these are what we call high glycemic foods, which means that they have a fair amount of starch that gets broken down to glucose in the gut. So when you eat bread, you actually generate a fair amount of glucose. And if you have, like continuous glucose monitor, things like that, you can actually sit a rise in your blood glucose. When you eat bread or rice or potatoes, it will go up, and it's also going up in your liver.

And do we know what the difference is in the portal vein? So if you're wearing a continuous glucose monitor and it's showing before you eat, Your glucose is 90 milligrams per deciliter, and after you eat, it's 150 milligrams per deciliter. Do you have a Sense of how high it is in the portal vein at that peak level.

We have not done those studies, but it would be very, very helpful to understand because there is what we call first pass effect, where food, when it goes through the liver, the liver uses up some of it before it gets into the blood. So a lot of the glucose that enters the liver is quickly sequestered in the liver cells and metabolized, and some of it passes through. Glucose in our blood is like the tip of the iceberg. The glucose levels in the liver are likely higher. Now, this enzyme that converts glucose to fructose is normally when we're born. It's very little of it's in the liver, but it gets induced over time. And I would love to develop an assay for looking at peripheral blood, for example, to see if you've turned on your. Aldose reductase is the name of the enzyme. Whether or not that enzyme is elevated in your liver or not, because if it is, bread is gonna be much more fattening than if you don't have that enzyme.

Where would you be measuring that, Rick, do you think, measuring that literally in the plasma? Would there be enough of it there, or is this something that's particularly inducible in the liver?

Well, it's inducible in the liver, but you can measure. So sorbitol is kind of a good marker of the activation of this pathway.

Is this the enzyme that turns glucose into sorbitol or sorbitol into fructose?

Yeah, the rate limiting enzyme is the enzyme that converts glucose to sorbitol. And that enzyme is called aldose reductase. And it's normally low in the liver, but it gets induced and it can be induced by high glucose. It's induced by high uric acid. So there's a positive feedback system because fructose is metabolized. When fructose is metabolized, you generate uric acid. Uric acid then goes back and tries to turn on the enzymes that can lead to more fructose metabolism.

What's the evidence for those two claims? What's the evidence that glucose and uric acid both induce the enzyme that turns glucose into sorbitol? Is there human data for that or is that all in mice?

High glucose activating aldose reductase has been shown in humans as well as in animals, as well as in cell culture. And it was the very basis for the original concerns about this pathway being important in diabetic complications. This has been known for 50 years. But the uric acid as A stimulus for Aldose reductase was published by our group based on animal studies and cell culture studies, but it was not based on human studies. So it would have to be shown in humans. But I believe it's very likely true. Based upon the animal data, the cell.

Culture data, and at what levels of uric acid does it start to become clinically relevant? Meaning, do you get enough sorbitol production that it leads to meaningful amounts of fructose generated de novo?

Most of our studies, when we do it, when we go from a normal uric acid to a high uric acid in a laboratory rat, the levels of high versus low are different in humans, but they seem to translate. When we've done studies like in human cells versus rat cells, the correlation is beautiful. So generally speaking, I would say levels of uric acid that might turn on this pathway are probably be over 7 milligrams per deciliter in a human. And certainly that's what you see in metabolic syndrome, what's very common in our studies. When we gave glucose to animals, my theory was that that would not cause obesity because glucose will maintain the ATP levels, blah, blah, blah. The fructose is activating this metabolic syndrome through dropping ATP levels. I did not think that glucose would really cause obesity when we gave it. We found that the mice over time became very, very fat and insulin resistant. And I was a little depressed, but I was hoping that we would find that the glucose was being converted to fructose. When we looked in the livers, we found that about maybe as much as 25% of the glucose was being converted to fructose in this laboratory mice.

I want to make sure we understand the conditions of which this experiments are being done. Are these animals being force fed glucose and if so, how much of a caloric surplus are they experiencing and what other macronutrients are factoring into this? I mean, are they literally just eating pure starch?

So the way we did this experiment was we gave glucose in the drinking water. So it was like 10% glucose in the drinking water and we gave it to laboratory mice.

Which strains?

I would have to look it up. The C57, I think it's called.

This strain's propensity for obesity is how much compared to the wild type behaves how here?

So the wild type mice, the control mice, they get fat when you give them fructose in the water. They get fat when you give them glucose in the water. It's pretty significant, but it takes weeks to months really to see the effects of glucose or fructose to cause obesity. It goes through a period of time, time, several months. And what happens is initially when you give glucose or fructose in the drinking water, the animals like it, so they drink a lot more water than they normally. And they're getting a fair amount of caloric intake from the water, from the drinking water because it has sugar in it.

So what are the control animals drinking? Just access to the same chow but no glucose in the water.

Right. Or we can do things like give artificial sugars. So we have done that, like give Splenda where they'll drink increased amounts of water similar to glucose or fructose, but they're getting an artificial sugar. And what happens is that when an animal is getting calories in its water, it will reduce how much food it eats. And that's a normal process. And it's true for sugar as well. It's true for table sugar, it's true for fructose, and it's true for glucose. But what happens is over a period of a month or so, suddenly they start eating more and more despite still drinking a lot. They end up being in a high caloric state. When we look at that, it's because they start developing leptin resistance and the leptin resistance. Leptin is a hormone produced in the fat cells that tells the brain that it's full. When leptin levels go up, say you've eaten enough. It's what they call a satiety signal. It says, okay, you've eaten enough.

Doesn't it work more in the reverse? I mean, isn't it really more that low levels of leptin tell you that you are low in your fat stores, but if you don't look at leptin receptor deficient animals, I didn't realize that high leptin had a satiety component. Otherwise, injections of leptin would curb appetite. But I don't think they do in normal mice.

In normal mice, if you inject an animal with leptin, they will reduce their food intake immediately, within hours, and they'll reduce it by 30%. So normally, leptin does signal satiety. If you inject animals with leptin, they will eat less.

But why does this not work in humans?

Because, people, when you become overweight, you become resistant to leptin, and, and the leptin resistance is at the hypothalamic level. So people who are overweight almost always have very high leptin levels. And the leptin is not signaling, is not working. We call this leptin resistance. It turns out that leptin resistance is how fructose causes animals to eat more. Because when you give animals fructose, takes like a month, but eventually the animals become resistant to leptin. Then you can inject them with leptin, and they continue to eat. So the way we test them is to actually inject them with leptin. So we do those experiments. Normally, animals are sensitive to leptin, and if you inject leptin, they'll reduce their intake. If they're born with low leptin, they're going to be hungry and they're going to eat more. And if they become resistant to leptin, they can have a high leptin level, but they will not respond to it, and so they'll eat more.

You diagnose leptin resistance based on the response to a leptin injection?

Correct, and we do that in all of our studies. And then we also look for the evidence of leptin resistance by studying the hypothalamus, because there's a characteristic change that occurs that you can look for with leptin resistance. We also test for that.

What is that change?

It's, I think, STAT 5 phosphorylation. I'd have to look it up again, but we do it. So that helps determine if the animal is leptin resistant.

And what's the mechanism of this? Rick, what causes leptin resistance?

Well, it's not fully known, but there's some evidence from some groups that it might be due to uric acid. And you can kind of induce a leptin resistance state by, I think, injecting uric acid in brains of animals. There's a group from China that they showed that it caused leptin resistance, but they definitely showed that it can cause inflammation in the hypothalamus. And the inflammation in the hypothalamus is thought to be the driver for leptin resistance. Getting back to the experiment, when we give glucose to animals, initially, they reduce their chow intake. Over time, they start increasing their chow intake. They become very fat, they become insulin resistant, they develop all features of metabolic syndrome.

And.

And when we look in their livers, they're making fructose, and they've turned on this enzyme, this polyol pathway is high, and so they are gaining weight and becoming fat related to fructose production. And to prove that it was the fructose, we gave glucose to animals that lack fructokinase. These are genetically manipulated mice where we've removed the gene or. Or knocked out the gene for fructokinase. And so what happens is these animals cannot metabolize fructose through this ATP depletion pathway. When we give them glucose, they can drink the glucose, they gain some weight and fat, probably related to the effects of insulin, but because glucose stimulates insulin and insulin can decrease fat breakdown in the peripheral fat. But what happens is these animals do not develop insulin resistance, they do not develop fatty liver. They're really protected from the metabolic syndrome and they gain much less weight and have less fat.

And just to be clear, Rick, these are absolutely isocaloric, these two animals.

Yeah, it's very close. It looks identical. Yeah, it's super close.

Can you do this? And pear feed the animals so that you have a fructokinase knockout pear fed with a wild type, and they're otherwise getting the same glucose in the water and the same chow and they're pear fed to match?

