Dr. Richard Johnson on fructose and how we store fat

In this episode of A Whole New Level, Dr. Casey Means sat down to talk with Dr. Richard Johnson about his new book "Nature Wants Us to Be Fat"


Article highlights

  • Fructose activates a "survival switch" that tricks the body into thinking it is starving, causing increased hunger, lowered metabolism, insulin resistance and fat storage.
  • High doses of fructose from added sugars drive metabolic syndrome, but small amounts in whole fruits are neutralized by fiber and antioxidants.
  • Glucose can also drive fat storage by being converted to fructose in the body via the polyol pathway when blood sugar is high.
  • Salt intake increases blood osmolality, activating the survival switch and driving fat storage over time.
  • Gentle, zone 2 exercise for 45+ minutes can restore mitochondrial numbers and function, reversing fatigue and metabolic damage from chronic switch activation.

Dr. Richard Johnson was formerly the chief of the Renal Division and Hypertension at the University of Colorado for nine years. He’s a physician that is trained in internal medicine, infectious disease, and nephrology. Along with having an active clinical practice, he is a widely cited NIH-funded scientist who has lectured in over 40 countries and has authored three books, The Sugar Fix, The Fat Switch, and the new Nature Wants Us to Be Fat. Dr. Johnson has a special interest in the role of sugar and especially fructose and its byproduct uric acid in driving metabolic and kidney disorders. Levels chief medical officer and co-founder Dr. Casey Means spoke to Dr. Johnson on a recent episode of A Whole New Level, and we’ve edited the conversation here. Casey and Rick dig into his new book about what really drives the development of fat storage.

Dr. Casey Means: How did you go from being a kidney doctor to having a strong interest in the underpinnings of metabolic disease and obesity?

Dr. Rick Johnson: It’s a great question because kidney disease seems to be quite a long distance from obesity and metabolic syndrome, so I understand where you’re coming from. I wanted to be an anthropologist, actually, or even an archeologist, but my father was in medicine and got me excited about academic medicine. I ended up going to medical school, getting my MD and joining a faculty where I really enjoyed patient care, and I still do. But I really liked research, and I found early on that it was great studying kidney disease, and I was doing all these studies that were translational.

But at some point, I realized I wanted to shift to high blood pressure, which is related to the kidney, and then that took me to metabolic syndrome and obesity. During that process, I started studying how various food items, like sugar and salt, could be involved in this process, and a substance called uric acid. My research really took me out of the kidney. I started doing not just classic lab research, but studies in nature; studies in animals in the wild. I did some evolutionary biology work, and I got interested in multiple areas, multiple ways to try to tackle this problem of what’s causing obesity. In the end, we more or less discovered that there’s a switch that animals use to become fat, and I call it the ‘fat switch’ or the ‘survival switch’, and I think that this is really important in human disease as well.

Dr. Casey Means: Your book focuses on the ‘survival switch’ as a unifying theory of why we are getting fat. So I’d love for you to describe what it is and why it is important to our obesity and metabolic disease epidemic?

Dr. Rick Johnson: First, we probably should just mention how people currently view obesity. A lot of science views it as being a disease of bad habit: that what’s happened is that we suddenly became affluent and have food readily available, and so we’re not controlling our appetite, we’re eating more than we should, and we’re exercising less than we should, and that can lead to obesity. But no one really has talked about a biologic switch that turns on and makes you want to gain weight. Our work really, definitely shows that there is a switch and that we have turned it on, and that this switch causes us to eat more and to exercise less and to actually put on fat. It’s used in the wild as a survival mechanism for many animals, so it actually exists.

Dr. Casey Means: In the book, you talk about the survival switch being used in nature and give many different animal examples. Why this is advantageous for some animals?

Dr. Rick Johnson: Normally, animals regulate their weight very tightly. They like to have a little bit of excess fat, but they really try to keep it at the same weight. In fact, there were studies a long time ago showing that if you took animals or laboratory rats and you fasted them, and then you stopped the fast, they would go right back to the weight they should be. The same thing [happened] if you force-fed an animal to gain weight. When you stopped it, they would go back to their normal weight. This was with standard chow.

