Why Sugar And Fructose Are So Deadly with Dr. Richard Johnson

Coming up on this episode of the Doctor's Pharmacy.

A lot of the obesity is driven by the production of fructose and fructose is actually what's responsible for activating the switch. So it's what makes the fatty liver and the insulin resistance and all this stuff.

Hey everyone, it's Dr. Mark.

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Episode of the Doctor's Pharmacy. Welcome to the Doctor's Pharmacy. I'm Dr. Mark Hyman, and that's Pharmacy with an F, a place for conversations that matter. And if you've ever struggled with weight or wondered about what you should be eating to lose weight and why you can't lose weight, and what something called the fat switch is. You might pay attention to this conversation because it's with a key researcher in this field, someone who has a lot to say about why we are an obese nation and an increasingly obese world. Dr. Richard Johnson, he's a professor at the Medicine at the University of Colorado in Denver and has been a practicing doc and clinical scientist for over 25 years. He's recognized for his seminal work on the role of sugar, which you know I care a lot about and its component fructose. We're gonna talk about fructose because we talk about sugar in a general way, but I think we need to get more specific and Dr. Johnson's work about fructose is so important and it's how it plays a role in obesity and diabetes particularly. And he basically has suggested that fructose has a really fundamental role and particularly in how it affects something called uric acid, which we'll talk about and how it's generated during fructose metabolism in pre-diabetes, what we call metabolic syndrome, which by the way affects about 88% of Americans. that's almost nine out of 10 of us. So you're listening to probably maybe you. Dr. Johnson has been a prolific scientist doing research that's been funded by the NIH since the 1980s. He's a member of the American Society for Clinical Investigation. Over 700 papers, a lot of papers, lectured over 45 countries, and he's a highly cited scientist. He previously authored a book called the Sugar Fix with Timothy S. Gower in 2008 and Fat Switch in 2012. And his new book, Nature Wants Us to Be Fat, is out now. It's an important book and it's really quite a different spin on it. And the full title is Nature Wants Us to Be Fat, the Surprising Science Behind why We Gain Weight and How We Can Prevent It and Reverse It. And you might wanna get that book. So welcome, Dr. Johnson.

Hi, Mark. It's just great to be on your show.

Oh, I'm so glad to have you. Okay, let's get right into it. Now we know that sugar is bad. And certainly anybody paying attention to my work for the last 25 years has heard me talk about sugar till they're probably sick of it. But okay, how is sugar such a threat and why is it so deadly? I mean, tell us in your perspective as a scientist doing the research on this, what makes sugar so bad?

Well, sugar contains glucose and fructose, and these are two different sugars that are bound together to make table sugar or sucrose. And it turns out that fructose can activate a biological switch that tells a person or sets off a program to gain weight. So when you eat sugar, you're actually triggering, you know, this biologic process to gain weight. At the same time, sugar tastes really good. We have these sweet taste buds. that really like sugar and we're eating a ton of sugar and high fructose corn syrup as you know, like 15% of the diet. And then it's being put in all these foods. So, you know, it can be a real menace. And, you know, and what's really interesting about sugar, just as an aside, is that if you take an animal and you genetically alter it so it can't taste sweet or it can't taste at all. It still likes sugar. It loses its flavor or desire for artificial sugars, but it still will seek out foods that are sweet.

Really, that's fascinating.

And they'll still get fat from this sugar, even though they can't taste it.

That's amazing. So, so this fat switch you're talking about is quite interesting. And, and what do you mean when you say fat switch? It literally is there, is there some kind of metabolic switch that gets turned on that makes us store fat and gain weight? How does that work?

Yeah, so this was one of our kind of big discoveries. Everyone knows that obesity is linked with eating a lot of calories, bad foods. And one of the classic theories is that it's driven by the fact that we eat too much and we exercise too little. and so there's excess energy that we end up eating that is not used and that gets stored as fat. And so when this hypothesis came out in the 1920s, it was, you know, we were the ones to blame because it's over nutrition. You know, we're eating too much, we're exercising too little, all the da-da-da-da. But we- It blames the victim.

It blames the victim essentially. It's your fault if you're overweight. It's your fault, so wait.

Exactly, so quit eating, you know, why are you getting such a big plate of food, you know? Don't go back for seconds, you know, it's your fault.

Exactly, exactly.

You're taking the escalator when you should be taking the steps, you know. And so this has been the classic teaching, but it turns out that there are certain foods that trigger you to want to eat more and trigger you to not satisfy your appetite so that when you eat, you don't feel full. So you want more. And there's certain foods that actually will reduce how much energy you have. So it will actually make you drop your energy metabolism. So the formula is the same. You end up eating more and you exercise less, but the issue turns out not to be because it's your choice. It's because you've eaten specific foods that activate the switch.

Yeah.

So your work is sort of very similar to Dr. David Ludwig's work. So the whole idea that it's our fault we're overweight is one that is promoted by the food industry, by the government, by most doctors, and certainly most nutritionists, which is really about this whole idea of the energy balance hypothesis, which is it's all about calories in, calories out. And what you're saying, what I hear you saying, what Dr. David Ludwig who's been on the podcast is saying, is that it's actually the quality of the calories that matter and the information in the food that matters and that not all calories are created equal.

Now, that's 100% right.

We know this kind of, you know, if you ask a fifth grader, if a thousand calories of soda or a thousand calories of broccoli are the same, they would go, no. But if you, and I'm, by the way, Richard, I have asked this question to the vice chairman of Pepsi. I said, okay, who by the way was a diabetic. I said, look, I said, let me ask you this. Is a thousand calories of Pepsi the same as a thousand calories of almonds when you eat them? He's like, yes. I'm like, okay. So, you know, this is a great narrative if you're selling junk because it just all about moderation, right? There's no good or bad calories. It's all about moderation. It's all about exercising more, eating less. What you're saying is that there's a different biological imperative, which is that our bodies are designed to store fat under certain circumstances, which is a great adaptation to scarcity. But we have a problem of abundance. We don't have scarcity anymore. We have on every corner, in every gas station, and pretty much everywhere we look, there's an overabundance of food. And so what is happening with this ancient mechanism? Tell us exactly how it works. When we eat sugar, we slow our metabolism and we actually want to exercise less because we slow metabolism.