Yeah, well, we do a lot of paraffin studies. In this case, the animals are drinking basically the same amount of glucose. I mean, I think that it's within 5% or 3% difference. I mean, it's very, very similar.

And what's the difference in body weight or body fat at the end of this?

Oh, it's remarkable. It's remarkable.

What percent is the difference?

Have to go back to the study now. We did it two different ways and we did get slightly different results. So when we gave just glucose alone, the animals gained a little bit of weight, they drank a lot of glucose, they still gained weight a little bit compared to a mouse that didn't get glucose even when the fructokinase was knocked out. But it was probably significantly more weight gain than a mouse that got glucose. A mouse that just gets glucose alone really gains weight. A mouse that gets glucose in which they cannot metabolize fructose, it's dramatically less, but it's still a little bit more than normal.

Again, to make sure I understand this, both animals are only getting glucose, and they're getting it in liquid form and solid form, though there's also chow. Right. One animal has a functional fructokinase, one does not. Now, it's interesting that both animals presumably can make the same amount of fructose. Correct, because you're not impairing the conversion of glucose to sorbitol to fructose. You're just impairing in one animal the conversion of fructose to fructo1 phosphate and therefore the metabolism of fructose that Whole pathway we discussed at the outset?

Yes, that's correct. So their fructose levels are still high in the fructokinase knockout. It's just. They can't metabolize them.

Yes. So are they experiencing fructoseuria? Where is the excess fructose going in that animal?

They do have fructoseuria.

Where I'm going with this, Rick, is I'm trying to understand from an energy balance perspective what accounts for this difference. Is it that the fructokinase knockout is peeing out the excess energy and that explains the difference in weight? Or is the energy expenditure different in these animals and that explains the weight?

What happens is, when you block fructokinase, animals regulate their weight, regulate their caloric intake. So, as I mentioned, if you give fructose and glucose to animals, initially, they reduce their chow so that they maintain the normal weight. But after the leptin resistance kicks in, they start eating more chow than they need. And so they go into a positive energy balance where they're eating a lot more than they normally do. And this is associated with weight gain. When you give glucose to an animal that is a fructokinase knockout, what happens is it continues to keep its chow low. So even though it's drinking a lot of glucose, the chow stays low so that the overall energy intake is only very mildly increased.

So I misunderstood. I thought these animals were isocaloric across the board, but they're not. The fructokinase knockout is eating less.

Yes. They get the same exact amount of glucose. They're drinking the same volumes of glucose.

Right, but they're eating different amounts of chow.

But they're eating exactly.

The chow contains everything. Fat, protein, and glucose.

Yes, but we have done. And in that experiment, we did do an isocaloric experiment, too, where we compared mice that were getting glucose and eating. We did a lot of animals, so we did paired them up where the animals were actually eating the same total amount of calories. And when you do that, you still see a very dramatic difference in things like fatty liver and insulin resistance.

Just make sure to understand. You're saying when you do pear, feed the animals so that you have fructokinase knockouts and wild types. Again, I think the whole liquid versus chow thing complicates this experiment. Let's just keep it simple. If you just are feeding them isocaloric amounts of food that contain glucose, protein, fat, your hypothesis would be that the fructokinase knockouts would be protected from the negative effects of fructose Both the fructose that they're eating directly and the fructose that they will make from glucose in the event that they do so.

So just to really simplify it, what we've identified is that fructose stimulates obesity and metabolic syndrome. And it does it through two major ways. One way is by encouraging an animal to eat more, and it basically stimulates hunger and stimulates food intake. Part of that is through the brain, and part of that is through this leptin resistance, which is also kind of a brain. And so the animals eat more and they also drop their resting energy metabolism. So they're both metabolizing less and they are eating more. And that causes the weight gain.

And what's the relative contribution of those? This is very important to me because, look, I think, Rick, there are a lot of people out there vociferously that calorie for calorie, they're all the same. It doesn't matter if you're eating a calorie of glucose, a calorie of fructose, a calorie of fatty acid. If you can regulate the intake, it's all the same. So when you look at what you just said, which is fructose ingestion can lead to weight gain through two mechanisms. One, it can drive you to eat more. So on the intake side of the ledger, it's causing you to eat more, but it can also lower your energy expenditure. And I assume that could be both deliberate and non deliberate. It could reduce, if that's true, resting energy expenditure. And it could presumably even reduce drive. Energetic drive, which would be spontaneous energy expenditure. What's the contribution of these?

No, so actually that is still the first mechanism. The first mechanism is it makes you gain weight by increasing energy intake and dropping energy metabolism. What happens is a lot of weight gain from sugar is because you are eating more and exercising less.

Moving less.

Yeah, moving less. Less resting energy metabolism.

Can you quantify those too? How much is the increase in intake? The way you would do this, I think in animals would be because you're letting them eat ad libitum. In this case, you'd have to let them eat ad lib. You could quantify the difference in energy intake and you could say, does that difference explain the weight gain fully? If it does, then none of it has to do with the decline of energy expenditure. If it doesn't, you would see what the gap is.

Right. Let me explain that. Most weight gain from sugar is due to eating more. Some weight gain is due to a decrease in energy metabolism. And if you do isocaloric diet, so all the animals, the controls and the sugar fed animals are eating the exact same amount weight gain. There's basically minimal difference in weight gain in the short term. If you go for two months, if you give sugar versus starch after two months in animals, there's very little difference in weight gain. There's a little bit of weight gain because of the decreased energy metabolism in the fructose group, but it can be hard to show. And the high fructose corn syrup industry loves this. So they say, hey, the problem is people are eating too much. But if you control for how much sugar you're eating, and we do isochloric studies and we look at short term studies, there's no difference in weight gain. And they publish this like in the Annals of Internal Medicine, and they say sugar's safe, but they miss the point that the sugar is actually causing hunger. And by forcing an isocaloric diet, the people are hungry, but they're not able to eat because they're not allowed to eat. And so if you do a short term study, like several weeks to months, you can't show a difference in weight gain. If you went longer, like a year, you probably would show a difference in weight gain because of the difference in energy metabolism.

Yeah. Just to put some numbers to that, if feeding somebody a high fructose isocaloric diet compared to a high glucose diet, if the high fructose group was driven to eat an extra 300 calories per day while simultaneously experiencing a reduction of energy expenditure of 25 calories per day, the increase in the drive to eat 300 calories a day would be readily apparent. Again, this is very back of the envelope math.

No, no, you're totally right.

And this is overly simplifying things because it doesn't work out to be quite this straightforward a math. But by the numbers I gave, every 12 days, you could gain a pound on the intake side, but it would take months to show a gain of a pound on the energy expenditure side.

You're absolutely right. And the other problem is, like in the industry, they'll compare fructose to glucose, but we know that some of the glucose is being converted to fructose. So it's really not a fair comparison. But there's another major mechanism. And the other major mechanism is that even if you pair feed animals so that they're eating the exact same amount. Yes. There may not be a difference in weight gain because they're all eating the exact same number of calories. And even Though these guys are leptin resistant, they can't eat what they want to eat.

So presumably they're less happy.

Yes, they're less happy, they're hungry, they're like feeling they're on a diet. But even when you control the exact same diet, all the other metabolic effects of fructose are still going on. They're still becoming insulin resistant, they're still getting fatty liver, they're still getting hypertension. And you can see this beautifully in animals. It's very easy. I've seen clinical evidence of this in people too. A great example, and I may have told this story last time when we were on, but we were doing a pair feeding study of 40% sugar versus starch. And so the animals were getting the exact same amount of food. And pair feeding means you take a group of animals, let's say you have 10 animals in this group and 10 animals in this group, they have to eat the same amount of food each day. And what that means is that the animal that eats the least amount of food, all the other animals have to eat that least amount of food. So if you have one guy who's got a problem and isn't eating a lot, all the animals are forced to do that. So we were doing this study, Carlos Roncall, and our group was doing the study to look at pear feeding and he did not know that one of the animals had cancer and that animal was eating hardly anything. So we had an experiment that went for four months in which all the animals are eating like hardly anything. They're all eating the exact same food. They are on a severe diet, but one group was on a 40% sugar diet and the other was on a starch diet. Everything was equal. They were eating the exact same amount. At the end of the four months, the sugar fed animals tended to be higher weight, but it wasn't significant. But it was from that resting metabolism, from the fact that they had a lower energy metabolism, and it looked like it would have been significant. We'd gone a little bit longer.

How long did you go?

Four months, I believe just to put.

That in perspective and give a sense of magnitude, four months in mice is about 10% of their life. It's about 15% of their life.

They live two and a half years.

