#229 – Nature Wants Us to Be Fat | Dr. Casey Means & Dr. Richard Johnson – (Replay)

A lot of what we think about obesity is wrong. It’s not caused by bad habits. Studies have shown that it’s actually caused by a survival switch that all animals have. In the short term, this switch can protect us, but in the case of modern life, it instead leads to obesity, diabetes, and other chronic diseases. In this episode, Dr. Casey Means, Chief Medical Officer of Levels, speaks with Dr. Richard Johnson about his new book, “Nature Wants Us to Be Fat.” They discuss his insights on the “survival switch” and what triggers it.

04:25 – The fat switch

Obesity is not caused by laziness or bad choices. It is caused by a biological switch that exists in humans and other animals.

A lot of science views it as being a disease of bad habit. What’s happened is we suddenly became affluent and have food readily available. And so we’re not controlling our appetite and 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 when it turns on makes you want to gain weight. But 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. And it’s used in the wild as a survival mechanism for many animals. And so it actually exists.

11:39 – Metabolic syndrome is linked to survival Hibernating animals develop metabolic syndrome where they become insulin resistant, increase glucose, and store fat in order to survive the winter.

We call this the metabolic syndrome and everybody thinks the metabolic syndrome is pathologic. It is sort of pathologic for us. We don’t want it because it’s a major predictor for the development of hypertension and diabetes. And obviously we don’t want it, but it’s in nature. It’s not a pathophysiologic problem, it’s not a disease. It’s a survival tool. And 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. So when they’re fasting or when they’re hibernating, they’re burning the fat to produce calories that helps keep them going, keep them alive through the winter. When they burn the fat, they also produce water. Well, this is sort of interesting because normally fat doesn’t really contain water, but when you burn fat, you make water. And so it’s another source of water and it turns out that a lot of animals have fat so that they can provide a source of water, like the whale.

13:36 – The switch is good for short term survival, bad for long term

This switch turns on short attention span, low-grade inflammation, and reduced oxygen needs that help with survival, but all these things lead to bad health outcomes if they’re chronically activated.

There’s also a foraging response and these animals will start foraging where they have to go into areas where they’ve not been before. So the there’s a little bit of risk-taking and 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. So their attention span has to be short. And that helps them with the foraging. So it’s an actual behavioral response that these animals do. And that’s part of this survival response, foraging. And there are other responses too, the 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. And when it gets in that low oxygen state, it starts to activate the switch and that allows it to reduce its oxygen need 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, high blood pressure, fatty liver.

17:40 – Sugar triggers the switch

Studies have shown that this switch has a clear trigger: fructose.

We noticed this with birds, there’s studies that show that when they switch to a fruit-based diet in the fall, that that seems to be associated with the triggering of the switch. So we became interested in fruit and fruit contains a sugar called fructose. And it’s also known as fruit sugar and 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. And so 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 and we found that rapidly this switch got turned on and suddenly it took like about a month to make them leptin resistant.

19:39 – Sugar leads to metabolic syndrome, not extra calories

One of Dr. Johnson’s studies found that even with a controlled calorie intake, increased fructose would lead to the development of metabolic syndrome.

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. So they would tend to increase their weight because their metabolism was slower. And so 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 months or three months, or even four months, you couldn’t really see that greater change in weight. So 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.

23:40 – Fructose depletes energy

Fructose causes cellular energy to fall, which then tricks the body into thinking it’s starving and needs to forage for food. That leads to a cascade of activations.

What happens is the energy level falls in the cell and stays low for several hours. And when that happens, it’s like a Mayday signal. So normally an animal if it had low energy in its cells, it 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. So 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 a low energy even though you have all this fat stored that can provide energy. So it tricks the body into thinking that it’s starving. And when that happens, it activates foraging, it activates hunger, it activates thirst, it activates all these things.

31:28 – Vitamin C is protective against obesity

Because of a long ago mutations, higher levels of vitamin C can help to prevent fructose-activated obesity.

So the low dose is sort of the kind of vitamin C blood levels that you see in people who are overweight. And the high levels of vitamin C that we gave was to give kind of a healthy vitamin C level in the blood. And 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. And 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. So 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. And unfortunately, it increases our risk for obesity today.