It's exactly. So it turns out that that normally animals will try to stay at a certain weight. They don't want to gain a lot of weight. They, and they'll maintain their weight. If they eat more one day, they'll eat less the next. If they exercise more one day, they'll exercise less. So they try to keep their weight normal. But there's some animals that really do want to gain weight. And those animals will gain weight by, you know, like in preparation for hibernation, for example. like when the winter is coming and they know there's not gonna be much food around. So these animals will suddenly, they'll be regulating their weight fine for most of the summer and then sometime in the fall, suddenly they start to eat a lot more. And they will eat thousands and thousands and thousands of more calories. A bear will start gaining 10 pounds a day. And I mean, it's just, it goes crazy. and the animal will stay hungry and thirsty and go foraging for food. And that's actually part of this behavioral response. And then they'll start storing fat and they do it by both synthesizing more fat, but also by breaking down the burning of fat. And so the fat starts to accumulate and they will become insulin resistant. as part of this. And it's actually a survival mechanism because, you know, it keeps the glucose elevated in the blood, which the brain likes because the brain doesn't really need a lot of insulin for it to work, whereas the muscles really do need insulin. So by making the tissues resistant to insulin, the glucose, instead of going to the muscles, is staying in the blood and it's good for the brain. So it helps shunt the glucose from where it would be used in muscle to the brain. So insulin resistance is part of this survival response. Blood pressure goes up, you know, because they want you to have strong circulation in this kind of setting. And so all this happens, and we know it in humans as the metabolic syndrome, but it's actually something that long distance migrating birds do before they migrate. Animals do it before they nest. and it seems to be like triggered. So, you know, our big insight, first one was that there was this trigger that created this. And so, and that- Is that what.

You call the fat switch?

Yes, a biologic switch. You know, I also call it the survival switch when it's for these animals because it's the same thing. Initially it's there to help you survive, but when you're chronically activating it, it becomes a fat switch.

And yeah, you know, so funny. I remember going to Admiral the island, my daughter years ago on a kayak trip in Alaska. It was where they had the greatest density of grizzly bears in the world. And they were, they were fishing for salmon. We were watching them. It was this one little postage area, postage stamp area you could stand on with the guy with a shotgun. And when the grizzly bears were all over and they were just chowing down on the salmon and, and, you know, and then they go up into the mountains and the end of the summer and they just chow down on the berries and they gain 500 pounds. you know, and, and unlike, unlike, unlike the Game of Thrones for us, winter never comes. Winter never comes. So we just keep storing, and then winter never comes, and we just keep in this process. And I think, you know, I think.

The other thing that I sort of.

Happens is that if we eat the wrong food, we're hungrier. And I want to talk to you about this because, you know, I remember the study was, I think Kevin Hall did, where he looked at people who ate Ultra processed food versus Whole Foods and people, and they can eat as much as they want to buy. There are those two groups. or I think it was a crossover study. And they actually found that the people who got to eat the ultra-processed food ate 500 calories more a day. Now, in a week, that's gaining a pound a week. In a year, that's 52 pounds of extra weight simply by eating processed food, which is 60% of our diet. This is the problem, right?

It is a big problem because processed food is often filled with sugar and it's also filled with salt. And I know we're going to talk about that later because it turns out that this fructose pathway can be activated by many different foods. So it's not just the sugar we. So, so, but anyway, so, yes. So what our discovery was, was that this switch is activated by fructose. And when we gave fructose to animals, they, they got the very exact switch. They start foraging, they get hungry, they're thirsty, all the things that we talk about in the biologic switch. and so fructose turned out to be it. One of the big questions we asked was, is the weight gain because they're eating more? Is it this energy balance? Or is there another thing besides? And what we found, the way you do that is you actually feed animals the exact same number of calories. So one group gets sugar, and another group gets other foods that don't have sugar, and everybody eats the same. And if one guy doesn't eat very much, then all the guys can't eat very much. And so we actually did this, we did this study multiple times, but one time we did it, there was a little guy that did not eat much food. And so everybody was eating less than normal. All these laboratory rats were eating about two-thirds what they normally eat, but one of them was eating a high sugar diet and one was not. And the high sugar diet rats, they became diabetic. They all became diabetic. Every one of them. They all developed fatty liver. They had fat in their tissues, their blood pressure was high. So the sugar was activating this switch even though they weren't gaining weight because they were on a caloric restriction.

Now when we looked at weight, metabolically they were fat even though they weren't overweight.

Right. So weight is driven, you know, it is related to energy balance. So, you know, when we measured their metabolism, their resting energy metabolism was lower. So even though they were eating the same amount of food, they were spending less energy. So they tended to be a little higher. They were like 10%, you know, maybe 5% higher in weight.

You just said something really important. I want to highlight it and I want to let you continue because what you said was so important. I just want to underscore it. When you eat sugar, your metabolism slows down. Is that what you just said?

That's correct.

That is mind-blowing, right? If you eat sugar, your metabolism slows down. That should get everybody to pay a lot of attention.

Yes, it absolutely does. But it's your resting energy metabolism, actually. So when you're foraging, nature didn't want you to not be able to forage for food because you're, you know, they're worried that, you know, you're preparing for a bad time ahead. So they want the sugar, you know, the fructose still allows you to forage. It's when you're resting instead of kind of moving around, like I tend to, you know, jiggle at my seat and so forth. But I'm just sitting because I have a lot of energy, right? But, But when you're eating a lot of sugar, your resting energy metabolism falls. So your net energy metabolism drops. And so even though these rats were eating exactly the same amount, one group actually started losing weight, but the other group actually gained a little weight because of that. The sugar group gained a little weight, but it wasn't significant. The bottom line is that the major thing driving weight gain is the number of calories you eat. That's what drives weight gain. And so the energy balance people always focus on the weight. But if you look at what the specific calories are doing, this metabolic switch includes blood pressure, fatty liver, fat, and those things in insulin resistance, they are not driven by excess calories.