Animals do tend to regulate their weight, but a great exception are animals like hibernating animals. What happens is they maintain a completely normal weight during the summer and then suddenly, in the fall, they suddenly start eating more. They will eat not just a little more; they’ll eat twice or more [than] what they normally eat, and they become hungry, they’re foraging for food, and they eat all this food and put on a lot of fat. Then, once they have enough fat and as the fall progresses to early winter, they will actually hibernate, where they will suddenly stop eating, they’ll drop their body temperatures, and they will burn their fat during the winter while they’re in their den and so forth.

Then in the spring, they wake up, and now they’re back to their normal weight or even possibly a little bit below their weight, but they rapidly get back to their regular weight and they repeat the cycle, where suddenly in the fall they trigger this switch and they suddenly start eating lots of food and get quite fat. It’s not just hibernating animals, actually. There are birds that go on long-distance migration. They do the same thing. There’s even a lemur that, during the hot, dry season, will basically hibernate during the summer. [The term is] “estivate.” It’s got a different name, but they do the same thing. They build up all this fat in their tail and then they live off the fat while they’re in their summer hibernation. The question is: what turns on that switch? Also, is it more than just accumulating fat?

Dr. Casey Means: The way I’m hearing it is that it is a survival mechanism—in animals, something biologic happens in them where they actually want to eat more and the body knows to store it as fat so that they can make it through the winter. This is, of course, not the world we’re living in anymore, and we have access to fruit and fructose all the time. Are we essentially getting fat because we are activating the survival switch all the time?

Dr. Rick Johnson: You’re exactly right. One of the things that we learned when we started studying this was that these hibernating animals are not just storing fat in their fat tissues, but they’re putting fat in their liver. They’re getting fatty liver, and they’re getting increased fats in their blood—triglycerides and cholesterol, but especially triglycerides. We know that they become insulin resistant as well. You might say, “Well, why is insulin resistance involved in survival?” But what happens is that when you become resistant to insulin, the insulin is not very effective at helping muscle take up glucose. Glucose is the main sugar in our blood, and it’s used as a primary fuel. The muscles love to use glucose. When you become insulin-resistant, both the liver and the muscle become resistant to the effects of insulin, so there’s less glucose taken up, and glucose goes up in the blood.

Now, the reason that’s a survival benefit is that the animal’s thinking there’s not much food around, and so by reducing the amount of glucose to the muscle and letting it go up in the blood, it helps allow enough glucose to be available for the brain. When you’re starving, you need to have a functioning brain because you have to go out there, find food, and be able to get back to your den safely. You have to be alert, and you have to be thinking. Preserving the energy for the brain is really helpful. The other thing they do is they drop their metabolism, but it’s the resting energy metabolism. While they’re resting, they’re burning less energy. But when they’re actually foraging, they’re able to use energy pretty well. [They] conserve the energy [for] when they need it to look for food, and when they’re resting, they drop their metabolism.

We call this the metabolic syndrome, and everybody thinks the metabolic syndrome is pathologic. It is pathologic—for us. We don’t want it because it’s a major predictor for the development of hypertension and diabetes. In nature, it’s not a pathophysiologic problem, it’s not a disease; it’s a survival tool. Having metabolic syndrome really helps these animals store fat and store the energy they need so that they can survive the winter.

Another thing that we learned from this is that the fat they store isn’t just a source of calories. When they’re fasting or hibernating, they’re burning the fat to produce calories that helps keep them alive through the winter. But when they burn the fat, they also produce water. This is interesting because normally, fat doesn’t really contain water, but when you burn fat, you make water. It’s another source of water. It turns out that a lot of animals have fat so that they can provide a source of water, like the whale. The whale doesn’t drink seawater, so where does it get its freshwater? It gets it from the food it eats, but it also gets it from the fat that it makes. When it makes the fat and the fat breaks down, it gets the water that it needs. It’s the same thing with desert animals, like the camel.

Fat turns out to be a survival tool. It was a good thing for animals in the wild, especially when they’re in situations where food and water are not easily accessible, particularly when winter’s coming or you have to go on a long-distance flight and things like that. This switch gets triggered and then that turns on this whole system to get metabolic syndrome.

Metabolic syndrome only partially explains all the survival responses. There’s also a foraging response, and these animals will start foraging where they will start [going] into areas where they’ve not been before. There’s a little bit of risk-taking. They can’t spend a lot of time in any one place because they have to find food and get it back, so they’re on the move. They have to be active, and they can’t deliberate on things. They have to make quick decisions. Their attention span has to be short, and that helps them with the foraging. It’s an actual behavioral response that these animals do. That’s part of the survival response: foraging.