35:12 – High glycemic foods help our bodies make fructose

Our bodies can produce fructose and you don’t have to eat sugar to cause it. Foods like rice, bread, and potatoes will increase its production.

It turns out that the body can make fructose and it does, and 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. And what your company does, which is to measure the glucose levels in the blood, because when you eat foods that raise glucose in the blood, that triggers the production of fructose in the body. So you don’t have to eat sugar to get into trouble from sugar. You just have to eat high glycemic carbs like bread, and rice, and potatoes, will actually generate fructose in your body. And 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 and I think insulin is driving some of the weight gain, but most of it is coming as a result of the fructose.

44:29 – Whole fruit is healthy because of the fiber

Whole fruit contains fructose, but it’s still good for you to eat one or two fruits at a time. Pure fruit juice or soda without the fiber is what will get you in trouble.

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. So if you eat 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. And it turns out that the liver responds to the concentration of fructose, not the amount. So the more you eat, the higher the concentration. So the more you eat, and if you drink a soft drink with 25 grams of fructose, you’re going to get a huge load. The concentration’s going to be high, and there’s no fiber in that soft drink, and you’re just going to absorb it. Boom.

53:48 – Salt can trigger fructose production

Because salt causes mild dehydration, which mimics that hibernating state, it is another activating trigger for fructose production and weight gain.

The way we can create mild dehydration in animals, a very easy way, is to give salt. And when you eat salt, the concentration of salt goes up in your blood and it mimics like the effect of losing water. And so when you eat salty food and you get thirsty, it’s because the osmolarity has gone up in your blood that triggers thirst because your salt concentrations are high. And that actually is activating this pathway to make fructose. So we started thinking about this. We thought, well geez, everybody views salt as potentially a problem in blood pressure. And certainly I’ve studied it and I do believe that salt has a role in blood pressure in certain groups, 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.

Dr. Richard Johnson (00:00:06):

Suddenly, they really lost control of their appetite and they started eating more and more and they got very fat and they developed insulin resistance and they developed all these features, the switch. So we realized that fructose was somehow doing this.

Speaker 2 (00:00:32):

Here at Levels, we’re building tech that helps people to understand their metabolic health. And this is your front row seat to everything we do. This is a whole new level.

Dr. Casey Means (00:00:44):

Hi everyone, this is Dr. Casey Means, and I am so excited to introduce Dr. Richard Johnson to the podcast today. 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 upcoming, Nature Wants Us To Be Fat. Dr. Johnson has a special interest in the potential role of sugar and especially fructose and it’s byproduct uric acid in driving metabolic and kidney disorders. Today, we are going to dig into his new book about what really drives the development of storage, which is relevant to the vast majority of people living in the Western world, given our monumental rates of overweight and obesity, which are now topping 72% of adults. Welcome to A Whole New Level, Dr. Johnson.

Dr. Richard Johnson (00:01:56):

Thank you, Casey. It’s really a delight being here.

Dr. Casey Means (00:02:05):

So you have an incredible professional background. How did your path unfold from leading you from being a kidney doctor to really this strong interest in the underpinnings of metabolic disease and obesity?

Dr. Richard Johnson (00:02:17):

Well, 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, even an archeologist, but my father was in medicine and got me excited about academic medicine and 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 the metabolic syndrome and obesity. And during that process, I started studying how various food items like sugar and salt could be involved in this process.

Dr. Richard Johnson (00:03:15):

And also substance called uric acid. My research really took me out of the kidney and then I also, 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 pretty much multiple areas, multiple ways to try to tackle this problem of what’s causing obesity. And 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 (00:04:00):

Amazing. And really the book focuses on this term, this survival switch that you’re introducing and which is really mind blowing as a unifying theory of why we are getting fat. So I’d love for you to describe to everyone listening, what is the switch and why is it important to our obesity and metabolic disease epidemic?

Dr. Richard Johnson (00:04:25):

Sure. First, we probably should just mention how people currently view obesity. A lot of science views it as being a disease of bad habit. What’s happened is we suddenly became affluent and have food read available, and so we’re not controlling our appetite and 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 when it turns on makes you want to gain weight. But 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. And it’s used in the wild as a survival mechanism for many animals. And so it actually exists.