So in other words, your blood pressure, your cholesterol, your blood sugar, fatty liver, inflammation, diabetes, prediabetes, all are driven by the quality of the food you're eating, by the quality of the calories. Because in the sense that, you know, we're eating really crappy quality calories, that's what's driving this problem. And it, you know, reminds me of a study that David Ludwig did years ago where he took rats and he fed them, you know, either high fat, low starch sugar diet or a regular kind of high carb diet, which is what we all recommended. In fact, what we were recommending for the diabetics was eating a lot of carbohydrates, which is crazy. Anyway, he found that basically he had to keep reducing he had to keep increasing the caloric intake of the low starch sugar rats, the high fat rats, because they were losing too much weight. And then at the end of the experiment, it's kind of awful, but he opened them up and the ones who, and they were eating exactly the same calories, the ones that were eating the high sugar diet had all this fatty liver and fat around their organs and fat, like all this visceral fat, belly fat. And the other ones didn't, even though they were eating exactly the same calories.

Because they were eating high fat, low starch sugar. Yeah, you are 100% right. And Dave Ludwig, you know, that's, it was a beautiful study.

And he always says, it's not overeating that makes you fat, it's being fat that makes you overeat. That's flipping everything on its upside down.

And that's pretty cool. I hadn't heard that. That's really cool. Well, one of the questions we asked, I mean, which was a question that actually Ludwig, so a lot of people say that the the primary problem with carbs is that they stimulate insulin and then the insulin drives the glucose into the tissues and then that causes the fat accumulation. And that turns out from our research that's partly true, but it's not completely the story. So what we did is we had animals that could metabolize fructose you know, normal animals. But we also had animals that we genetically modified so that they could not metabolize fructose, but they could still, you know, metabolize glucose. They could still produce insulin, all that kind of stuff. And what we did was we gave them, we gave them fructose and we could block the effects of fructose in the animals eating fructose. But then we gave them sugar. We gave them soft drinks, high fructose corn syrup. And so when we gave high fructose corn syrup, that contains both glucose and fructose. So we could see which was the more important player. And what we found was that if we blocked fructose metabolism, they still drank a lot of high fructose corn syrup.

Because.

But they did not get fat. They did not get fatty liver. They did not even gain weight very much. And that they gained a little but very little. And so that told us that it wasn't really the insulin that was causing the obesity, but really it was the fact that the fructose present in the high fructose corn syrup was really what was driving obesity.

Well, this is really a remarkable statement because, you know, we, we. And this was like a, a common belief among nutritionists and doctors was that, you know, fructose was good for diabetics because it doesn't raise blood sugar.

Right, right. Exactly.

And, and, and then the other thing about fructose is that, you know, in sugar, in regular sugar, it's bound tightly with with glucose. In high fructose corn syrup, it's free fructose. And the high fructose corn syrup may be 55 to 75%.

Right.

Fructose. We've never seen this before. Now, the other thing that's so fascinating about fructose, and I want to unpack what and take us down the fructose conversation, how it works to actually generate fatty liver, insulin resistance, obesity, diabetes in a minute. But, but what really struck me years ago is, you know, Dr. Bruce Ames is a Ritcher, very famous guy. I hope he's alive. I don't even know.

Yeah, I think.

I think he's still.

He's, like, really old.

He writes about aging now, but he basically said that they were doing studies looking at fructose requiring a lot of energy to be absorbed.

And.

And the high fructose corn syrup leads to a ATP depletion in the gut, meaning that the energy source that we need to actually keep our our gut intact, preventing leaky gut, was impaired because when you have a lot of fructose in your diet, the energy gets depleted and the little tight junctions that keep our cells together in our gut, the little lining together, preventing leaky gut, starts to break down. So then you get all these proteins from food and bacteria crap actually in your bloodstream causing inflammation, which causes even more insulin resistance and more weight gain. so can talk about that and talk about why, why is high fructose corn syrup so bad? Because if you listen to, you know, the food industry and everybody else, like, oh, it's just the same. It's all the same high fructose corn syrup sugar. There's no difference. And I, I wrote an article years.

Ago called five reasons why high fructose corn syrup will kill you. I remember reading that. No, I actually, it's, I have to compliment you, you know, on your, your knowledge and what you've been doing and how you've been helping people.

Oh, thank you. I really appreciate that.

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Episode of the Doctor's Pharmacy. So we actually did studies where we compared high fructose corn syrup to to sucrose or table sugar and in general, even when you level the playing field by giving high, so high fructose corn syrup is free fructose and free glucose mixed together and sucrose, they're bound together. So one will be absorbed more differently, more rapidly, the high fructose corn syrup. And when we give them so that the high fructose corn syrup is 50% fructose and 50% glucose, and you give exactly the same amount of food that the animals that get high fructose corn syrup will get worse fatty livers. So there's something beyond, you know, it's more than just the fact that there's more fructose, but it's also the problem that it's free fructose. And we also, you know, have done studies. Actually, I was one of the first ones to to show that fructose affects the gut, causes a gut leak syndrome. Oh, I, you know, actually there were people who were doing studies before me, but, but it was one of the early studies and we showed that fructose could disrupt the intestine and cause what's called a leaky gut. And I'll tell you the story.

People used to make fun of me for that. I mean, honestly, Richard, I was in conversation with doctors 20 years ago talking about leaky gut and they just thought I was a nut job.

You were ahead of everybody. You were totally ahead of everybody.

I'm serious about that.

Well, I'll tell you a pretty cool story. It's not, so what happened was I went to a lecture where Steve Dreskin, an allergist, was presenting, was very interested in this why peanut allergies and shrimp allergies are affecting all these children and it's been increasing over years. and so the question is, you know, what's driving this allergy? And he had an animal model where he could create a leaky gut by giving cholera toxin. So this is a really bad toxin, right? And then he would give peanut, a little peanut proteins, you know, what they call them antigens, but they're protein. And so when he gave the peanut protein to this special mouse that had A leaky gut, the mice would anaphylax and have these terrible allergic reactions to peanuts. Wow, So I knew that I had just shown that giving sugar or fruitose could cause this leaky gut. So I went up to him and said, Hey, you know, do you really need to give cholera toxin? Why don't you just put these guys on fruit juice and you know, and.

And fruit juice, which we give all the heck?

Say exactly what we would give to our children, juiceboxes and exactly. so he did that experiment without the choleratoxin or with very minimal amounts of choleratoxin and the animals anaphylaxis. So we actually put in a patent to see if blocking sugar would be a way to prevent food allergies. We ended up not following through with the patent or anything.

Well, I think that's amazing.

That's amazing.