There are other responses too. Low-grade inflammation occurs and that helps them ward off infections and so forth. There’s also even some evidence that they reduce their oxygen needs. There’s a little animal called the naked mole-rat that will burrow deep into the ground. When it gets in that low-oxygen state, it starts to activate the switch, and that allows it to reduce its oxygen needs.

This switch is a very powerful mechanism of survival. But obviously, if it’s activated chronically and you keep storing fat and you become progressively more and more insulin-resistant, then it’s no longer something that helps you survive. It creates all these diseases, many of which are afflicting our society, like obesity and diabetes and high blood pressure, and fatty liver. All these come directly out of activation of this pathway.

Dr. Casey Means: Can you talk about the pathways that actually lead to this biologic change?

Dr. Rick Johnson: When we realized that there was a switch and that it involved not just storing fat but becoming insulin-resistant, and that it involved even more than metabolic syndrome, the question was: What triggers the switch? We did note early on that many of these animals that hibernate change their diet. In the fall, as you mentioned earlier, you start getting ripe fruits. And bears, for example, will eat thousands of grapes at a time. They do this in the fall, and it’s associated with staying hungry and becoming resistant to a hormone called leptin, which normally controls satiety. When you become resistant to leptin, when you eat, you don’t feel full, so you keep eating. These animals develop leptin resistance and hunger, and it seems to be associated with eating ripe fruit. There are also studies that show that when [birds] switch to a fruit-based diet in the fall, that seems to be associated with the triggering of the switch.

We became interested in fruit. Fruit contains a sugar called fructose, and it’s also known as fruit sugar. Fructose is also present in table sugar, and table sugar is actually sucrose or a disaccharide that consists of one fructose molecule and one glucose molecule bound together. When you eat sugar or high-fructose corn syrup, you’re actually getting a fair amount of fructose. We began by doing experiments where we gave sugar to animals—this was 15 years ago. We found that the switch got turned on. It took about a month to make them leptin resistant.

Initially, when they were eating sugar, they were just eating less of other foods. But after about two to four weeks, suddenly they really lost control of their appetite and they started eating more and more, and they got very fat, they developed insulin resistance, and they developed all these features of the switch. We realized that fructose was somehow doing this. And then the natural question that came out of this was: were they simply getting fat because they were eating too many calories, or could you get fat just by eating the sugar without eating more calories? Because when you were eating the sugar and the fructose, it was making you hungry, so you ate more.

We decided to do studies where we control for how much the animals ate. It’s called pair feeding: basically, you feed a group of animals sugar or starch, for example. Then the next day, you record how much each animal ate. The animal that eats the least, that’s what all the other animals have to eat because you want everyone to eat the same amount. So, now, they’re all eating the same as the guy that eats the least. After several months, because they’re all eating exactly the same amount of food, you can see if it is just from eating too much food that they were getting fat, or not. What we found was pretty profound.

When you fed animals fructose, even if you controlled for their caloric intake, they developed most features of the metabolic syndrome. They would get fatty liver, they would get insulin resistance, they would get high triglycerides in their blood, they would get high blood pressure. They would get all these characteristics of metabolic syndrome, even if they weren’t eating extra calories. But interestingly, weight gain was linked a lot with eating more. They would tend to increase their weight because their metabolism was slower. Over time, I’m sure there would be a difference in weight if you went out months and months, but in a short-term study, like two to four months, you couldn’t really see that great a change in weight. To me, it looks like the weight gain is driven more by increased food intake that’s biologically driven, but the rest of the metabolic syndrome occurs from the sugar, independent of calories.

The question was why—how does fructose work? As you say, what are the cellular mechanisms? Fructose and glucose look pretty similar. They’re six-carbon carbohydrates, they’re simple sugars, they seem to go through pretty similar metabolic pathways. But there is a trick, and the trick is that fructose is different from glucose. When it’s metabolized, the very first enzyme that works on fructose is called fructokinase, or sometimes I call it KHK because its nickname is ketohexokinase. This enzyme drops the energy in the cell. Now, normally when you eat food or any nutrient, you make energy. That’s why we’re eating the food. But when you eat fructose, the energy level actually falls in the cell, not goes up. That’s because of this unique enzyme that uses energy to burn or metabolize fructose. It drops ATP, which is the energy currency in our cells, and it drops the energy in the cell.