Dr. Casey Means (00:05:24):

What is so neat about the book is that the beginning really talks about how this survival switch is used in nature and many different animal examples. And so I think some of those, especially the examples around hibernating animals are a really helpful way for people to understand why this is advantageous for some animals and when resource horses are scarce and maybe only present at certain parts of the year, but in our culture of abundant access to food, we can sometimes hijack these pathways that are advantageous in nature. So could you describe a little bit about what’s going on in the animal world and maybe historically for the human world and how things are different now?

Dr. Richard Johnson (00:06:03):

Sure. So normally animals regulate their weight very tightly and 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 long time ago, 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. And the same thing is if you forced fed an animal to gain weight, when you stopped it, they would go back to their normal weight. This was with standard chow and stuff. So animals do tend to regulate their weight, but a great exception are animals like hibernating animals. And what happens is they maintain a completely normal weight during the summer. And then suddenly they turn on in the fall, they suddenly start eating more and they will eat not just a little more they’ll eat twice or more, what they normally eat and they become hungry and they’re foraging for food and they eat all this food and they put on a lot of fat.

Dr. Richard Johnson (00:07:11):

And then once they have enough fat as the fall progresses to early winter, they will actually hibernate eight 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. And 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 the switch and they suddenly start eating lots of food and get quite fat. It’s not just hibernating animals actually. I mean, there’s birds that go on long distance migration. They do the same thing. There’s many examples in the animal kingdom happens. There’s even a primate, a lemur, the dwarf fat tailed lemur that… Wait, wait [crosstalk 00:08:07].

Dr. Casey Means (00:08:06):

Did that five times fast.

Dr. Richard Johnson (00:08:07):

Fat tailed dwarf Lemur. But anyway, there is a lemur that during the hot dry season, they will basically hibernate during the summer. It’s called the estimate. It’s got to different name, but they do the same thing. They build up all this fat in their tail, then they live off the fat while they’re in their summer hibernation. So the question is what turns on that switch and also is it more than just accumulating fat? And so, one of the things we were very interested in was trying better understand the nature of the switch.

Dr. Casey Means (00:08:44):

The way I’m hearing it. And the way I understand it from the book is that it is a survival mechanism because in the winter we don’t have… I’m saying we, as if we’re the hibernating bear here, but we might not have access to all of these abundant calories. It’s harder to find and forage food, or maybe find animals. And so in the fall, when there’s all this ripe fruit around the animals, something biologic happens in them where they actually want to eat more of it. And the body knows to store it as fat, so that or survival purposes, they can make it through the winter. And this is, of course not the world we’re living in anymore, where now we have access to ripe fruit and fructose and other things all the time. So is that sort of getting at why we are essentially getting fat because we are activating this survival switch really all the time?

Dr. Richard Johnson (00:09:40):

You’re exactly right. And one of the things that we learned when we started studying this was that these hibernating animals are not just storing fat and they’re fat tissues, but they’re putting fat in their liver. They’re getting fatty liver. They’re getting increased fat in their blood, triglycerides and cholesterol, but especially triglycerides. We know that they become insulin resistant as well. And with that, 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 and glucose is the main sugar in our blood and it’s used as a primary fuel and the muscles love to use glucose. And when you become insulin resistant, both the liver and the muscle becomes resistant to the effects of insulin.

Dr. Richard Johnson (00:10:44):

And so there’s less glucose taken up, and so glucose goes up in the blood. Now, the reason that’s a survival benefit is that the animal is thinking there’s not much food around. And so by reducing the mono of glucose to the muscle and letting it go up in the blood, it helps allow enough glucose to be available for the brain. And when you’re starving, you need to have a functioning brain because you have to go out there and find food and be able to get back to your den safely. So you have to be alert and you have to be thinking. And so 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. So while they’re resting, they’re burning less energy, but when they’re actually forging, they’re able to use energy pretty well.