It ties into some other work, which I don't know if you know about, but Dr. Alessio Fasano, who's a world expert on gluten, and celiac disease at Harvard, basically discovered that cholera, and this reminded me of it, cholera actually incites the production of something called zonulin, which is a protein that causes leaky gut. So he actually figured out this whole idea of zonulin. And then he discovered was that gluten also triggers the production of zonulin. which is what Cholera does. And what's happened to our wheat is that we have way more gluten proteins because of the hybridization of wheat. So we've got way more inflammatory gluten proteins, which is why we see a 400 increase in celiac. So you take the dwarf wheat with the sea. I mean, you have to combine that with a fructose. I mean, it's no wonder sugar and flour are driving this metabolic syndrome. And the thing that is going on for most, for most people, is this phenomena we call metabolic. endotoxemia, which essentially means that there are toxins in the gut. I mean, it's poop basically after all. It's crap. And it's actually leaking into your bloodstream and right underneath your gut is all your immune system and it's creating all this inflammation which then just creates this vicious cycle of more insulin resistance because inflammation causes obesity independent of anything else. So it's just like everything perfect totally.

And if you give sugar to an animal or fructose to an animal, you can measure endotoxemia. So that, that's been shown because it's part of that gut leak syndrome.

Wait, wait, wait. So just back up. So you just said that, like, if you drink your can of soda or have your, like, high fructose corn syrup in all the food, it's in everything, by the way. So I think, I think what did, what did Robert Lustig say? There's, like, probably, like, 600, 000 food products on the market, and 80% of them have sugar, high fructose corn syrup, you know, and we didn't even eat, we didn't even have high fructose corn syrup till about 40 years ago.

Right.

And that's when you saw the hockey stick spike in the diabetes and obesity epidemic, right? Right.

That's exactly right.

It's crazy. And so really we're seeing that this elevations in fructose in our diet are causing these problems. So take us through how fructose actually causes a problem. You eat fructose and how does it get all the way down to take us on the scientific pathways that you- Dr.

So it turns out that, you know, almost all basically anytime you eat calories, the calories are then go in and they're used to help produce energy and you produce energy. Energy is called ATP and a lot of it is produced by these energy factories called mitochondria. So when you eat food, you're trying to make energy and that energy is used to help, you know, us do whatever we want. Yeah, there's really, there's really two, maybe three types of energy. Really, there's the immediate energy that we make, which is called ATP, and that's what we're using to, you know, and I'm using to talk to you is on my brain is using ATP, et cetera. If there's excess energy, it can be stored as fat and stored fat is a stored form of energy. And then, you know, the burning of the produced production of energy can also generate heat and heat is kind of a wasted or dissipated energy. but anyway, basically, when you eat food, you're trying to make energy. So. So when we eat fructose, instead of making all the ATP we normally would make, we start. We actually dampen the production of ATP and produce more stored fat. So there. There's the. The mitochondria, which are normally making the ATP. are suppressed. There's a suppression of the mitochondria. And so they make less ATP and so more of the calories that we're eating go into fat. And this is associated with a fallen ATP in the cell. So I call it a fallen energy. It's true, it's not a true fall in total energy because more stored energy is being formed, more fat is being made, as there's less ATP being made. And so it's kind of shunting the calories to fat and reducing the amount of ATP. Now, when that happens, you have a lower ATP in the cell. And so your body reacts to that by saying, hey, I don't have enough energy. I'm going to eat more. I'm thirsty. I'm going to drink more. I'm going to forage for food. You know, this is, it triggers these biologic responses. that what makes you end up eating more and so forth and eventually exercising less.

Right.

And exercising less. Yes.

And, and so the way basically what you're saying is if being overweight and storing the fat makes you eat more and exercise less.

Yes. I guess.

Exactly. What? Exactly what David said.

Yeah. Yeah.

So, so anyway, so what? The way it works is. that when fructose is metabolized, there is this production of uric acid. Ah, okay.

Now we're getting into it.

Yes. And so uric acid is a breakdown product of energy. And what happens is, you know, we always use a little bit of energy to make energy. So, you know, you have to use some energy to absorb the food you eat. you have to use some energy to break down the food we eat. Fructose is like all foods this way, but the enzyme that breaks down fructose breaks it down so rapidly and it uses a little energy in the process that there's a drop in the ATP in the cell to about, you know, goes down 30%. And that's not true for other foods. So this is unique about fructose. Alcohol does it too, by the way, but fructose is really the only only food that really does it. And when that happens and the energy drops, it triggers a reaction. And that reaction of all things tends to remove, you know, ATP gets converted to, you know, AMP and then AMP goes back to ATP. But this, there's a reaction that sweeps away the AMP and makes uric acid from it. And now, now you can't rejuvenate your ATP very well. It's hard to make it because you've removed, you know, it broke down and then you can't repair it so well because you've removed it to make uric acid.

Okay, okay, that's a lot. Okay, hold on, hold on, that's a lot. I was gonna unpack that because people are listening and I'm trying to follow you and this is my thing. So, so just let me unpack it a little bit. Cause so basically saying is you absorb fructose, you eat fructose, by the way, when you eat fructose, it uses extra energy to be absorbed. So that causes an energy deficit. Then you store fat, which actually causes you to actually want to eat more but exercise less. But then it, when you're, when you depleted the energy in the cell, you actually, you actually, you create like AMP, which is basically a, the, the byproduct of actually.

Yeah, well, let me, let me take you through this again.

Okay.

So what happens is when you, when you eat fructose, you burn ATP faster than normal. And so that ATP level drops, and then there's the generation of uric acid from that, when the energy drops, that triggers a reaction to make uric acid.

Got it.

And then the uric acid goes into where the energy factories are, what we call the mitochondria, and causes oxidative stress to those mitochondria. And that's the key. And that suppresses the mitochondria from making the more ATP. So there's an initial consumption and then there's decreased production.

So it's a double whammy.