Then there’s a series of enzymatic reactions. It’s a series of biochemical reactions in which the ATP that is consumed is further broken down and ends up as uric acid, which accumulates in the cell. When you eat glucose, you don’t generate this uric acid, and you don’t have this energy depletion. But when you eat fructose, there’s this drop in energy and the formation of uric acid. The uric acid actually works on the mitochondria, where we make most of our energy, and slows down the mitochondria further so that they’re making less energy. It initiates glycolysis, which is another type of energy that can be made independent of oxygen. It doesn’t need oxygen, whereas the mitochondria need oxygen.

The energy level falls in the cell and stays low for several hours. When that happens, it’s like a Mayday signal. Normally, [if an animal] didn’t have enough calories to make ATP and its levels fell, that would be like an alarm, and you would want to go out and get food immediately. If you’re a starving animal and your ATP levels fall, you’re going to go foraging for food and you’re going to try to get food to survive. But in this case, we’re faking the system; we’re tricking the host. We’re creating a sensation that we have low energy, even though we have all this fat stored that can provide energy. So, it tricks the body into thinking that it’s starving.

When that happens, it activates foraging, it activates hunger, it activates thirst, it activates all these things. Your blood pressure goes up, you get fatty liver, you start storing fat as a survival mechanism. You become insulin-resistant to protect the brain. This is all supposed to be a good thing, right? Animals use fructose as their main way to activate this system. And it turns out that when you eat glucose, it’s like glucose is like a good fuel that creates satiety, makes you feel full, it keeps the energy levels high, and fructose is the counter molecule. It’s there to actually make you eat more and to activate the switch. They really have major different biologic functions.

Dr. Casey Means: It’s just mind-blowing. [Fructose] is a root cause of so much of the disease we’re seeing in the country right now. Think about an average person in America, going to the movie theater. They get a soda, they get candy. It’s filled with fructose. As they’re downing that liquid fructose, the candy, it is molecular hijacking of a system in our body, that, in these big doses, is just driving us to seek more food, to actually lower the energy in our cells, therefore driving us into a cellular panic mode, to acquire more. And generating this byproduct, uric acid, which is causing mitochondrial dysfunction of the energy makers of our cells, therefore shunting us towards storing energy as fat and driving us to, of course, be craving more and more and more. I mean, it’s amazing, this molecule.

Dr. Rick Johnson: It really is. I love your phrase, molecular hijacking because it’s exactly what’s happening. Nature has evolved in a system where the animals are helping the plants and the plants are helping the animals. When early, immature fruit has very low sugar in it and very high vitamin C, and vitamin C actually counters some of the effects of sugar, and so animals don’t like to eat the fruit early because there’s not much fructose in it.

Dr. Rick Johnson: But as the fruit ripens, then the fructose content goes up and the vitamin C content drops so that the tree has it set so that when the fruit ripens and falls off the tree, that it is ripe, it’s high in fructose, it’s low in vitamin C, it’s going to help the animal get fat, which nature would like because then the animal will eat it because it’s trying to make it through the winter and then it will disperse the seeds, which are now mature. It’s all working out as a system that helps the trees as well as helps the animals. Yeah, it’s an incredible system.

Dr. Casey Means: From my understanding, vitamin C can act as an antioxidant and mitigate some of the mitochondrial oxidative stress that’s happening from uric acid. Can you touch on some of that data about how that can be helpful?

Dr. Rick Johnson: It turns out that vitamin C is an antioxidant that reduces oxidative stress in the mitochondria. It’s true that the way the fructose and uric acid are working, one of the ways is it’s causing oxidative stress in the mitochondria, which over time can destroy mitochondria, but acutely has effects that lead to insulin resistance and fat storage. Also, it depresses mitochondrial function and allows glycolysis to take over, which is a protective system as well because it reduces the oxygen needs of the animal, as we mentioned with the naked mole-rat that can live much longer in the burrow than a rat because it actually produces fructose in its body that allows it to survive.

We realized that vitamin C is a vitamin for us because we lost our ability to make vitamin C way back when. I became interested in why we would lose an antioxidant? We know it’s beneficial, so why would we lose the ability to make an antioxidant? It’s a long story that I talk about in the book, but very briefly, it turns out that that mutation occurred shortly after the dinosaur extinction and this big asteroid hitting the earth. It was a time when there was a lot of extinction and our ancestors, which were just little primates at the time, they were barely surviving. We figured out that the vitamin C mutation occurred at that time and that it might have helped them survive with dwindling fruit supplies.