Okay, yeah, yeah, yeah. So that's like 15 years in a human. That would suggest, by the way, that at least in a calorie controlled state, excess fructose does not alter energy expenditure in any clinically relevant manner. If after 15 years, which is effectively what that was in humans. After 15 years there was no difference in weight. But between the groups, despite one mainlining fructose and one not, you would say, at least in the context of low calorie intake, which is what they were. Energy expenditure is not a driver of adiposity.

I think over decades it is.

That's one and a half decades. That's a long time.

Maybe as much as a half a pound a year, I would say could be from this half pound to a pound perhaps just depends on the individual. But you're right, it probably by its, you know, we can't completely separate it from the increased food intake that accompanies this in people because we're not parafeeding. But you might be right. But the other thing that happened is these animals that got sugar, every one of them became diabetic, every one of them had severe fatty liver. I mean, it was a very dramatic difference from the starch fed animals. The islets of the pancreas were showing changes of type 2 diabetes as well. And so I think what we've shown, and we've shown it multiple times, is that there are many, many effects that are independent of calories from fructose. And it's due this energy depletion pathway. One of the consequences of this energy depletion is that it stimulates food intake. And so part of obesity really is eating more and exercising or moving less. I mean, that really is true. It's just that it's not so much behavioral driven. It's not your fault. You are activating biologic pathways in your body. It's a biology certainly advertisement encourages you to go to movies and be more sedentary. There's lots of things that are pushing that and people are serving bigger plates of food, but maybe they're serving bigger plates of food because they know that you're going to leave hungry if you don't have that extra food because you are becoming leptin resistant and you're eating more as part of this problem.

So is it safe to say that neither of these animals were overweight at the end of this study, but one of them became very skinny fat, you know, to use the term that we now describe for the lean metabolically unhealthy phenotype.

Yes, you're right. These people exist out there calorically restrict themselves, but are still eating the wrong foods.

So if you had done that study long enough, Rick, which by the way, it's an elegant study that you sort of did accidentally, it would be interesting to see if there was A survival difference.

I think that this whole pathway is very important in aging.

Well, it's hard to imagine it's not. It's one of those studies where I feel like if you can devote the resources to do the experiment for two and a half years and say, look, we're going to go after the holy grail outcome which is all cause mortality. And again, I like the way that these animals were calorically restricted because it gets you away from obesity is the problem. I've always felt that obesity is a passenger that comes along for the ride. But it's the metabolic derangement that lies under obesity that's highly correlated with obesity, but is quite separate from obesity that's the root cause of our mortality. And this would be an experimental way to demonstrate that. That I think would be again, not beyond the realm of doing.

I've actually proposed to do that study. I'll tell you some things that really suggest that this is important in aging. The first thing to talk about is that there have been studies done in fruit flies looking at the effects of sugar on aging. Sort of interesting, the fruit fly actually seeding fruit. I mean, that's what they like. They are always on some fructose, but they're not getting highly concentrated fructose because the fruit also has lots of other things in it, fiber and other things that they're probably getting. The flavonols and everything in there that some of them neutralize some of the effects of sugar. But if you give a fruit fly sucrose or table sugar, which is really fructose and glucose together, a liquid sucrose, they'll love it. And there's studies showing that they will develop obesity, believe it or not. So you'll have obese, insulin resistant flies and they die early. And also when they die, they die from complications related to uric acid production, which is really interesting. They develop equivalently kidney failure for their equivalent of their kidney.

I'm going to wait and see the mice data on that.

Yeah.

Yep.

Now I want to move to the mice. We were interested in whether or not mice that lacked fructose metabolism might live longer than normal mice. And we happened to have some that we were keeping around and they were on a normal mouse chow diet that is very low in fructose. So these animals are eating almost no fructose. It's like less than 3% of their chow.

How much glucose on their chow?

They get a fair amount of starch and protein in the chow. They are getting a fair amount of.

Carbohydrates what are the approximate macros of the three?

I would have to look it up. I can't tell you at the moment. But standard chow, which is basically.

But it's a very low sugar chow.

It's a low sugar chow. We took them out to like a little bit over two years, and we found that they had stayed lean compared to the control mice. They were more lean. And when an animal age develops kidney disease.

Sorry, was that statistically significantly lean?

Yes. Tended to have normal blood pressure or lower blood pressure than the control animals.

How do you measure blood pressure in the mice?

You put a cuff on their tail, it's called a tail cuff. And you can measure the systolic pressure.

What's a typical mouse blood pressure?

It's very similar to ours. It's like 100 to 120. Yeah.

And so if they were statistically significantly leaner than the non fructokinase wild types, could you document how much less they were eating?

We did not actually measure that.

Oh, my God. That's like the single most important piece of information you'd want.

Yeah, exactly. In retrospect, what is very important to know. It's hard to do that over a two year period. It's a lot of laboratory time. But anyway, what was striking, and I just bring this up, is that normal mouse showed aging changes in the kidney. And all mice and rats and humans, we all get aging changes in our kidney, but the fructokinase knockout had no aging changes in their kidney. It was very exciting.

And how much of that do you think was due to blood pressure differences? Was the blood pressure basically the same in these animals?

They were pretty normal. It tended to be a little bit lower in the fructokinase knockout. But we did do a study and showed that if you give them salt, normal animals would show a much more rise in blood pressure than these animals than the fructokinase knockout. So there is a difference in response to salt, which has also been reported with aging. People become more sensitive to the effects of salt with aging, but baseline blood pressure was not really different.

So what do you hypothesize was the difference between the kidney function in these two animals?

The dramatic thing is that the fructokinase knockout were protected from aging associated changes to the kidney. And so it suggests that endogenous fructose production is maybe more important than we think and that it could have a role in the aging process.

How can we quantify endogenous fructose production?

Well, there is a way. It can be done. There was recently a study that looked at labeling fructose and giving it to people and they were able to, maybe it was giving a label glucose and measuring the label on the fructose. But there is a study that shows that when you give a soft drink, you increase the production of fructose by three fold, three to four fold.

Over the amount of fructose that's in the soft drink?

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

I'm trying to figure like a quantify. So I'll give you an example. Right. If I have a patient with fatty liver disease, the first thing I do is restrict fructose and alcohol. We stop all alcohol and we drop fructose dramatically to typically 5 to 10 grams per day, which basically means vegetables and a handful of berries if they must have some fruit. But it's basically a minimal fruit diet and no alcohol. And that's step one. We don't start with caloric restriction. We don't start manipulating other macros, carbohydrate restricting or anything like that. We just take alcohol out of the picture and basically get fructose out of the diet. That usually improves NAFLD in most people. And by the way, that may or may not accompany weight loss. So that's the interesting thing there is you don't have to lose a staggering amount of weight to reverse NAFLD under the conditions I just described.

It's so true.

You often do lose weight with that intervention because generally the people who have acquired NAFLD are also in a state of positive energy balance. So it is a little bit difficult to disentangle that. And as I'm sure you're aware of a number of studies, David Ludwig's group, Rob Lustig, Miriam Voss, a number of people have looked at this. And one of the challenges that all of these investigators have had is maintaining the weight of the fructose restricted group. In other words, you almost have to force feed them extra glucose to try to keep their weight on par with the control group to disentangle this. Now, I haven't looked at this literature in a year, so it might be that there's a new study out there that has managed to overcome that obstacle, which is to say they've managed to pear feed the humans such that you can maintain weight while reversing nafld. Are you aware of such studies in humans?

I think Rob Lustig did an isochloric fructose restriction and did see an Improvement in fatty liver.

Did the weight stay the same?

Think that there was still some weight loss, but I'm not sure. The observation that fructose could be a cause of fatty liver was actually first reported by our group. Which way back when nonalcoholic fatty liver disease was first being recognized as an epidemic, we came interested in the possibility that fructose could be playing a role. And with Manal Abdel Malik at the University of Florida, we did a study on patients and found that they were drinking large amounts of soft drinks, that they had high uric acid levels. And we even looked at liver biopsies and found an increased expression of fructokinase.

By what amount?

Oh, it was like three to four fold increase. And ended up publishing that. And then I started putting people on low fructose diets for fatty liver in addition to alcohol. It really does work. In fact, one of the people in my lab had a son who had developed fatty liver, was skinny, but had fatty liver. But it turned out he was drinking soft drinks almost every day. Just cutting that out was enough. That was one of the precipitants for me to write that first book. The dramatic effects we could see in some people with fructose restriction. But now we know that it isn't just the fructose you drink, it's the fructose you make.

I kind of got off track there, and I apologize. That's really where I wanted to go with that observation, which was, do we know what the average American consumes in terms of fructose per day?

First, about 15 to 20% of the diet is from sugar, and sugar is half fructose and half glucose.

So 10% of the diet is fructose.

10 to 15%, because we also are getting fructose from fruits and other foods besides added sugars. Sugar in the diet can vary. Some people are eating as much as 25% of their diet is sugar. So people can be eating as much as 15, even 20% of their diet is fructose.