It's a double whammy. So it lowers the ATP but then doesn't let you bring it back up very quickly. And so everything's kind of suppressed. Now you have a low ATP. and when that oxidative stress occurs to the mitochondria, it blocks the mitochondria from working but opens the pathways to make fat. And it also blocks the burning of fat. So there's this shunting of calories into fat, and now the fat can't get burned. So it starts to accumulate, but your energy is still low. So you've been eating all this food, but your energy is still low, so you keep eating. and you keep eating until it repairs. But what's happened is you've lost your control, your normal month that you would eat. Now you're going to eat more and you're going to be accumulating fat. So it's this brilliant system by reducing the ATP, it reduces, it keeps that ATP level low and no other nutrient does that. It's just fructose. It drops the energy level. and it makes you feel hungry, makes you thirsty, make you want to eat more. But instead of the food making the ATP levels go back up, the energy is going into the fat. So the energy balance is maintained. Energy balance is maintained, but the energy is going into stored energy, which is fat, not in, you know, it's so the energy balance, people, you know, the law of thermodynamics is true and. and, and, but what's happening is your energy levels are low and you're still hungry, so you're going to keep eating. And so this is the trick. But the key here is that, is.

It, you know, thermodynamics. Who can argue with that? It's physics, and I'm not about to overturn the laws of physics and the mind of God. Okay. But the, what people don't realize about the first law of thermodynamics, which is basically all energy is conserved, right?

Right.

It means all energy is conserved in a closed system. So in a vacuum, a thousand calories of broccoli, a thousand calories of soda are exactly the same. They basically release the same amount of energy, which a calorie is the amount of energy required to raise one liter of water, one degree Celsius. That's it. Right? And so you literally would create the same rise in temperature of the water with a thousand calories of broccoli or soda. But when you eat them, there's all these other stuffs happening. Like you're talking about leaky gut and metabolic toxemia and how it it affects your liver and how it affects fat storage and ATP. So it's not a closed system. So the energy balance doesn't quite work in a closed in a, in a, in a, in a metabolic.

Yeah.

So if you give a thousand calories of sugar and a thousand calories of broccoli and you clamp me so that I don't eat anymore because that, if I eat the sugar, I'm going to stay hungry. Okay. I would eat more, but you clamp me so that I don't eat anymore. the fat, the calories from sugar are going to activate, cause oxidative stress to my mitochondria. And I'm going to start making fat from glucose and so forth that I have in my blood already. It's going to start working to make fat from what I have. So even though both groups got 1000 calories, I'm going to start getting fatty liver and I'm going to become insulin resistant and I'm going to get a leaky gut, all that from the sugar, even though they're the exact same number of calories. But if I measure my weight, it's going to reflect that fact that each group got a thousand calories. The only difference is that the sugar also drafts my energy metabolism, so it's going to make me gain a little bit more weight than the other one. because, but is that true? Is that true?

Because, because, like, you know, that David Ludwig study where he took, he did this with rats, then you with humans, where they, they basically gave a, if it was a feeding study where they took insulin resistant patients and they, they kind of created a basic Cal, like equalization in the patients. And then they had basically had them do a crossover trial where they, where they ate a high fat, low carb diet or a high carb, low fat diet. And, and the ones when they were eating the high fat, low carb diet, they burned 400 more calories a day, even eating the same amount of calories. Like they're eating the same amount of calories. So the energy balance thing, I just wonder, how does that work?

Yeah, yeah, yeah.

Explain that.

So on the low carb diet, they're gonna burn more calories, and on a high carb diet, they're gonna burn less calories. so, so if you, even if they're getting the same number of calories, okay, so the, the energy balance equation says that my weight is going to reflect how much I eat and how much I burn. And if we have everyone eat the same amount, but one's a low carb, high fat, the low carb is going to cause more calories to be burned. So the burning it doesn't relate to how much comes in. It relates to what you're eating, right? Yeah. So when you have a high carb diet, you want to eat more and you want to burn less. And if you eat a low carb diet, you're going to want to eat less and burn more. A low carb diet is great. You and I both know this. And so a low carb diet is going to make, you know, is going to create more satiety. You're going to feel more full easily. But let's say, for argument's sake, let's.

Say, okay, I mean, obviously we should be meeting high fructose corn syrup. We should be in junk food, processed food. And most people are aware of that. But let's talk about carbs kind of in the context of this fructose conversation, because, you know, it wasn't that David was feeding these people a high fructose corn syrup diet. They were eating like a high starch diet. which was beans, grains, healthier starches. And yet, you know, when you look at, at the, you know, the data with vegans and meat eaters, it's super confusing. And I, you know, I think people are trying to sort through what makes sense and, and is a vegan diet a healthy diet or not? And how does this relate to this conversation about fructose and insulin resistance and, and.

Well, there is a big story here, which we haven't really talked about. and that is, you know, originally when I was studying this, I was focused on sugar and high fructose corn syrup because they contained fructose. But people pointed out to me that things like bread and starch can also cause obesity. And so how can I account for that if the story is about fructose? And if you look in the wild, there are a lot of animals that will get fat that are not eating fruit or fructose, you know, that, you know, how does the whale get?

Not just eating berries, right? The whales eating a lot of them.

Yeah, they're not eating too many berries, I don't think. So, so the question was, you know, what is that? And we realized that the body can also make fructose. It isn't just about the fructose that you eat, but it's also that the body has one way it can make fructose and it makes fructose from glucose. And so what we did is we did a study where we gave glucose in the drinking water to mice. And lo and behold, they became fat and insulin resistant and diabetic, all the, all these things. And they weren't eating fructose, they were.

Eating starch or pure glucose.

Pure glucose. and so we said, you know, how is, can this be? Is it, maybe it's the glucose insulin pathway. And so what we did is we, we looked in their bodies and we found that when they're eating a lot of glucose, that they were making fructose in their bodies. And so what we did is we gave the glucose to animals that could not break, metabolize fructose. so they're not getting, so these mice are eating glucose, they're making insulin, but they're not able to metabolize fructose. And they were, guess what? They still gained weight, but not as much. It was much less. And they still got a little bit of fat, but not as much as the control animals, even though the control animals were eating the same amount. And, but what that was striking was the fructose resistant or the animals that could not metabolize fructose, they were completely protected from insulin resistance. They were completely protected from fatty liver.

Even if they had a lot of glucose.

Yeah, and they were not eating fructose. They were just, they were making fructose from the glucose. And so, so what we now know is that high glycemic carbs, cause obesity two ways. One way is because when the glucose goes up in the blood after you eat these things like bread, rice, potatoes, you know, makes your glucose go up in the blood and that triggers the production of fructose as well as the secretion of insulin. And the insulin is driving a little bit of the obesity. This is what Dave Ludwig's work has shown.