Dr. Richard Johnson (00:11:39):

So this conserves the energy. So when they need it, which is to look for food and when they’re resting, they kind of drop their metabolism. So all these are features that we know. We call this the metabolic syndrome and everybody thinks the metabolic syndrome is pathologic. It is sort of pathologic for us. We don’t want it because it’s a major predictor for the development of hypertension and diabetes. And obviously we don’t want it, but it’s in nature. It’s not a pathophysiologic problem, it’s not a disease. It’s a survival tool. And 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. So when they’re fasting or when they’re hibernating, they’re burning the fat to produce calories that helps keep them going, keep them alive through the winter.

Dr. Richard Johnson (00:12:46):

When they burn the fat, they also produce water. Well, this is sort of interesting because normally fat doesn’t really contain water, but when you burn fat, you make water. And so it’s another source of water and 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 sea water. And so where does it get its fresh water? It gets it from the food it eats, but it also gets it from the fat that it makes. So when it makes the fat and the fat breaks down, it gets water that it needs. Same thing with desert animals, like the camel and so forth. So fat turns out to be a survival tool. It is a good thing for animals in the wild, especially when they’re in situations where food are not easily accessible.

Dr. Richard Johnson (00:13:36):

And then that’s particularly like when winters coming or when you have to go on a long distance flight and things like that. And they seem to trigger this and this switch gets triggered. And then that turns on this whole system to get the metabolic syndrome. And as well as other features, it turns out the metabolic syndrome only partially explains all the survival responses. So there’s also a foraging response and these animals will start foraging where they will start looking. They have to go into areas where they’ve not been before, so the there’s a little bit of risk taking and 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.

Dr. Richard Johnson (00:14:29):

So their attention span has to be short. And with that helps them with the foraging. So it’s an actual behavioral response that these animals do. And that’s part of this survival response foraging. And there are other responses too, the 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. And when it gets in that low oxygen state, it starts to activate the switch and that allows it to reduce its oxygen need 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, fatty liver. All these come directly out of activation of this pathway.

Dr. Casey Means (00:15:45):

When this switch is activated, we are biologically cellularly, more are prone to storing fat. There’s really a molecular different pathway that’s happening, which is fascinating. And I think a lot of our listeners, they love the science, they love the mechanism. And so I’d love to talk about what is that pathway in the cells that is shifting to make it such that we are actually shifting towards more fat storage. Just going into maybe a little bit about what are the triggers environmentally that lead to the switch, particularly something like fructose? And then what are the downstream sort of [crosstalk 00:16:22].

Dr. Richard Johnson (00:16:22):

How does it work.

Dr. Casey Means (00:16:23):

… Of that fructose process that actually lead to this biologic change? I also want to touch on at some point that you talked about more, the psychological component. We’re hungry rear. We are searching for food more, which is a whole nother set of downstream ramifications. But maybe we can start with just the cellular fat storage pathways.

Dr. Richard Johnson (00:16:41):

Yeah. So, 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 the metabolic syndrome, the question was, what is the trigger? 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 will, for example, eat thousands of grapes at a time. And they do this in the fall and it’s associated with staying hungry and becoming resistant to a hormone called lectin, which normally controls satiety. So when you become resistant to lectin, when you eat, you don’t feel full. So you keep eating. And so these animals develop lectin resistance and they develop hunger and it seems to be associated with eating ripe fruit.

Dr. Richard Johnson (00:17:40):

And also we notice this with birds, there’s studies that show that when they switch to a fruit based diet in the fall, that that’s seems to be associated with the triggering of the switch. So we became interested in fruit and fruit contains a sugar called fruit dose. And it’s also known as fructose sugar and fructose is also present and table sugar. And table sugar is actually sucrose or a disaccharide that consists of one, fructose molecule and one glucose molecule bound together. And so 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 and we found that rapidly this switch got turned on and suddenly it took like about a month to make them leptin resistance.

Dr. Richard Johnson (00:18:39):

So 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 started eating more and more, and they got very fat and they developed insulin resistance and they developed all these features of the switch. So, 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 even 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. So we decided to do studies where we control for how much the animals ate. So it’s called pair feeding. But basically what it is, you feed a group of animals sugar, right? Or starch, for example.