Let's just do the math and say, conservatively, it's not hard to eat 100 grams of fructose a day. 400 calories of fructose could represent 15% of your caloric intake.

Absolutely correct.

Okay, so if you take the average American walking around eating, let's just give a range, 75 to 100 grams of fructose. That's their exogenous consumption of fructose in that individual, who we assume is a little bit insulin resistant, maybe a little bit leptin, resistant, but not off the charts. What would you expect their endogenous production to be? How much are they adding to that till?

I would suspect a fair amount. I know you want a quantitative amount.

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

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

And that's based on animal data?

Based on our animal data. Now, there's three major sources of fructose that we can make, and we've only talked about one of them. The first one is high glycemic carbs. Rice, potatoes, bread, chips. We think maybe a quarter of that can be turned into fructose. And I think that that's playing a major, major role in metabolic syndrome. So what happens is, when you're young and you don't have this polyolenzyme pathway activated, eating things like potatoes and french fries may not cause so much weight gain. You may feel you're invincible. But as this pathway gets activated and aldose reductase starts being highly expressed in the liver, then potatoes and bread may cause much more weight gain. And we think it's because of this fructose conversion. Because we actually did another study, Peter, where we gave soft drinks, a high fructose corn syrup to animals, and they got really fat and insulin resistant. But if we blocked fructokinase, we completely blocked development of metabolic syndrome. So with soft drinks, really was all fructose, even though there's a lot of glucose in there. We saw a little bit of weight gain with glucose alone. But when we give high fructose corn syrup, it was pretty much all from the fructose that was causing them to gain weight and to get metabolic syndrome.

Rick, before we go to the other two sources of substrate for making fructose, you mentioned almost in passing that when you're young, you can tolerate lots of high glycemic foods. I think anyone listening to this can relate to that, or probably 90% of people can relate to that. I know. I certainly. Ken, what is it about just aging that alters our sensitivity or vulnerability maybe is a more accurate word to glucose. Throw another wrinkle at you, because we've had a lot of questions about this from women. What is it about menopause that for many women also seems to almost overnight or certainly within the span of about a year, also alter the sensitivity or vulnerability that one has to glucose and by extension fructose?

There's three or four different reasons. And so let me just go through the list real quick. The very first one is that when we're young, we tend to have very healthy mitochondria. A lot of kids are active, and we keep the mitochondria healthy. And the way that this fructose works is it has to cause oxidative stress to the mitochondria to activate these pathways. But if you have really, really powerful mitochondria, you won't show these metabolic effects as easily because they're more resistant to the effects of fructose. And you can still see this in super athletes. They have fantastic mitochondria. Many of them feel like they can drink a lot of sugar and they're immune, and it's because they have really, really healthy mitochondria.

Tell me more about what that means. What does healthy mitochondria mean? We talk about this, but give people a sense of what a healthy mitochondria does that an unhealthy one does not do. And why is mitochondrial dysfunction viewed as one of the hallmarks of aging?

So your mitochondria are one of your major places where you make energy. And in fact, it's the high output energy producer. So it's producing the ATP that we need to drive everything we do. Over many years, the mitochondria get less good at making the energy because of damage, recurrent damage. And it's thought that oxidative stress to the mitochondria can cause this damage. And so when you want to try to store fat, mitochondrial oxidative stress is part of the requirement to store fat. And fructose works to store fat by stimulating mitochondrial oxidative stress. And initially, that is a reversible, very easily reversible mechanism. The oxidative stress goes on, inhibits these enzymes, it leads to fat production and so forth. So it's a survival pathway. But what happens is if you keep stimulating mitochondrial oxidative stress, and it's been shown with fructose, for example, the mitochondria start to decrease and the mitochondrial change. They become smaller and less efficient. And what happens is the mitochondrial function starts to reduce in number, and so you have less mitochondria. And when that happens, you make less ATP. It's associated with feeling more fatigued, more tired. If you have lower ATP levels in your muscle, it's associated with muscle fatigue. Your natural gait will slow down as your mitochondrial function decreases. And it's all associated with aging.

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 mouse and you did muscle biopsies. Obviously there's a quantitative assessment that you would do. You would say per gram of muscle, there's this many mitochondria versus this, they're this big versus that big. How are you assessing ATP output and how are you quantifying the functionality on a per unit of mitochondria basis?

Well, first off, you can measure the mitochondria themselves by looking at electron microscopy. You can measure it indirectly with a PCR technique looking at mitochondrial DNA divided by nuclear DNA. You can measure ATP levels in the tissues. There's all kinds of ways, ways to do it. What we do know is that mitochondrial function tends to decrease as we get older. There's a very good evidence that recurrent chronic oxidative stress to the mitochondria is involved in this. We think that fat storage is associated with mitochondrial oxidative stress. So if you're continually stimulating these pathways with fructose, that may actually wear down the mitochondria. We did do a study in humans where we put people on a low fructose diet and showed that we could increase mitochondrial biogenesis in people within 30 days. And we had a very dramatic increase in mitochondrial production. Fasting is thought to increase mitochondria probably the same way. And actually even caloric restriction. The concept that caloric restriction can promote aging is probably through this pathway. Reduce aging by reducing mitochondrial oxidative stress. Think about this. When you're eating, whenever you're storing fat, it seems to involve some mitochondrial oxidative stress. And so if you eat less food, you're going to have less oxidative stress to the mitochondria and you'll have less fat stores, but what will happen is you will live longer. So in an animal, they always want to have some extra fat on board because they're living in the wild. The they don't know if there's going to be a food shortage suddenly or not. So they want to try to maintain a little bit extra fat. So if you take animals and you put them on 70% of their normal caloric intake, their fat stores are very minimal. They have less oxidative stress to their mitochondria and they're going to live longer, their mitochondria are going to stay healthier. But if you take those animals and you put them in the wild, and remember, when they're in a lab, they're being fed certain amount of food every day, so they're Safe. You put them out in the wild now they have no fat stores and the first big crisis suddenly kills half of them because they can't survive because they don't have enough energy stores. So animals in the wild want to have a little bit of extra fat.

It seems that we do, too. I mean, the obesity paradox is hard to ignore, that low levels of obesity actually seem protective of.

Absolutely. So if you have cancer or heart failure or any kind of chronic disease, you'll actually live longer if your fat stores. If you have a BMI of like 27, that's going to do better than a BMI of 20. When you have a chronic illness, even.

28 is going to do better than 24 as you age, based on the overall data, which is, again, quite a paradox.

Yes, it's because of that need to have a little bit of fat storage. If we get back to the original question, which is, you know, why is it that when I'm young I can eat bread and there's no problem? One is that our mitochondria are healthier at that point and we have what we call metabolic flexibility. We can metabolize things very easily. Everything's kind of young, but over time, the more sugar we eat, the more we get better at metabolizing it. So normally in the beginning, when we eat sugar, the transporter for fructose in our gut is expressed at low levels. And animals that get fructose when they're young tend not to absorb it as well. But the more we get exposed to sugar, the better we get at absorbing it. We turn on the enzymes and the transporters that allow us to absorb fructose more readily. So if you give an animal sugar for a month, for example, you'll upregulate all these pathways and maybe you can stop the sugar for one day. And then if you give them a bolus of sugar, they get a very dramatic activation of this switch. And the fallen energy is very dramatic compared to a normal animal that's not been exposed to sugar that gets a single dose. And that's because we turn on these pathways, so we turn on the ability to metabolize sugar. So we did a study in children where we gave them a dose of fructose. And we had lean children, we had children that were obese, and we had children that were obese that had biopsy proven fatty liver. When we gave them a dose of fructose, the lean people only absorbed about 70% of the fructose and they metabolized it slowly.

And this was a Liquid bolus?

Yes.

How much?

It's like 1 gram per kilogram body weight, as I recall. I would have to go back to the paper.

A pretty good dose.

Yeah, they got a good dose of fructose and they absorbed it only partially. Then we looked at the kids that were obese and they absorbed much more fructose and they metabolized it a little bit faster, but they still didn't absorb at all. And then we gave the fructose to the kids that had fatty liver and obesity, and they absorbed 100% of it and they metabolized it faster. We think it's because of prior exposure to sugar and so forth. It's possible there could be genetic differences, but the bottom line is in animals, the more sugar you give them, the more they'll absorb it. And we think that this carries over to people as well, likewise. And actually there's other data in humans to support this. So that's the second mechanism. And then the third mechanism is this polyol pack pathway also gets turned on over time. By the time you have metabolic syndrome, you probably have this enzyme turned on because you have a high uric acid. And as I mentioned, that that can activate this pathway too. So now you're able to convert glucose to fructose. So let's say you're overweight. You say, 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, hey, I'm still gaining weight. And it's probably because your body's now making a lot of fructose, and it's from those high glycemic carbs. And that's like your number one food that converts, that is used to generate fructose. And so those are your main mechanisms that make you more resistant or more sensitive to fructose over time.