Yeah.

But, but, but A lot of the obesity is driven by the production of fructose. And fructose is actually what's responsible for activating the switch. So it's what makes the fatty liver and the insulin resistance and all this stuff. And then we said, oh my God, there's another way to get fat from fructose and that's to make fructose.

Wow. So basically you're screwed because if you're eating bread, whatever, you think, oh it's got no fructose, but actually it's starch is basically a lot of glucose molecules stuck together. that in itself can generate through this pathway more fructose in the body, which then causes more fatty liver, more weight gain, and vicious cycle of prediabetes and diabetes.

So now the high fructose corn syrup and the table sugar is a double whammy because they contain fructose, but they also contain glucose. And as you mentioned earlier, if you eat fructose, it's a little hard to absorb it. But if you mix it with glucose, you can absorb the fructose really easily. And the fructose also increases the glucose absorption. So you're getting a double whammy. When you're drinking a soft drink, you're getting the fructose in the soft drink, and then the glucose is coming in and it's stimulating insulin, which isn't so good, but it's also being converted to fructose. And then the fructose causes insulin resistance. and then that makes the insulin levels high all the time, and that helps block the fat from burning too. So now you've got this big story where, and then you realize why low-carb diets are so beneficial, why you can go on a low-carb, high-fat diet and not gain weight because the low-carb is blocking both the starches and the fructose, which are really key for activating the switch.

So, so take us back to the vegan conversation then because, you know, the, the theory is that, you know, if you're a vegan, you'll be healthier, you'll reverse diabetes, you'll lose weight. And yet, you know, I, I don't always see that in my practice. I, I often see vegans struggle with, you know, more insulin resistance and obviously nutritional deficiencies.

So what's your perspective on that? Because I think, well, there, there are different types of vegan diets. Right. And my understanding is that vegan diets, you know, they can eat They can eat bread, right? And they can- yeah, but let's say.

It'S a healthy vegan diet. Let's say you're eating whole grains and whole beans and you're eating lots of vegetables and nuts and seeds. Is that a problem in this scheme of glucose? Because these are, you know, just for people listening, we used to think about carbohydrates as simple and complex, right? Simple as sugar, complex as bread. That is a terrible definition that really has no scientific relevance and it really is about the glycemic index for load of the carbs and how quickly they're absorbed. bread is actually worse than table sugar in this context, just for people to understand.

Well, so it turns out like most vegetables, even if they have a little bit of fructose, usually the, you know, work by one of my collaborators, Josh Rabinowitz, showed that the intestines can inactivate about four or five grams of fructose. So like that's what you see in like a lot of vegetables. So like if you do have you know, a low, low glycemic vegetable and it has a little bit of fructose in it, you, you, you probably it's safe because your, your intestines will inactivate small amounts of fructose and natural fruits, you know, have a lot of fiber and they have a lot of good things. And if you eat a small amount of natural fruit, like if you have one or two fruits, you're probably only getting like seven or eight grams of fructose. and, you know, five of that is going to be inactivated. So you're going to get very, very small amount. And then you get fiber, which slows the absorption and you got and the antioxidants. Yeah, the antioxidants. Vitamin C sort of blocks some of the effects of fructose. So natural fruits are actually fine. And we, we did studies where we did put people on a low fructose diet where we reduce sugar and high fructose corn syrup and then, and fruits. and then one group got back natural fruit supplements and both groups did great. So the natural fruits are, you know, won't affect us, whereas things like fruit juice and so forth, you know, aren't good because then you get a lot of sugar and a lot, a lot of fructose in a short period of time. And, you know, the way the switch works, it's the concentration that the body sees. So if you drink a soft drink rapidly, you're taking a lot of sugar in a short period of time so the liver gets a big wave and the switch is activated. But if you took that same soft drink and you sipped it very slowly over three hours, it would be more like just the calories because you wouldn't get the concentration of fructose to activate the switch.

Yeah, but people are saying don't get any ideas about this. He's not saying just drink your Coca-Cola. coke over three hours? No, don't do that.

Yeah, don't do that. First off, it's almost impossible. Have you ever tried to eat a.

Piece of cake over four hours? No way.

Yeah, right.

But anyway, yeah, you're totally right on that, Mark. So let's talk about this uric acid because I just think it's so interesting. I've been measuring this for years in my patients and you always see people who are insulin resistant, diabetic, overweight, they often have very high uric acid levels as part of this whole phenomena. and I think you're finally explaining why and how it's a byproduct of energy depletion in the cells and the energy depletion is a problem because the mitochondria are so critical to how we feel, to how we age, to our metabol- it is our metabolism. When we say, oh, our metabolism is slow, that's where it's all happening. That's where you metabolize food. It's where you breathe oxygen and eat calories and they get burned. And it is one of the central things that goes wrong with aging. And it's why we see- and I know, Rich, I'm working on a book called Young forever about longevity. And one of the central features of all of the sort of age-related initiatives to sort of extend life and improve health and reverse disease, it's really about optimizing mitochondrial function. And what you're saying here just in a nutshell is that fructose, especially high fructose corn syrup, not just like fruit, but basically junk food, fructose, and sugar, even just regular sugar, drives the pathways that deplete our energy, which is so fascinating to me. And this whole, I just want to say it again, because it's such a, it's such a flip on its head idea. We don't get fat by overeating. We, we basically overeat because we're fat and we exercise less because we're fat. So once you start accumulating a little bit of belly fat, that fat is driving everything. It's driving your metabolism to be slower. It's driving you eat more, it's driving you to exercise less. This is essential problem we're having and it's why 88% of Americans are so overweight and also metabolically unhealthy.

Yeah, I mean, the uric acid that's generated from these foods goes into the energy factories and stuns them, causes oxidative stress and initially that activates the switch. And then what happens is the over time, the repeated oxidative stress, the mitochondria cause the mitochondria to start to function less and less well, even when you're not eating fructose or making fructose. And then what happens is you start making less mitochondria, you have less mitochondria. And at that point, you have chronically low energy, you're aging, and your fatigue mark, you don't have the energy you want. and you're overweight. And now when you lose weight, there's this big push to go right back to that increased weight you've been carrying for a while. And the problem is the mitochondria. They've been damaged. And so you can't, what's wonderful is you can rejuvenate those mitochondria. When we put people on a low fructose diet, we could show an improvement in their mitochondria within one month.