We did an experiment where we used mice that were vitamin C deficient and we gave them vitamin C, either a low dose or a high dose. The low dose [were] the vitamin C blood levels that you see in people who are overweight, and the high levels of vitamin C gave a healthy vitamin C level in the blood. Then we fed them high-fructose corn syrup, where they got to drink it like a soda drink, and they could drink it all the time. After several months, both groups drank the same amount of sugar, but the group that got the high doses of vitamin C were protected. They got much less obesity.

We were able to show that vitamin C really is a protector from obesity, but also, we found that the vitamin C mutation probably occurred to aid survival. Unfortunately, it increases our risk for obesity today. There’s also a mutation in uric acid metabolism that also was a survival mechanism millions of years ago and we got this mutation, so we are particularly susceptible to sugar. If you give a mouse or rat sugar, you have to give them fairly large doses to get them to become obese. But in humans, you can do it with much lower doses because we’re more sensitive to sugar.

Dr. Casey Means: Basically, we lost that ability to break down the uric acid and so it’s accumulating more in our cells and pushing us towards this mitochondrial dysfunction that ultimately leads to fat storage. That could have actually been advantageous if we needed to store more fat, i.e., in a time like a famine. Similar to vitamin C, losing the ability to make it has downstream effects on the mitochondria. Both essentially allow us to be in this state that stores more fat. Is that the way to look at it?

Dr. Rick Johnson: Yeah. When you eat fructose, you make uric acid, and the uric acid plays a role in this whole process by causing oxidative stress on the mitochondria. Normally, when you eat fructose, you make a certain amount of uric acid. Most animals only make a small amount of uric acid, like when they eat sugar. But normally, when you make the uric acid, it’s degraded by this enzyme, uricase. We had a mutation in the uricase so when we eat sugar, we get a much stronger uric acid response. I worked with this wonderful scientist, Eric Gaucher, who actually resurrected the extinct uricase that primates used to have, but we lost it. And we were able to show that when we put that uricase into liver cells, for example, it would blunt the amount of fat produced from fructose.

When we had the mutation and we lost uricase, we doubled our ability to make fat from the same amount of fruit. It was a great way to survive. The uricase mutation also occurred during the period in time when we almost went extinct. It turns out that we survived a couple of times because of the survival switch, and what happened is we had these mutations that helped keep us from dying of starvation. They weren’t by themselves enough to make us fat. They were really to protect us from dying when food was really sparse.

But then what happened, of course, is we had that advent of sugar where suddenly sugar intake dramatically increased. As you probably know, in 1800, the average intake of sugar was, like, 18 pounds of sugar a year. In 1700, it was four pounds a year. Sugar really wasn’t around back then, except for the wealthy, and the wealthy were the ones that were getting obese. Then around 1900, sugar intake starts going up very significantly, and we’ve seen the emergence of obesity and diabetes and hypertension and all these diseases link with the rise in sugar intake. It looks like sugar is the major player driving the switch.

We did have another discovery, Casey, that was really disappointing, and that was that there are other foods that can activate the switch. While sugar—fructose—is the main one, it turns out that the body can make fructose and it does. It can make it from certain foods, but it can also just make it when you’re in trouble. When you’re under great stress, you can actually make some fructose.

But the number one way to increase fructose production is probably by eating high glycemic carbs. When you eat foods that raise glucose in the blood, that triggers the production of fructose in the body. You don’t have to eat sugar to get into trouble from sugar. High-glycemic carbs, like bread and rice and potatoes, will actually generate fructose in your body. We know from our animals that if we block the metabolism of fructose, we can feed them rice and potatoes and they won’t develop metabolic syndrome. They will gain some weight. I think insulin is driving some of the weight gain, but most of it is coming as a result of the fructose.

I’ve had some nice conversations with Gary Taubes recently, who’s a big believer in the insulin pathway. It is kind of an interesting thing, Casey, that when you become insulin-resistant, the fat cells may actually still be sensitive to some of the insulin. The insulin might be working to increase fat accumulation in the peripheral fat, but that insulin resistance is developing because of the fructose that is made in your body when you eat high-glycemic carbs. This continuous glucose monitor that you have actually is very helpful because not only does it help tell you how much insulin you’re going to stimulate, but it also tells you how much fructose you’re going to make.