Dr. Richard Johnson (00:19:39):

And then the next day you go and you record how much each animal ate. And 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. And then after several months, you can determine because they’re all eating all their food and they’re all eating exactly the same amount of food. And then you could see if sugar did something more than just was it from eating too much food that they were getting fat or not? And 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.

Dr. Richard Johnson (00:20:33):

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. So they would tend to increase their weight because their metabolism was slower. And so 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 months or three months, or even four months, you couldn’t really see that greater change in weight. So 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. So then the question was, why? How does fructose work? And as you say, what are the cellular mechanisms, and fructose and glucose look pretty similar.

Dr. Richard Johnson (00:21:33):

They’re like six carbohydrates, they’re simple sugars. They seem to go through pretty similar metabolic pathways, but there is a trick. And the trick is that the fructose is different from glucose. And when it’s metabolized, the very first enzyme that works on fructose is called fructokinase, sometimes I call it KHK because it’s nickname is ketohexokinase. Anyway, this enzyme drops the energy in the cell. Now, normally when you eat food or any nutrient, you make energy, right? 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. And that’s because of this unique enzyme that uses energy to burn or to metabolize the fructose. And so it drops ATP, which is the energy currency in our cells. And it drops the energy in the cell.

Dr. Richard Johnson (00:22:37):

And then there’s a series of enzymatic reactions. It’s all biochemistry. I don’t know if you want me to go into it, but I’m happy to. But anyway, it’s a series of biochemical actions in which the ATP that is consumed is further broken down and ends up as uric acid and the uric acid accumulates in the cell. And when you eat glucose, you don’t generate this uric acid and you don’t have this energy deplete. But when you eat fr dose, there’s this drop in energy and the formation of uric acid. And then 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 kind of initiates glycolysis, which is another type of energy that can be made independent of oxygen. It doesn’t need oxygen, whereas, the mitochondria needs oxygen.

Dr. Richard Johnson (00:23:40):

What happens is the energy level falls in the cell and stays low for several hours. And when that happens, it’s like a Mayday signal. So normally an animal if it had low energy in itself, it 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. So 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 a low energy even though you have all this fat stored that can provide energy. So it tricks the body into thinking that it’s starving. And when that happens, it activates foraging, it activates hunger, it activates thirst, it activates all these things.

Dr. Richard Johnson (00:24:42):

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? And animals use this fructose as that system. That’s their main way to activate this system. And it turns out that when you eat glucose, it’s like glucose is like good fuel that creates satiety, it 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 this switch. So they really have different functions, major different biologic functions.

Dr. Casey Means (00:25:27):

Oh my gosh, it’s just mind blowing. I feel like that was a tour to force over really a root cause of so much of the disease we’re seeing in the country right now, because here you think about a person, average person in America, they go into the movie theater or something. They get a soda. They at candy, it’s filled with fructose and really what is happening there 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, causing dysfunction of the energy makers of ourselves, therefore shunting us towards storing energy as fat and driving us to, of course, be craving more and more and more. It’s amazing.

Dr. Casey Means (00:26:36):

This molecule, actually, it’s almost like should be revered how fascinating and smart biology is to create something like this, that in a situation like autumn, where there’s ripe fruit everywhere, the animal, once they get a taste of it and after a couple weeks of taste, they become leptin resistant. They become desiring of this food and they want to eat more so that they can then get through winter. I mean, it’s mind blowing.

Dr. Richard Johnson (00:27:04):

It really is. I love your phrase, molecular hijacking, because it’s exactly what’s happening. And it’s also true how wise nature is. I mean, nature, even if you think about it, nature has evolved in a system where the animals are helping the plants and the plants are helping the animals. So 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. But as the fruit ripens, then the fructose content goes up and the VI 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.

Dr. Richard Johnson (00:28:06):

So 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 (00:28:16):

Yeah. And just to quickly touch on that point you made about vitamin C because this gets talked about in the book a bit. From my understanding part of that mechanism is that vitamin C he can act as an antioxidant and sort of mitigate some of the mitochondrial oxidative stress that’s happening from uric acid. I think it’s just an interesting way of highlighting how so much of this is centered ultimately around the mitochondria and when the mitochondria is working properly, we can generate ATP. We can generate that cellular energy. We can process it. We don’t have to shunt towards fat storage and antioxidants can help support that by minimizing this overload of oxidative stress that can come from many different parts of our diet and lifestyle. But of course, uric acid being a big one in this story.