That's amazing.

It's wonderful. And when we block fructose metabolism in a normal animal, we can block aging changes in the kidneys, we can block aging associated hypertension, and even when those animals are not fed fructose, just from blocking the effects of low-grade production of fructose in the body, so it turns out that this pathway is very much linked with aging. And when you go on a caloric restriction, I believe that the way caloric restriction blocks aging is through this pathway. So anyway, so what's, what's, what's cool is that the, that you can rejuvenate those mitochondria and, and the, one of the very, very best ways is by exercise and the, the, the benefit of exercise is not really to burn calories so much as it is to help those mitochondria regenerate. And it really requires exercise in a specific way. You have to like do it like 30 to 60 minutes of what we call zone two exercise. You want to kind of exercise just enough so that you're not really accumulating lactic acid. And so that's to you need to bring your heart rate up as my friend Indigo San Millan says, what you want to do is you want to be able to exercise where you can talk to the person next to you, but it's a little difficult to talk.

Yeah, yeah, yeah. Right. It's called aerobic exercise as opposed to anaerobic. But also sprinting and anaerobic bursts of exercise do seem to stimulate mitochondrial function to improve and recruit new chronic to be made and actually increase overall metabolic rate.

So I think both systems worked. You know, I think that the aerobic one is, you know, is really been proven very well. The other one definitely is good. It's good to mix it up a little bit, but the aerobic one really has been shown, I know, by a number of people, to really help the mitochondria.

So let's make this super practical. One, nobody should ever eat anything with high fructose corns ever, ever, ever, ever, ever again. Like, number one, two, three, never do that. It's like if you, if you get rid of that and trans fat, which the government said is not safe to eat about seven years ago, but I literally went to the grocery store the other day and it's all over the place. So I don't know how that works, but it's like a loophole or something. I don't know. So those two things will save your life. And then second, make sure you exercise. and do both cardio and I think also strength training because that also helps you build muscle, which is where your mitochondria are and more mitochondria. And third, be really conscious of where you're getting your starch. If it's whole grains and beans and whole fruit, it's probably okay. But if it's bread and flour and quickly absorbable starch, probably not so good.

I 100%. The other thing might be to just talk a little bit about salt. I don't know.

Before we do that, I just want to ask you one question you talk about in your book, is the idea of antioxidants. Because what you just said is that uric acid is produced when we eat too much fructose and it's produced in this sort of chemical pathway that depletes our energy and that is compounded by the fact that the uric acid then goes into the mitochondria and poisons them by oxidative stress or rusting or free radicals.

Right.

And so there's a lot of data that's been published that contradicts the notion that antioxidants are good. we thought, oh, well, people should take beta-carotene or vitamin C or vitamin E. And all those studies seem to not show a significant benefit. And yet you say that we should be taking vitamin C to help. And, and I'm wondering, what is the data behind that? And, and how, how do we think about this? Because should we all be taking antioxidants now? Because we, we, we know, we, we know that our body has its own antioxidant systems like catalase, superoxide dismutase and so forth. Glutathione peroxidase. These are our body's own antioxidants, which actually are more powerful than anything you can take, I think. But, but the, you're do, you do say to try vitamin C. So tell us about the D and the vitamin C. Yeah.

Not all antioxidants are equal. And some antioxidants, like vitamin E, really have not panned out. In fact, can be sometimes associated with complications where they, and part of it is where the accident gets to, does it get to the site where where it's really important. And our work really suggests that oxidative stress to the mitochondria really is where the action is. And that's where you want your antioxidants to get. And vitamin C does get there. And so it turns out that we are all vitamin C deficient and we lost the ability to make vitamin C a long, long time ago. right around the time of the dinosaur extinction.

Us and the guinea pigs, right?

Yeah, us and the guinea pigs. That's right. But it turns out that some early primates were living at the time of the great asteroid impact and those primates appeared to have acquired vitamin C mutation right around that time. And we think that there was a benefit to that. And it turns out that when you, vitamin C can naturally block the oxidative stress to some extent in the mitochondria. And so we were thinking that when the vitamin C mutation occurred, that these poor primates probably didn't have a lot of access to fruit because of the terrible Holocaust-like, the impact winter and the dust that went into the air. a lot of life became extinct. And so we wanted to test that. And we were thinking to ourselves, well, maybe what happened is the, when you lost the vitamin C to ability to make it, then when you ate fruit, that you could generate more oxidative stress to the mitochondria, and that would lead to more fat production for the same amount of fructose. And so what we did is we took mice that do not, we, a special type of mouse that does not make vitamin C. And of course, these mice, when they're, have no vitamin C, they will, they will develop scurvy. So you have to give them a small amount of vitamin C so they don't get, you know, sick.

Scurvy.

Right.

Right. So what we had is we had these mice on either low doses of vitamin C. and so that they had vitamin C levels close to what people who are overweight tend to have. And then we gave them a higher dose of vitamin C, which correlates better with the kinds of blood levels that lean people tend to have.

Yeah.

Yeah. And, and then we gave them high fructose corn syrup, and both groups drank the same amount. But the group that had the low vitamin C levels got a lot fatter than the control We haven't published that paper yet, but that study was very strong and it tells us that vitamin C actually can block some of the effects of fruit dose.

So what would be the dose for a human?

500 milligrams.

That's a lot.

Yeah, so it turns out- so maybe.

Linus Pauling wasn't crazy.

No, he wasn't crazy at all.

I mean, he won two Nobel Prizes. It was pretty smart guy. you probably new stuff.

Yeah, I would back him up. Yeah, no, he's, he was an amazing person. But, you know, it's possible that higher doses might be more beneficial, but there's two problems with high doses. One is it can increase the formation of kidney stones, and we don't want that. And then the second problem is there's some controversial, but data in the literature that high doses of vitamin C can block the effects of exercise to stimulate mitochondria growth. So, oh, wow. And we, and we don't want to block that. So the data that, where there's a little bit of evidence that it might is with high doses greater than a gram a day. So in my book, I recommend 500 milligrams because I know that's a safe dose, and I know that it will provide some benefit.

Yeah.