Dr. Casey Means: I’m so glad you brought this up. This is a topic that I want to dig into a little bit more because I think this might be the first time anyone listening has ever heard the concept that one of the ways that glucose makes us fat is not just by glucose stimulating insulin, which can block fat oxidation, but that it is actually glucose converting in the body to fructose that actually generates more of the fat storage. This is probably a bomb drop for a lot of people listening, so I think it’d be great to unpack it more. Can you describe the pathway from glucose to fructose, and what’s happening when we have the glucose spike?

Dr. Rick Johnson: There is only one way in humans that you can make fructose, and that’s from glucose through an enzyme pathway called the polyol pathway. It’s actually two enzymes that convert glucose to sorbitol and then sorbitol to fructose. It’s triggered by high glucose levels. When you have high glucose levels, that turns on this enzyme to start making sorbitol from the glucose, and then the sorbitol gets converted to fructose. We’ve known about [the polyol pathway] for a long time because people who are diabetic show evidence for activation of this pathway. That was the trick when we discovered this because we knew that diabetes was associated with the activation of the polyol pathway. When you eat high-glycemic carbs, you’re also getting transient rises in blood glucose, but even more so in the liver. The glucose levels are very high and it turns out that where the switch really is working is in the liver.

We gave glucose to animals and we found that, sure enough, this enzyme got turned on in the liver and it started making fructose, and that fructose was 100% responsible for the fatty liver, 100% responsible for the insulin resistance, and drove much but not all of the obesity. Then, we gave animals high-fructose corn syrup, which consists of fructose and glucose. When we gave that combination, again, we found that insulin is stimulated by glucose, but when we knocked out fructose metabolism, we could really block everything—all the aspects of metabolic syndrome, and even obesity was minimal. When you drink a soft drink and you’re getting the glucose, the glucose is responsible for driving some of the obesity, but it’s not the way we think about it. It’s because the glucose is being converted to fructose.

Dr. Casey Means: You said it’s the fructose that’s causing insulin resistance, and this is different than what a lot of people think about insulin. Can you describe in this paradigm how fructose leads to insulin resistance?

Dr. Rick Johnson: We don’t know the full pathway, but it does involve the Akt mechanism for sure. A number of groups have linked mitochondrial oxidative stress with being critical for the development of insulin resistance. All I can truthfully tell you is that our studies clearly show that fructose drives insulin resistance. It’s linked with uric acid; it’s linked with mitochondrial oxidative stress. That’s pretty much all I can tell you about. But I know that there are many other groups now that are looking at this pathway, and there’s a Dr. Samir Softic who actually has identified several good candidate pathways for this.

Dr. Casey Means: I think people listening might be like, “Oh, my God, I never want to touch fructose again. I can’t eat fruit again.” Which we know is not totally true. What framework should people be using to think about fructose in their own life?

Dr. Rick Johnson: Natural fruits are associated with good health, not bad health. So how is it that animals in the wild can eat fruit to activate the switch and we’re saying that eating fruit may actually help protect you from the switch? It seems like it doesn’t make sense, but the way it works is the following. The first thing is when a bear or these animals in the wild eat fruit, they gorge on fruit and eat as much as they can and as quickly as they can, and they actually can eat enough that it really turns on the switch. When we eat natural fruit, the first thing to know is that a natural fruit only has three or four grams, maybe six grams of fructose. Some have higher, but many fruits are around five or six grams, and that’s a very small amount.

The work done by Josh Rabinowitz showed that the intestine is a shield for small doses of fructose. When you eat three or four grams of fructose, the intestines will actually neutralize it and the fructose will not get to the liver. You really have to eat more than four or five grams before the fructose gets to the liver. If you eat a lot of fruit together, you could get a fructose load to the liver. But if you eat just one or two fruit at a time, the amount of fructose that gets to the liver is blocked a little bit by this intestinal shield.

Another thing that blocks it is fiber, and the fiber in the fruit slows the absorption. It turns out that the liver responds to the concentration of fructose, not the amount. The more you eat, the higher the concentration. If you drink a soft drink with 25 grams of fructose, you’re going to get a huge load, and the concentration’s going to be high. There’s no fiber in that soft drink and you’re just going to absorb it. Boom. But if you eat natural fruit, you’ve got the fiber that slows the absorption, so the concentration is not going to be as high. Also, there’s not as much fructose in fruit. The fruits also contain vitamin C, which we told you can neutralize, and also things like epicatechin and flavanols that actually counter it too.