And what about menopause? What effect do you think that has?

Estrogen increases uric acid excretion. So young women tend to have lower.

Uric, have very low uric acid levels.

Low, low uric acid compared to men. But when you go through menopause and estrogen levels fall, uric acids increase. And suddenly, postmenopausally, women have the same, suddenly develop obesity, diabetes, heart disease, more like males, premenopausal estrogen is providing some protection. You can certainly overwhelm it by eating a lot of sugar, of course, and so forth. But menopause, I believe it's related to this change in uric acid and not.

Anything to do with Fructokinase or insulin or other hormones.

Fructose metabolism will be upregulated by uric acid. So when uric acid goes up, not only does it turn on the polyol pathway, but it actually upregulates fructokinase as well. So. So we've shown in animals that when you raise uric acid, you raise fructokinase, and you also amplify the effects of sugar.

And how direct is the relationship between uric acid and aldose reductase?

It's pretty direct.

Meaning if you give a person allopurinol and you knock their uric acid from 7 to 4 and make no other change, do you reduce the conversion of glucose to sorbitol?

We have not actually done that experiment. It's a great experiment, Peter.

Let's get on it. Let's get on it.

It's a good study.

Before we leave this subject and go on to the next thing I want to talk about, which is blood pressure, kidney function, I want to go back to something to make this more practical for people, which is, what do people need to be wary of? I mean, I think the other question that emerges from a discussion like this for many people is, oh, my God, do I need to not eat any fructose? This means I can't have any fruit. Tomatoes have fructose in them, By God, I can't have tomatoes. You know, so how do we provide some insight to people so that they can figure out how to adjust the dose of something that isn't it? Something that, by the way, is ubiquitous, completely ubiquitous. So if you want to go on a zero fructose diet, boy, you're going to have a hard time.

Yeah, no, it's not going to work.

How do people get a sense if they're consuming too much fructose?

Okay, so the very first thing I would recommend, Peter, would be to really try not to drink liquids that have a lot of sugar in it. So immediately get rid of soft drinks and fruit juices. I would drink minimal because there's a fair amount of fructose in that, and it can kind of overwhelm the system. Sports drinks are sort of interesting. Some sports drinks are relatively low in fructose. So maybe they're 2 to 4% fructose with 4% glucose or 6% glucose.

Let's explain to people what that means. Right, so a 6% glucose drink means there is 60 grams of glucose per liter.

Yeah. So soft drinks are like 11%. They have like 6% fructose and 5% glucose, and that really is bad stuff. Soft drinks should. I think they should be banned, right?

So that's like 110 grams of total sugar per liter.

Huge amount teaspoons and teaspoons. Teaspoons. So soft drinks are really bad. Sports drinks were developed originally by Bob Cade and the invention of Gatorade. People who are exercising a lot are losing salt, lots of salt in their sweat. They're burning up glucose. And some of them were getting hypoglycemic on the fields. And sports drinks were really meant to help replenish the electrolytes and to fix the glucose problem and to provide glucose as fuel for the muscle during these heavy exercise bouts. We often use a lot of glucose during exercise. The original sports drinks were glucose rich and had a lot of salt and water, of course. And then there were some studies that showed that oxidation of glucose could be facilitated by having a little bit of fructose in the drink. Having a small amount of fructose actually accelerated glucose uptake. It's working in the gut, primarily. And actually your performance was increased by having small amounts of fructose, like 1 to 2%, maybe 3% fructose. And the optimal glucose from sports drinks was found to be around 5 or 6%. Now, some sports drinks actually have more fructose in it because it tastes better. And so that's a problem, a little bit of a problem. If you're out there exercising, if you're using it for what it's meant for, which is a sport, I think sports drinks, for the most part, are fine. But if you're drinking sports drinks in front of a tv, watching a movie, and you're drinking a lot of this stuff, it probably is not good.

I want to go back to the juices. If I take oranges and I squeeze them into, put my little juice squeezer and I ratchet it down, and I just make concentrated orange juice. What is the concentration of glucose and fructose in freshly squeezed orange juice?

Pretty significant. It's probably about two thirds of a soft drink if you made it with apple juice. Apple juice is so sweet, it's equivalent to a soft drink. And so you can get a lot of sugar from juice, unfortunately. So the Pediatric society a long time ago realized that juice has so much fructose that it was being associated with obesity in children. So they made recommendations to limit fruit juice to, like, 6 ounces or less for older children and like 4 ounces or so for really small children. And I think that we should even limit it more and Fruit juice is, I think, a real problem in children because of all the sweetness of sugar that's in it. Natural fruits are different. So natural fruits have, like, much less fructose in an individual fruit. When you make fruit juice, it's multiple fruits that are put in there. Eat like a orange and it has like six grams of fructose.

That's news to me. I didn't realize an orange would only have six grams of fructose. That's surprisingly low. I mean, we're talking about a real orange here, not like a little Christmas orange. Right. Like a real orange would only have 6 grams of fructose.

I believe it's like 6 to 8 grams. I don't think it's over 8 grams. It's closer to 6 grams, I believe.

An equal amount of glucose.

Yeah, it has some glucose in it too, for sure. But I think there's about 6 grams of fructose in an orange.

So if that's the case, outside of someone maybe with nafld, you'd have a hard time making the case to not eat an orange.

Yeah, I think that natural fruits are.

Fine, including like fake fruits like grapes. I call grapes fake fruits.

There are certain fruits that are high in sugar. Mangoes, figs. Oh my God. They're very, very enriched in fructose. Figs are probably something that we should avoid.

Figs, Dates.

Oh, dates, yes. Mangoes are high. Apples and pears, plums, they tend to be fairly high, like around 9, 10 grams, I think. Oranges are around 6 grams. Bananas are fairly high. Glycemic. They have a fair amount of fructose, but. But it's probably in the range of 6 to 8 grams.

I think what we'll do in the show notes is we'll have our team pull together a table of.

Yeah, I have a great table.

Typical sizes. This is actually news to me. I would have guessed fruits would have a little bit more. But it'll be good to know that.

Most fruits are between 3 grams and 9 to 10 grams max. And most fruits are around 4 to 6 grams. Some fruits have much less sugar, like kiwi, like berries, strawberries, blueberries. They're very healthy. People should be encouraged to eat those. And we actually did a study. We gave people a low sugar diet where they was low in refined sugar, low in high fructose corn syrup. One group got natural fruit and the other group, we restricted that too. So it was either a low fructose diet that was low fructose in all aspects. The other was low sugar, low fructose but you're allowed natural fruit fruits. So that actually was sort of a modest total fructose intake. And when we did that, we found equivalent improvement in metabolic syndrome. The presence of natural fruit did not block the ability of the low sugar diet to improve metabolic syndrome.

So the takeaway here is don't drink it and don't consume added sugar. And I think this is a difficult thing for people to differentiate. So added sugar is when a food has sucrose or high fructose corn syrup are typically the most common agents that are added. It's literally added to the food. So if you go out and get a jar of pasta sauce, they added sugar to it?

Yes, absolutely.

That's not the sugar that you're seeing from the tomatoes that go into making that. It's the deliberate addition of sucrose or high fructose corn syrup to make it taste sweeter.

And remember that the intestine does act as a shield for up to like 5 or 4 to 6 grams of fructose. So if you eat 4 or 5 grams of fructose in a fruit, the intestine's going to protect you. In addition, you have fiber in a natural fruit and that slows the absorption. So the concentration of fructose that gets to the liver is lower. So there's less ATP depletion.

Now what about dry versus not dry? So if you take. If you take the equivalent of apple chips versus apples, but you take equal amounts of the actual calories. So it's just obviously one is a lot bigger because it's got more water and things in it. What's the difference in how we metabolize that?

The trouble with dried fruit is that it still has all the fructose, but a lot of the good things are removed. So that's the problem. Dried fruit is sort of like candy.

So it's not just the loss of water that's problematic.

There's right. Things like vitamin C tends to be low in dried fruit and stuff.

Why is that? I guess vitamin C is water soluble. Is that why?

Maybe that's it.

I always thought the issue was more that you lose the satiating benefit of the water. It's hard to eat more than two apples in one sitting. It's not hard to eat more than 10 apples worth of apple chips in one sitting. So I really thought it was more of just a regulation of quantity.

It's probably the amount you're eating. I certainly have read that dried fruits do not contain as much of the good nutrients, but we should probably check this before we put it on your show. This is something we should fact check.

We'll have the show notes, we'll assess that.