Okay. Well, this is so fascinating. So basically, just to summarize quickly, fructose is bad for you. Don't eat high fructose corn syrup. Make sure you exercise and take 500 milligrams of vitamin C. That's really clear. And, and, and I think this, this, your book, Nature Wants to Be Fat really unpacks all this in great detail for people who wanna know. I just wanna close with this conversation about salt because there's a connection between salt and. blood osmolality, which is the concentration of your blood and the fat switch and obesity. And, like, there's so much controversy about salt. Some people say, oh, it's not as bad as we thought, or it is bad. Oh, don't worry about it.

So can you talk about it? Because I think there's a lot of confusion about it. So I spent a lot of my career studying salt, and it looks like a lot of people, you know, in the early part of my career, I became convinced that some people have trouble with salt. where they have trouble excreting it. And when they have that trouble excreting it, it can increase their risk for hypertension. And we actually did all kinds of studies to try to figure out how that happens.

And.

So that's its own story in a sense. But so I do believe that salt is important. If you have high blood pressure, and particularly if you're like over age 50, salt is associated with hypertension. and some people get hypertension.

And there's genes that make you more likely to have hypertension from eating salt. So it's not everybody.

Right, right. It's not everybody. But then when we discovered that the body can make fructose, we realized that eating salty food might also trigger the production of fructose. And that's because when you increase salt concentration in the blood from eating salt, that triggers that same polyol pathway, this enzyme pathway that can convert glucose to fructose. And that's, you know, like, so when you eat french fries with, you know, that are very salty.

Oh, that's terrible then, right?

Or salted pretzels. The salt.

Don't tell me french fries are bad for you.

So it turns out that the salt turns on the enzyme to convert the glucose to fructose. So if you're on a low carb diet and you're not eating a lot of glucose, Salt's not going to do it. But if you're in the regular world eating lots of carbs, salty food may actually enhance the production of fructose. And so we actually did studies where we gave salt to animals and initially they didn't gain weight, but after several months they became hugely fat and obese. And we could show that it was due to the fructose. And then we went and looked at people. who are overweight and obese. And we found that, that the vast majority of people who are overweight are eating a lot of salt. And not only that, when you look at their, their blood tests, they have about a two and a half to 12 times more likely to be dehydrated. And when you eat salt and you get thirsty, you're actually creating dehydration. And so, and they, and so, like, when we went on and studied it more, and it turns out that salty foods stimulate fructose, which create fat. And then we had a big insight that the fat is actually nature's way of storing water. Because when fat, when you burn fat, you not only burn, you not only make calories, which, you know, bears like when they're hibernating, but you produce water. And when an animal hibernates or it migrates long distance, it gets its water from burning the fat. And when you're out in the desert, you need to have some fat to make water. So the camel is chronically a little bit dehydrated and he makes fat so that when he gets really dehydrated, he can break it down and get the water. The whale is one of the fattest animals in the world and it doesn't drink seawater, so it gets about one-third of its water from its fat. so it turns out that this survival pathway is also driven by very, very mild dehydration. And that mild dehydration stimulates the production of fat as another way to help it survive. And salty foods and the reason deer like salt licks and things like that may be to stimulate the conversion of this grass and stuff.

That's funny.

So that they can get more calories, they can get more fat from it by stimulating this enzyme that converts glucose to fructose.

So it's kind of a double whammy. When you eat salt, you actually retain, you know, more concentrated blood, right?

Yeah, exactly.

And, and that makes you thirsty and makes you turn on this fat switch and makes you gain weight. But it's interesting when you have, look at the other side of it, insulin actually causes you to store more fluid and actually salt. So when you, when you stop eating sugar and starch, people dump a lot of fluid. They just pee a lot of fluid because they're dumping all this fluid because the insulin levels go down.

Yeah.

When you're, if you go on a low carb diet and the insulin levels fall, what happens is you first you burn all the glycogen in your body and the glycogen also holds a lot of water. So when you burn it, you get this very rapid increase in urine output, which is the water being released from the glycogen. then when you're burning fat, you will also release some water when you're burning fat. But it's glycogen actually has the most water. So you, you know, so when we store energy, we store some of the energy as starch or what we call glycogen. And some of the energy stored is, most of the energy stored is fat. When we, when we fast or go on a low carb diet, you first burn off the glycogen. and then you burn the fat. So there is this initial water and it's all coming from the fat and the glycogen. So anyway, so if we, we did a study where we gave salty soup to animals, I mean, excuse me, to people. We gave salty soup and we could show that it activated their biologic switch just from drinking the soup. Their blood pressure went up immediately along with the salt concentration. But if we gave them water, with the soup, we could block that switch activation. So, if we could keep this serum salt concentration, drink a lot of water, basically.

Yeah.

And actually drink the water before you eat. That's fascinating. I have a friend who's obsessed with.

Drinking water and she's drinking so much water and she lost all this weight. I was like, wow, this is really cool. So, Richard, your work is so important. You published 700 scientific papers. We're just scratching the surface. everybody should get the book Nature Wants Us to Be Fat, basically about how to fix it and turn off the fat switch. Thank you so much for what you do. It's such a light in the world. If anybody is listening to this podcast and they love what they heard, share with your friends and family. If you know anybody who's overweight, I'm probably you don't because who's overweight, right? Make sure you share with them. How have you struggled with your weight? What have you found works? Let's let us know about it. Leave a comment. Subscribe wherever you get your podcasts. And we'll see you next time on the Doctor's Pharmacy. And thank you so much for being.

With us today, Dr. Johnson. Thank you so much, Mark. It was just a pleasure.

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Hi everyone. I hope you enjoyed this week's episode. Just a reminder that this podcast is for educational purposes only. This podcast is not a substitute for professional care by a doctor or other qualified medical professional. This podcast is provided on the understanding that it does not constitute medical or other professional advice or services. If you're looking for help in your journey, seek out a qualified medical practitioner. If you're looking for a functional medicine practitioner, you can visit ifm.org and search their find a practitioner database. It's important that you have someone in your corner who's trained, who's a licensed.

Healthcare practitioner, and can help you make changes, especially when it comes to your health. Don't forget, there's a way to listen completely ad free with Hyman Plus on Apple Podcasts. You can enjoy every episode without any breaks. Just open Apple Podcasts and tap try free to start your seven day Day free trial.