We actually did a study where we put people on a low fructose diet, and in one group, we supplemented them with natural fruit and found that supplementing with natural fruit was equally effective at lowering weight in these people. In fact, there was even a little bit more weight loss with the natural fruit, and that was given along with the low fructose diet or low sugar diet because the natural fruits obviously contain some fructose.

The reality, though, is that if you drink fruit juice, where you take multiple fruits and you blend it and you create a juice, then you can get a large dose of fructose. It’s definitely linked with obesity in children and the pediatric community recommends limiting fruit juice in children. And likewise, dried fruit, which we love, right? Unfortunately, is really rich in fructose and has lost a lot of its good nutrients in the process of the drying, so I don’t recommend dried fruit either.

One or two natural fruits and maybe even three or even four over a day is probably going to work okay. Now, you have to be careful. As you told me, some fruits, like bananas, can really raise glucose levels significantly. I have documented that as well. I do think we have to be careful with certain fruits, that we don’t overdo it and trigger fructose production and so forth.

Dr. Casey Means: I would love to touch on the concept of salt and osmolality. Can you talk about how salt and blood osmolality can lead to the switch and drive obesity, and comment also on how people should be thinking about salt in their diet?

Dr. Rick Johnson: When we learned that animals use fat as a source of water, it became apparent to me that dehydration might be a stimulus to activate the switch. When you get dehydrated, your osmolarity goes up in your blood. Osmolarity is a fancy term, but what it means is that the salt concentration in the blood goes up and that’s because you’re losing water. When you get dehydrated, you’re losing water from sweating or from exercising or maybe from diarrhea or something, and the salt concentration in your blood goes up and that is another trigger of the polyol pathway, so it will lead to fructose production. We actually found that in animals, if we dehydrate them, they start making fructose.

With mild dehydration, animals will be able to get around and look for food and water. But if you’re severely dehydrated, you’re kind of out for it. A very easy way we can create mild dehydration in animals is to give salt. When you eat salt, the concentration of salt goes up in your blood and it mimics the effect of losing water. When you eat salty food and you get thirsty, it’s because the osmolarity has gone up in your blood and that triggers thirst because your salt concentrations are high and that actually is activating this pathway to make fructose.

We thought, well, geez, everybody views salt as potentially a problem in blood pressure. Certainly, I’ve studied it and I do believe that salt has a role in blood pressure in certain subgroups of people. But then when we started looking at it, we found that there are papers that show that people who eat a lot of salt tend to become overweight over time. It has not been viewed very carefully, but there are quite a few papers. There’s an investigator, Jodi Stookey, who’s done some really beautiful work showing that people who are overweight or obese also tend to be dehydrated and to be eating a lot of salt.

In addition to things like sugar and high-glycemic carbs, it made us realize that salt might be another mechanism to increase fructose production. We gave animals salt over several months, and we found that over time—it took four or five months; it’s a slower process than with sugar—eventually, they became extremely fat and diabetic. The switch was turned on in every way. When we looked inside them, we found that they were making a lot of fructose. When we blocked the fructose, we could block the development of obesity. We realized that high-salt diets are a potential way to trigger the fat switch and cause obesity.

We also went on and discovered that when salt concentrations go up in the blood, it activates a hormone called vasopressin, and vasopressin is a hormone that helps conserve water. We said, well, okay, it conserves water by concentrating the urine, decreases water vapor loss through the lung, we believe. It’s thought to be a hormone that should protect animals from dehydration. We thought, well, what if it also stimulated fat production as another means to protect the animal from dehydration? Because fat will produce water when you break it down.

We noticed that there was literature pointing out that people who are overweight or obese have high vasopressin levels in their blood, and we studied it. We were able to show that vasopressin does have a role in driving how sugar causes obesity, and it’s working through a particular receptor called the vasopressin 1B receptor. People really didn’t know what that receptor was doing. Now we know that it actually is a fat hormone. Vasopressin is a fat hormone. It’s how sugar stimulates fat production and it’s working through and along with this biochemical pathway that we’ve described.