Dr. Casey Means (00:28:59):

And then there’s the opposite of this, which is where we have mitochondrial dysfunction, which we generally, I think of as a bad thing because it can lead to aging and cellular damage and whatnot. But in this unique situation, it can be temporarily beneficial by helping the animals store more fat. But the vitamin C, if you want to just touch on maybe briefly some of that data about how that can be helpful for us [crosstalk 00:29:27].

Dr. Richard Johnson (00:29:26):

So it turns out that vitamin C is an antioxidant that works on the mitochondria and reduces oxidated stress in the mitochondria. And it’s true that the way the fructose and uric acid are working, one of the ways is it’s causing oxidative stress for the mitochondria, which over time can destroy mitochondria, but acutely has effects that lead to insulin resistance and fat storage. And 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 barrel than a rat because it actually produces fructose in its body that allows it to survive. And so, with the vitamin C story, it turns out that we realized that vitamin C is a vitamin for us because we lost our ability to make vitamin C and way back when.

Dr. Richard Johnson (00:30:30):

So I became interested in why would we lose an antioxidant? Antioxidants should be beneficial. We know it’s beneficial, so why would we lose the ability to make an antioxidant? And so, it’s a long story, I do talk about it 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. And it was a time of where there was a lot of an extinction and our ancestors, which were just little [private 00:31:05] at the time, they were barely surviving. And we figured out that the vitamin C mutation occurred at that time and that it might have helped them survive with dwindling fruit supplies. And the way we showed that was 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.

Dr. Richard Johnson (00:31:28):

So the low dose is sort of the kind of vitamin C blood levels that you see in people who are overweight. And the high levels of vitamin C that we gave was to give of kind of a healthy vitamin C level in the blood. And 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. And 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. So 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. And unfortunately, it increases our risk for obesity today. And there’s also a mutation in uric acid metabolism.

Dr. Richard Johnson (00:32:19):

That also was a survival mechanism millions of years ago, and we got mutation. And so we are particularly susceptible to sugar. So 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 very much lower doses because we’re more sensitive to sugar.

Dr. Casey Means (00:32:42):

Mm. So basically we lost that ability to break down the uric acid. And so it’s accumulating more in our cells and pushing us more towards this mitochondrial dysfunction that ultimately leads to the fat storage. And so that fat could have actually been advantageous if we needed to store more fat, I.e in a time like a famine or something like that, similar with 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 sort of the way to look at it?

Dr. Richard Johnson (00:33:19):

Yeah, it is. So when you eat fructose, you make the uric acid and the uric acid plays a role in this whole process by causing oxidative stress of the mitochondria. And normally when you eat fructose, you make a certain amount of uric acid. And most animals only make a small amount of uric acid when they eat sugar. But normally, when you make the uric acid, it’s degraded by this enzyme uricase. And we had a mutation in the uricase so that when we eat sugar, we get a much stronger uric acid response. And I worked with this wonderful scientist, Eric Osher, 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, that it would blunt the amount of fat produced from fructose.

Dr. Richard Johnson (00:34:16):

And so when we had the mutation and we lost uricase, we could, we doubled our ability to make fat from the same amount of fruit. It was a great way to survive. And the uricase mutation also occurred during the period in time when we almost went extinct. So it turns out that we survived a couple times because of this survival switch. And what happened is we had these mutations that helped keep us from dying of starvation, but 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. And as you probably know, in 1800, the average intake of sugar was like 18 pounds of sugar a year.

Dr. Richard Johnson (00:35:12):

In 1700, now it was four pounds a year. I mean, sugar really wasn’t around back then, except for the wealthy and the wealthy were the ones that we’re getting at these. And then around 1900, sugar intake starts going up very significantly. And we are seeing the emergence of obesity and diabetes and hypertension, and all these diseases linked with the rise in sugar intake. It looks like sugar is the major player driving the switch. But we did have another discovery, Casey, that was really disappointing. And that was that there are other foods that can activate the switch and sugar while it’s the main one. Fructose is the main one. It turns out that the body can make fructose and it does, and 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.