Yeah, I'm not 100% certain about the vitamin C issue, and I would hate to actually be quoted if I'm wrong on that. But it's been said, Peter, that dried fruits are thought to be primarily devoid of the good components that are in fruit. And we know that there are many other good components in fruit besides fiber. There's potassium and flavanols, and there's a substance called epicatechin that's in a lot of fruit that actually can block some of the effects of fructose and other things like luteolin and mangosteen. And some of these things also seem to block the effects of fructose, astol and different flavanols.

So, last question I have before we leave, at least fructose from this standpoint is we talk about fructokinase knockouts in the lab. I'm sure most people listening to this, if they're like me, are thinking, two thoughts. One, how do I knock out my fructokinase? And maybe more interestingly, how much polymorphism exists in the fructokinase gene in humans that might account for differences in fructose tolerance? So while I don't think there are too many people born who have no fructokinase and therefore would seem completely immune to the effects of fructose, I would have to believe that there's a distribution across which people exist and where they have higher versus lower natural either quantity or activity of this enzyme. Has that been documented?

Well, first off, there is a condition called essential fructoseuria. This is a hereditary condition in which you do not have fructokinase.

Right. So you pee all your fructose out?

Yeah, well, you pee. About 10% of the fructose you eat goes out through the urine and the rest is metabolized by the glucose enzymes because some of the glucose enzymes can metabolize fructose dose. And to date, no one has ever been reported with type 2 diabetes with this condition. No one has ever been reported to have obesity. It seems that it's associated with normal lifespan or maybe even prolonged lifespan, but certainly with normal lifespan. I'm in connection with a small kindred, a family that has this condition. And interestingly, they can eat all the sugar they want, but they tend to prefer other kinds of food.

They don't have a taste affinity for sugar.

They tend to prefer salty foods. To sugary foods.

Okay, so last question on that then is basically, what is the hope for a pharmacologic agent that could block fructokinase as a treatment for obesity, type 2 diabetes, NAFLD disclosure.

I have a small company. We're trying to develop fructokinase inhibitors for the treatment of metabolic syndrome and other conditions associated with fructose. But there are also several large pharma that are actively working on making fructokinase inhibitors. Eli Lilly, for example, is one that's actively trying to make fructokinase inhibitors. And so I think it's a very exciting future if we could develop these inhibitors. Look like they hold great promise in, you know, in animal studies, they can block sugar induced obesity and diabetes and fatty liver. So there's a lot of promise with these.

These agents already exist because I always thought in animal studies you were doing it genetically.

No, we have developed fructokinase inhibitors in our laboratory. But there's also Eli Lilly and Pfizer made fructokinase inhibitors. And Pfizer actually had a success in a phase two trial where it reduced fatty liver pretty significantly and improved insulin resistance.

And so where is that Pfizer drug today? Is it in phase three?

Sadly, Pfizer recently stopped progressing with this despite a positive phase two result. I'm not sure what the reason was. They have another drug they're developing for fatty liver that also had very positive results. And it may be that they're focusing on one versus the other. But I don't know exactly why Pfizer stopped developing their drug. Eli Lilly is, I believe, doing phase one trials right now with theirs. So the Pfizer thing is kind of a mystery, and you may not want to discuss it at this point since we don't really know.

I love discussing stuff for which we don't know the answer. I'm totally fine with that.

So, yeah, Pfizer just decided to not proceed.

And there was no toxicity that you were aware of in the phase two?

No. And what was reported, it looked very promising.

Okay, so let's talk a little bit about blood pressure. Seems to play a very important role in really all of the major chronic diseases, except for cancer. And if there's a role in cancer, I don't know what it is, but who knows? Maybe somebody knows that. But certainly, certainly when we come to neurodegenerative disease, cardiovascular disease, cerebrovascular disease, and renal disease, which are really the main pillars of death, hypertension seems to work against you. So what is it about everything that we've spoken about that ties into hypertension?

Yeah. So high blood pressure, which is sometimes called primary or essential hypertension, is extraordinarily common in our country and throughout the world. Maybe one third of adults have high blood pressure.

How is it defined today?

In most places of the world, it's defined as a blood pressure greater than 140 over 90, 140 over 90 or higher. But in this country recently was redefined as being greater than 130 over 80. I think that for the majority of the world the definition is 140 over 90.

And from a physiologic perspective, where do you fit on that spectrum? I mean, you're the nephrologist, so you take care of the organ that is arguably the most sensitive to blood pressure. You could make a case that even more than the heart and the brain, the kidney is the first place that damage shows up. I don't know if you would agree with that. Is that a true statement?

There's actually three main sites where high blood pressure really causes problems. And the first one is stroke. It's the major cause of stroke. It's also the major cause of heart failure, and it's one of the two major causes of kidney disease. And so those are the three main pressure related conditions where pressure is driving. The higher the pressure, the higher the risk for stroke, heart failure and kidney disease. The studies show that the greatest risk for stroke, heart failure and kidney disease, or when the blood pressure is like 160 to 180 systolic, is kind of the turning point where when it's above that level, there's really a dramatic increased risk for these conditions. But it's been known for a long time that there's been tendency for a linear relationship between blood pressure and stroke and blood pressure and heart failure going all the way down to 120 over 80. So there are a lot of people that would like to say that 120, 80 or 13080 should be our cutoff because it's really a linear relationship. But most Studies done around 1900 showed that less than 5% of the population had blood pressures of over 140 over 90. Based upon the normal Gaussian curve of the population back then, probably about 140 or 90 was the cutoff for what was thought to be high. I'm a believer that 140 or 190 is a good mark for where we should be viewing hypertension as a condition that really should involve Active management.

So, Rick, does that imply that if somebody has a blood pressure of 135 over 85, which would be below the cutoff that you're saying you would deem the time to act of 140, 90 at 135 over 85, you could roll around at that blood pressure indefinitely without any damage to the kidney?

Yes, exactly. So there's relatively minimal risk with a blood pressure 135 over 85. In epidemiology studies over many years, you can show that, you know, 120 over 80 is superior to 135 over 85.

And the reason I bring this up, Rick, is not to be a pain, but it's to talk about what our standards are really about. I'm not a nephrologist, but boy, am I a freak when it comes to managing GFR in my patients. Why? Because I want people to live to 100. That's an aspiration. Most people aren't going to, but we make that the aspiration. If I'm talking to a 40 year old patient and their GFR is 85, well, most people would say that's normal. But I want that 40 year old not to live to 80. I want her to live to 100, which means I can't treat her like a 40 year old. I have to treat her like a 20 year old. I have to time shift her back to say I need her kidneys to survive another 60 years. So based on epidemiologic data, I can't treat her as a 40 year old and her GFR of 87 is not good enough. I want her GFR to be 107 because I need to know that at 100 her GFR is still 40. So that's why I push back on this idea. I really want to understand this. If we're in the business of trying to get people's kidneys to have a GFR above 40 at the age of 100, do we have to revise our standards on hypertension?

It's a wonderful comment that you make there. And I think that the answer is we would prefer a blood pressure of 120 80. But if it's 135 over 85 to put someone on a medication that they'll have to take for the next 60 years, I'm not sure that that's the best way to go. I think that doing nutritional and exercise related maneuvers when you're 135 or 85 should be the way to go. And we can fix it by diet by reducing salt and picking healthier foods and exercising. But the trouble with when you get to 140 over 90, if you can't lower your blood pressure by dietary means, you really probably should go on an antihypertensive because it will provide protection, protection over time. But when your blood pressure is like 135 over 85, I haven't seen any evidence that antihypertensives really provide long term benefit to that group. I do think that dietary measures though make sense and I agree with your general idea, the idea that optimize health as best as we can and that's your best chance to maintain health for the longest you can. So I like that idea. You're right on. But I don't know if we should be doing interventions. The trouble with defining blood pressure hypertension at a lower level is it implies that antihypertensive should be used at those lower levels. And I don't think that the evidence is strong enough to warrant that.

Yeah, but unfortunately the absence of evidence is not the evidence of absence. In other words, the challenge we would have in doing that trial, which by the way, I'm not advocating for that. I agree that I think most of the time a person's walking around at 135 over 85, you can fix it without medication. But it's an important point here because it's the same problem that we face when we try to think about this through the lens of cardiovascular disease, which is, is a 30 year old with an APOB of 100 worse off than a 30 year old with an APOb of 70? There's no study that can answer that question. Because if you study a 30 year old for the next five years, APOB of 70 versus hell, 170, you cannot see a difference over that period of time. You would have to study those people over their lifetimes. Now, I believe there would wholeheartedly be a difference in that population. Unquestionably, the 30 year old with the higher apob, all things equal, is going to have higher cardiovascular risk, just as the epidemiology would suggest. The person whose blood pressure is 135, 85 relative to 12080 is going to have lower renal function at the end of their life. So just because we can't do this study, because we can't. Right. If you looked at comparing 135 to 85 to 12080 over five years, you're not going to see enough of a difference. So it creates a bit of a problem with how you create guidelines, but it shouldn't confuse the underlying physiology.