That, of course, gave the idea that we might be able to treat obesity by giving people water. There’s a burgeoning literature that drinking water is healthy and that it can actually have a benefit on weight. When we studied it in our animals, we could largely block the ability of obesity just by increasing water intake in our animals fed sugar. We couldn’t completely block it, but we could really help reduce the development of obesity and diabetes by just increasing water intake.

In my book, I go into how much water we should be drinking. I do want to caution you, you don’t want to be drinking huge amounts of water because you can get water intoxicated, especially if you’re doing heavy exercise, like marathon running or following surgery. Please read my book before hydrating yourself too much. Six to eight glasses of water a day is a very good starting plan if you’re trying to lose weight, and it’s very healthy.

Dr. Casey Means: That’s a great practical tip and really fascinating physiology. I’m excited for everyone to have that one in their back pocket. What about thinking about a healthy level of salt intake per day?

Dr. Rick Johnson: It’s really the balance of salt and water that one eats that governs your salt concentration in your blood, and also how much you’re exercising and whether you’re in conditions where you’re losing water. We did an experiment that I think was really pretty cool. This was done by my collaborator, Mehmet Kanbay, in Turkey. What he decided to do with us was to give salty soup to volunteers. One of the great things about soup is you can mask how much salt is in there because of the flavor of the soup. He made a fairly salty soup that would raise the salt concentration just a little bit in the blood. When he gives this, the vasopressin went up in the blood, which we know is driving obesity, so it’s showing that the switch is being activated. Also, the blood pressure shot up as the immediate response associated with activating the switch.

Then he randomized it. We had three groups, [with] different amounts of water [provided separate from the soup]. As we increased the water with the soup, we could block the vasopressin response and the rise in blood pressure. The way salt raises blood pressure, at least acutely, is not from eating so much salt, it’s by raising the salt concentration in the blood. If you can block that by drinking water at the same time, you can actually neutralize the effect of the salt. In other words, if you go into a bar and you drink water before you eat that salted pretzel, you’re going to be better off, but as soon as you eat enough pretzels that you’re thirsty, you’ve triggered the switch.

Dr. Casey Means: Some of what you talk about in the book is that we ultimately need to get our mitochondria functioning better and keep them healthy and active. Can you leave people with a tip about keeping our mitochondria on track?

Dr. Rick Johnson: Sure. One of the problems is when the switch is activated a long time, it starts to reduce the number of mitochondria we have, and that is associated with progressive fatigue, aging, and all the things we don’t want, and then it makes it harder to lose weight. As we lose the mitochondria, it makes it harder to lose weight. When you activate the switch and you’re young and you haven’t been overweight so long and the mitochondria still are fairly healthy, you can lose weight very easily. But once you’ve been overweight a long time and your mitochondria are down, you can’t really lose weight very easily without doing a trick, and that trick is to bring back your mitochondria. The wonderful thing is animals do it, and we can too.

There are several approaches, but the one that’s probably the best, most effective approach is exercise. But not any exercise—it’s a specific type of exercise where you exercise at what we call zone two. You want to exercise just enough that you can talk, but it’s a little difficult to talk while you’re exercising. That actually gets you right into that zone two range. Some people are on medication that affects heart rates and things like that. It turns out that exercising to heart rate is not as effective as doing it the way that I’m telling you, but walking or cycling or things like that can really make a difference. You have to go a certain amount of time, at least 45 minutes each time, in order to really trigger the growth of the mitochondria. But it’s possible to give yourself back some of your youth by rejuvenating your mitochondria. There are other tricks as well, but I’ll save that for those who want to read the book.

Dr. Casey Means: But this is good news because this is not super intense exercise. This is, like you said, walking, maybe fast-paced walking. That’s great and very doable. One of the things I love about your book is that everything in it is actually pretty doable. The diet is not restrictive, the exercise is fairly gentle. Drinking water. But there’s a molecular basis to all of it and experiments to back every single recommendation up. It’s really a tour de force. One of the things that I also love about the book is, and for anyone who likes spy or Sherlock Holmes-type books, it is truly showing how science is unfolding this mystery, this detective case, and every experiment follows up prior experiments to just show one more layer of the onion.

I honestly think this book is going to make a lot of people want to get PhDs because it shows how fun it can be. The multi-decade journey of unfolding research to get to really actionable insights and the way you present it is astounding and beautiful and just really inspired me. It made me want to go back to the lab, so thank you.

Dr. Rick Johnson: Thank you.