Dr. Richard Johnson (00:36:14):

But the number one ways to increase fructose production is probably by eating high glycemic carbs. And what your company does, which is to measure the glucose levels in the blood, because when you eat foods that raise glucose in the blood, that triggers the production of fr dose in the body. So 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. And we know from our animals that if we block the metabolism of fructose, we can eat them rice and potatoes and they won’t develop metabolic syndrome. They will gain some weight and I think insulin is driving some of the weight gain, but most of it is coming as a result of the fructose. And I’ve had some nice conversations with Gary Tobbs recently, who’s a big believer in the insulin pathway.

Dr. Richard Johnson (00:37:20):

And 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. So 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 (00:37:57):

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 is what is actually generating 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. And I think you touched on this elegant study that you did, where basically you’re feeding these rats or mice high glycemic diets, which we’d expect to make them fat due to insulin’s effect on fat burning. And yet, if you block fructose metabolism, you can actually block part of that fat stimulus from the high glycemic diet. That is really interesting mechanism.

Dr. Casey Means (00:38:58):

So can you describe a little bit what that pathway is from glucose to fructose and what’s happening when we have the glucose spike?

Dr. Richard Johnson (00:39:07):

Sure.

Dr. Casey Means (00:39:07):

That’s ultimately feeding into the survival switch.

Dr. Richard Johnson (00:39:10):

So 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 and it’s actually two enzymes that convert glucose to sorbitol, and then sorbitol to fructose. It’s triggered by high glucose levels. So when you have high glucose levels, that turns on enzyme to start making sorbitol from the glucose and then the sorbitol gets converted to fructose. So this pathway, the polyol pathway, we’ve known about it for a long time because people who are diabetics show evidence for activation of this pathway, that was sort of the trick when we this, because we knew that diabetes was associated with activation of the polyol pathway. And 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.

Dr. Richard Johnson (00:40:18):

And so what we did is 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 a hundred percent responsible for the fatty liver, a hundred percent responsible for the insulin resistance and drove a much, but not all of the obesity. So then what we did is, we gave animals high fructose corn syrup, which consists of fructose and glucose. And when we gave that combination, again, we found that insulin is stimulated by the glucose, but when we knocked out fructose, we could really block everything, all the aspects of metabolic syndrome and even obesity was minimal. And so 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.

Dr. Casey Means (00:41:19):

And something you mentioned there that I know might spark some people to have an additional question, as you said, it’s the fructose that’s causing the insulin resistance.

Dr. Richard Johnson (00:41:29):

Correct.

Dr. Casey Means (00:41:30):

And this is different than what a lot of people think with insulin and this sort of repeated exposure to insulin causing the cell to become numb to it or chronic over-nutrition in general, causing intracellular or fat accumulation that leads to insulin resistance. But can you describe in this paradigm how the fructose is molecularly leading to insulin and resistance?

Dr. Richard Johnson (00:41:54):

That’s probably one of the few things 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 the uric acid, it’s linked with the mitochondrial oxidated stress. And 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 doctor, Samir Softic actually has identified several good candidate pathways for this.

Dr. Casey Means (00:42:38):

Really interesting, and I can’t wait to see how that unfolds. And I think just generally thinking about the mitochondrial dysfunction as a centralizing heart of this makes a lot of sense. So I think people listening might be like, “Oh my God, I never want to touch fructose again. This is clearly just doing this molecular hijacking. This is so bad. I can’t eat fruit again,” which we know is not totally true. You know?

Dr. Richard Johnson (00:43:06):

Yeah.

Dr. Casey Means (00:43:06):

The fruit epidemiologically is associated with longevity and as well as molecularly, we know that a lot of aspects of fruit are extremely positive so is or cellular biology. So what framework should people be thinking about actually fructose in their own life through, particularly as it pertains to whole food fructose versus liquid fructose and sort of the quantity and speed at which they’re consuming at?