Yeah, I totally agree with you on the physiology part. I think if you use these more stringent definitions of hypertension, then suddenly a very large number of adults have hypertension and if you then say that they need treatment for it in terms of like an antihypertensive, then you're talking about probably the majority of the population.

Well, or they need treatment via reduced insulin resistance.

Yes, I think that's the way to go.

Reduced metabolic syndrome is the treatment for which, frankly, drugs aren't great at reducing metabolic syndrome. I'll leave it at that. Let's talk about the role that fructose sodium play on hypertension through the lens of uric acid, vasopressin, fluid retention, whatever the effectors are.

Absolutely. So blood pressure. I've had a very long standing interest in the mechanisms driving high blood pressure. The way we kind of tracked it back, and I'm going to kind of track it back in the way that our work kind of uncovered it. The first issue was that it's known that salt is important in blood pressure and that animals that are sensitive to high blood pressure, you can make blood pressure a lot worse by giving them salt. And studies from 1900 showed that if you took people with high blood pressure and you put them on a salt restriction, that you could lower blood pressure. So it's been known for a long time that salt is very important in blood pressure. This has led to recommendations to restrict salt in people with high blood pressure. Not everybody is sensitive to salt. A lot of people when they're young can eat all the salt they want and they don't seem to have so much of a problem. But as we get older, we become more and more sensitive to the effects of salt and blood pressure. And you can show that as we get older, when you give salt, blood pressure tends to rise more. So the question is, why is that? And for years it was thought that problem is that the kidneys in people with high blood pressure can't excrete salt as easily or as well as normal people. And so that there was some defect in the kidney that could cause. Cause that. To make a long story short, we spent over a decade studying this and we discovered that people with high blood pressure have inflammation in their kidneys. They have low grade inflammation in their kidneys and it's due to T cells and macrophages. And they tend to be in the main part of the kidney where the tubules are and around the little blood vessels. We were able to Prove that the inflammation was actually maintaining the kidney in a state where it couldn't get rid of salt very well. And it did this by basically creating reduced blood flow to the kidney. So in people with high blood pressure, they all have reduced blood flow to their kidney. When you reduce the blood flow, you affect the ability of the kidney to excrete salt and you start to retain salt. When we discovered this, and others also followed this by noting this association of. It really emphasized the fact that high blood pressure is an inflammatory disease that is driven by inflammation. But then the question is, what was driving the inflammation? And what we found was that there are many things that can cause inflammation to the kidneys. There's drugs like things that are very vasoconstrictive. Cocaine, for example, and other things that constrict the renal arteries or activation of the renin angiotensin system, for example, can cause ischemia to the kidneys and bring in this inflammation. But one thing that seems to drive it is a high uric acid. When we found this, we did some studies in adolescents, and we found that these adolescents were overweight. Many of them had a high uric acid, and they were discovered to have high blood pressure. Did some studies, and we found that when we raised uric acid in animals that they developed high blood pressure. And so we thought maybe the uric acid could be playing a role in blood pressure in humans. And so we did a study done by Dan Feig, published it in jama. And what we did is we randomized adolescents with high blood pressure to drugs to lower uric acid or not. And these were kids with newly discovered hypertension. They'd never been on any kind of drug at all. We put them on allopurinol, which is a drug that can lower uric acid. And we had a remarkable 90% of them normalized their blood pressure when they lowered their uric acid levels.

Was this the study in, I want to say, 09, 74 men who were placed on a high fructose diet and then given allopurinol or not. Or is that a different study?

That was a different study. So this was a study in adolescents. They were like 14 or 15 year old kids. They were randomized to alpurinol. We had a big effect.

How much blood pressure reduction did you see in the allopurinol group?

The blood pressure completely normalized.

What was the starting point?

It was mainly done by ambulatory blood pressure, but also clinic blood pressure. It was like a 5, I would say 5 to 8 millimeter drop.

So they didn't really have high blood.

Pressure to begin with.

High for teenagers, but yeah, they were.

All defined as having high blood pressure. They weren't like 160 over 90 or.

But they weren't even 140. Right.

If.

How do we define a teenager's blood pressure?

There are standards of what is considered high. I'd have to go back to look exactly at what it was.

But that 2009 study where they were given 200 grams of fructose, so a lot of fructose with and without allopurinol, I think it was 7 millimeters of mercury systolically, 5 diastolically. Do we think that that's clinically significant?

That's clinically significant for sure. I mean, when blood pressure goes up that much, that is definitely associated with increased cardiovascular events over time. It's thought to be clinically significant. When you can lower diastolic by more than like 3 millimeters. And when you can lower your systolic by more than 4 or 5 millimeters.

How high did you induce the blood pressure in the group that was not getting allopurinol?

Their blood pressures all went up quite significantly. I. We'd need to go back and look, but I know that 25% of them develop metabolic syndrome de novo. It was mainly because of the rise in blood pressure. Yeah, we'd have to go back to look at the actual numbers. I've written about 800 papers, a lot of papers, to remember all the specific details.

And what do we think is the mechanism? Do we think it is all operating through the inflammation in the kidney? That's the most sensitive pressure sensing aspect of the body?

More complicated than that. So we know that to have chronically elevated blood pressure, you have to have this inflammation in the kidney. And we know that that inflammation in the kidney was associated with high uric acid. Uric acid is also raising blood pressure directly through effects on blood vessels. For example, it will inhibit nitric oxide. It will stimulate oxidative stress.

As we talked about, the elevated blood pressure will inhibit nitric oxide synthase or the uric acid will.

Uric acid will reduce endothelial nitric oxide.

Through the inhibition of nos, or what mechanism?

It does it through multiple mechanisms. One is it removes nitric oxide directly by binding to it. Another is it decreases the uptake of L arginine, which is used to make nitric oxide. There's some models that seems to be blocking the endothelial nitric oxide synthase. It's working through multiple mechanisms.

Have you looked at symmetric and asymmetric dimethyl arginine levels as well? There's some association between these elevated levels and decreased renal function. And it's also believed to work through the inhibition of nitric oxide synthase.

High blood pressure is a very complicated problem, and we think that it's initiated by eating foods high in salt and foods high in sugar. And if you give sugar to animals, blood pressure goes up acutely. And if you give sugar or fructose to humans, blood pressure goes up within minutes.

How much, like if you drink a Coke, how much does your blood pressure go up?

3 to 4 millimeters. With a 20 ounce coke to push.

Back on that for a second, when I exercise, my blood pressure goes up 40 millimeters of mercury and acutely, that's not problematic because, I mean, everything about exercise acutely is very dangerous. Blood pressure goes up, inflammation goes up, hepatic glucose goes up. I mean, if you analyzed a person physiologically in exercise, heart rate variability is down, heart rate's up, blood pressure's up. Like, you name a physiologic profile, it got worse. The question is, what's the chronic effect of it? Right? Because chronically, exercise reduces all of those things, though acutely, during the bout of exercise, it makes them worse. I'm always a little bit worried when we talk about, hey, you drink a Coke and this happens acutely without understanding what it's doing chronically, if that makes sense.

You're absolutely right. So let's go back to sugar. So sugar is linked epidemiologically with the development of hypertension. There are studies out there where people have put overweight people on low sugar diets and blood pressure comes down. And there's evidence that the fructose component is what's driving the blood pressure response. Because acutely, if you give fructose, blood pressure goes up in a person, if you give glucose, it acutely does not. So fructose has something it does that raises blood pressure. And our group discovered that when you give a salty diet to animals, that they actually start producing fructose in their bodies. So salty foods turned out to be another way to stimulate fructose production. And when you give salt chronically to animals, they get high blood pressure, they get hypertrophy of their heart, and they also develop metabolic syndrome. They actually develop obesity, insulin resistance and everything. That may seem surprising because we don't think of salt as driving obesity. It's non caloric. But actually there's data in humans that high salt diet also Increases the risk for obesity and insulin resistance.

Besides hypertension retention, what's the mechanism?

So the mechanism is that salt, when you eat salt, the salt concentration in your blood goes up. And when the salt concentration in your blood goes up, it activates the polyol pathway. It turns on this enzyme to make fructose.

Which one? The aldose reductase?

Yes, it turns on aldose reductase and that helps convert glucose, glucose to fructose. And so when you eat potato chips, the chips provide the glucose and the salt stimulates the enzyme to convert the glucose to fructose. So french fries are particularly fattening because they have the salt and the carbs that together really turn on this pathway to make fructose.

And how strong is the evidence for that in humans that serum sodium concentration activates aldose reductase?

Very high. That data is very strong. The data in humans that increased serum osmolality activates this pathway, or increased salt concentration in the blood can activate the aldose reductase pathways is very strong in humans. It's very strong in all organisms.

Is it the salt or is it the osmolality?

It's the osmolality.

So that's why elevated glucose could also do it.

Correct.

If you have someone with type 2 diabetes and their glucose concentration is 140 milligrams per deciliter, that's a huge osmolar load. So even if they have normal salt concentration, that could be activating it. What is it about osmolality that activates this enzyme?

In the promoter region of the enzyme, there's an osmol sensitive region that gets activated. It's a transcription factor called Tony bp and that activates aldose reductase and that converts glucose to fructose. And it's a major mechanism that animals use when they get dehydrated. Interestingly, that dehydration, or the increase in salt when you eat salty foods, when you get thirsty, it means the salt concentration in your blood is high. When you eat salt, the salt concentration in your blood goes up, you get thirsty, and you start making fructose in your body from the glucose you've been eating. And then that fructose appears to be enough, that over time, it's actually driving the metabolic syndrome as well as sugar. So salt and sugar both activate the pathway. When we give salt to animals, it takes them a longer time to gain weight than sugar. Sugar is pretty quick. But when you give salt, it takes a few more months before the animals really get overweight. And we've done epidemiologic studies in humans, and when salt intake is high, it increases the risk for fatty liver and diabetes. For example, in Japanese adults was one study we did. It increases the risk for blood pressure. That's the salt concentration. That's the greatest risk factor for high blood pressure. It's not not the amount of salt you eat, how salty the food is, and how much salt it goes up in your blood. So, for example, if you drink a lot of water and so the salt concentration doesn't go up, then the effect of salt to raise blood pressure is blunted. So we did a study in humans where we gave salty soup with or without water. And if we gave enough water to prevent the salt concentration to go up, we could prevent the rise in blood pressure. We know that this OSMO pathway, that salt increases the salt concentration in the blood that activates this pathway. And if we give salt to animals that cannot metabolize fructose, what we find is they eat the same amount of salt, they get that salt concentration goes up in their blood the same, but they don't gain weight, they don't become obese, and they don't become hypertensive. So that this hypertension and that left ventricular hypertrophy and all these things that are happening are driven a lot by the conversion of glucose to fructose in the body from the salt. So the salt and sugar work together, and then it's what they're doing to actually drive the blood pressure response and obesity. Now, interestingly, when salt concentrations go up in the blood, so does vasopressin. And vasopressin is a hormone that's produced in the brain that helps to conserve water. And so when you eat salt or if you eat sugar, vasopressin levels go up in the blood, and the vasopressin is released from the brain, goes up in the blood, and it helps hold onto water to try to help you conserve water. But what we recently found is that the vasopressin is also helping the fructose to dry fat. When you eat fructose or you eat salt, the fructose that's produced from the salt stimulates vasopressin. And the vasopressin actually binds to a specific receptor called the V1B receptor. And that actually is important in driving obesity. And if you block that receptor, you can block the effects of sugar to cause obesity, metabolic syndrome, and so forth.

How is that demonstrated?

So we took animals where we knocked out the different vasopressin receptors, and there's a vasopressin receptor called 1B. No one has known what the function of that receptor was. I mean, really, it's been a receptor that's had no real known function. And when we blocked that receptor, we had a remarkable finding. The animals could eat all the sugar they want, or they could eat salt, but they won't get obese because the obesity pathway is driven through that receptor. Exactly how the receptor works, we don't fully know. It stimulates a hormone called ACTH that stimulates cortisol steroids. It also stimulates the islets to produce glucagon, which counters the effects of insulin. And it also works to upregulate the fructose pathways in the liver.

Where is this receptor found? Is it only central?

It's central, but it's also in the adrenal gland and it's also in the islet. In obesity, it seems to be expressed in the liver.

How does this effect compare to the fructokinase knockouts? So if you took the fructokinase knockout mice and compared it to the mouse that has normal fructokinase but just has this receptor blocked and you give them the same amount of, of fructose, glucose, salt, et cetera, which one is more resistant to the obese phenotype?

So the fructokinase knockout tends not to want to eat sugar. They tend to not like fructose. You have to kind of force them to eat the fructose. But even if you force them to eat the fructose, they'll never get fat. The V1B receptor knockout, like fructose, they'll eat as a lot of sugar. The they won't get fat.

How are they disposing of their fructose?

They're totally regulating total caloric intake. So although they eat more fructose, they'll eat less chow. So they maintain their energy balance.

But how do they not turn into skinny fat mice who are lean? Because their overall energy balance is fine, but they still get fatty liver disease and they still get diabetes.

They do not get that. They don't get fatty liver, they don't get insulin resistant, they stay normal.

That's counterintuitive, right? Because you'd think that, remember the energy restricted high fructose animals, they were lean, but they were inside fat. They had visceral fat, they had liver fat, they had hypertension.

So remember that the metabolic syndrome was driven through the energy depletion pathway. The actual caloric pathway is still intact. What we know is that it's down regulating fructokinase. This is probably the key point. The V1B receptor knockout have less, they don't have as much fructokinase. They're turning it off. They're reducing the amount. Normally when you eat sugar, the fructokinase levels get higher and higher. They get turned on by Sugar and the V1B knockout doesn't do that. So the fructokinase stays at a low level. So my guess is that some of the fructose is being metabolized by other enzymes like glucose, glucokinase and stuff. What happens is they eat normal amounts and they stay normal weight and they don't develop metabolic syndrome, but they don't turn up their fructokinase.

Well, Rick, this has been an amazing discussion. We've managed to go a lot deeper into things that I think we already covered in some depth in the first podcast. But I've certainly learned a lot more in the interval of just two years. And I, believe it or not, think we got through many of the questions that people wanted to go deeper into. So again, thank you very much for providing your wisdom as always. And we'll make sure that the show notes are littered with a lot of the references that we spoke about and in fact, some of the things that we didn't know, we'll make sure we track down.

Yes, some of the fact checking. Thank you so much, Peter. It's great seeing you. I hope you can mention the book Nature Wants Us to Be Fat.

I will mention it in the intro, but pulled it up again so we'll talk about that yet. So the book is called Nature Wants Us to Be Fat and by the time this podcast comes out, it will already be on bookshelves. And I think the book, which is the follow up to the Fat Switch, really goes into a lot of the stuff that we talked about today. It goes into this next level of insight around fructose metabolism, uric acid byproduct of that and the sequelae of that. And do you mention also the vasopressin link and stuff in there as well?

Yeah, that's in the book. The one thing that we might want to point out that's a very important finding is that when we studied the fructose survival pathway, we found that the fat produced was not just being used as a caloric source, but it was being used as as a source for water. Because when fat is metabolized, when it's.

Oxidized, it generates a ton of water.

Yeah, it generates water. So Animals in the wild, when they store fat, they're actually storing it not just for calories, but for water. So the hibernating bear will use the fat as a source of water while they're hibernating.

And they must have very high vasopressin when they're hibernating.

Actually, while they're storing fat, vasopressin levels are high. But vasopressin levels pull plummet during hibernation. So that seems to allow them to burn the fat.

Well, that's interesting. Does that mean that a hibernating bear is basically peeing itself constantly?

They are making some urine, but their bladders stay permeable and so they reabsorb some of their urine. But I don't think they're making large amounts of urine. It's probably because of the low metabolism, because they drop their temperature and their body metabolism, so they're generating less urine. But their vasopressin levels typically are turned off during hibernation. And animals in the desert often have fat like in their tails or the camel has a hump because they don't want the fat on their body because that would increase the insulation and increase the body temperature. But they want to use the fat as a source of water. And they live in these environments. They do have very high vasopressin levels. And big breakthrough was to realize that vasopressins not just hold onto water by reducing the excretion, the volume of urine, but it's also holding on to water by stimulating fat. And the way it stimulates fat is through this V1B receptor. We know as this V1B receptor increases cortisol. Of course, high cortisol levels can lead to Cushing's syndrome, where you develop kind of metabolic syndrome. So we think that's part of it. And it also stimulates glucagon, which raises glucose counters some of the effects of insulin, so it creates an insulin resistant state. But also because the fructokinase in the liver seems to go increase in the setting where the V1B receptor is activated. And that may help produce more energy depletion by increasing the enzyme so that it can really metabolize the fructose as fast as it can. So I think that that's the mechanism. And animals that have the V1B receptor knocked out like sugar, they like salt, but they cannot metabolize the fructose very well. They seem to be protected from obesity.

Congrats on the upcoming book and thank you again for all your insights today.

Thank you. Peter, it was great being on your show.

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