Dr. Richard Johnson (00:43:32):

So it turns out you’re totally right. So fruit now, natural fruits are associated with good health, not bad health. And 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. So 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 just Gorge on fruit and they 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 like three or four grams, maybe six grams of fructose, some have higher, but many fruits are around five or six grams.

Dr. Richard Johnson (00:44:29):

And that’s a very small amount. And one of the work done by Josh [Ribenowoods 00:44:34] showed that the intestine is sort of 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. So if you eat 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. And it turns out that the liver responds to the concentration of fructose, not the amount.

Dr. Richard Johnson (00:45:24):

So the more you eat, the higher the concentration. So the more you eat, and if you drink a soft drink with 25 grams of fructose, you’re going to get a huge load. The concentration’s going to be high, and there’s no fiber in that soft drink, and you’re just going to absorb it. Boom. But if you eat a natural fruit, you’ve got the fiber that slows the absorption, so the concentration is not going to be as high. And also there’s not as much fructose in a fruit. And then the fruit also contained the vitamin C, which we told you can neutralize it. And also things like epicatechin, and flavanols that actually counter it too. So 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 we found that the supplemented with natural fruit was equally effective at lowering weight in these people.

Dr. Richard Johnson (00:46:18):

And in fact, there was even a little bit more weight loss with a natural fruit and that was given along with the low fructose diet. So our low sugar diet, because the natural fruits obviously contains the fructose. So the reality though, is that if you drink fruit juice, where you take multiple fruit and you blend it and you create juice, then you can get a large dose of fructose and it’s definitely linked with obesity and in children and the pediatric community commends limiting fruit juice in children. And likewise dried fruit, which we love, right? You like dried fruit. We all like dried fruit. The [GOP 00:47:03] and where you have dried fruit, unfortunately is really rich in fructose and has lost a lot of its good nutrients in the process of the dry. And so I don’t recommend dried fruit either.

Dr. Richard Johnson (00:47:19):

But basically, I think that if that 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 know, as you told me some fruits like bananas can really raise glucose levels significantly. And I have documented that as well. And so I do think we have to be careful with certain fruits that we don’t overdo it, it triggers fructose production and so forth.

Dr. Casey Means (00:47:49):

Yeah. So I think what I’m hearing is whole natural fruits, avoid the liquid fruit or liquid sugar in any way, whether that’s juice or sodas or sugar sweetened beverages, because it’s just going to overload the system. And same with dried fruit, it’s concentrated and so you’re getting a higher load. I think one of the frameworks that I took away from the book was just this idea that it’s not really the fructose so much that is the problem. It’s the byproducts of the fructose breaking down. And if you are eating just a tiny trickle of fructose, you’ve got all these cells in the liver and elsewhere that can process it and make that tiny bit of uric acid. But the body knows what to do with it.

Dr. Casey Means (00:48:39):

It’s not overwhelming the mitochondria. It’s not this on slot. But you can imagine, if you then just slug 28 ounces of fructose in a soda, you are just overwhelming the system. You’re flooding the cells with these byproducts of fructose metabolism. You’re overwhelming it. It’s just a totally different ballgame. So we can’t just lump all fructose together. And then of course, as you mentioned, certain foods like whole fruits have protective mechanisms to even mitigate some of the downstream stuff like vitamin C mitigating some of that oxidative stress. So it’s so contextual. And I think it really creates an important point around, we need to understand cellular biology to understand nutrition recommendations. There is not simple rules that we can follow like, “Avoid all fructose at all costs.” It’s more nuanced than that. But these series of experiments that you’ve done, help us actually get to those real truths behind a lot of the nutrition ideology.

Dr. Richard Johnson (00:49:40):

Yeah. The switch really is like a dimer rather than on and off. So if you take a soft drink and you drink it all at once? You’re going to really activate this pathway, the energy level’s going to fall very significantly in the liver and trigger this reaction. If you eat just a small amount of fructose, the ATP levels may fall very little, if at all. In fact, I think if you sipped a soft drink over a couple hours, as opposed to drinking in five minutes, you would not get so much of an ATP depletion and it might just function like a calorie more than some kind of activation of the switch.

Dr. Casey Means (00:50:22):

Yeah.

Dr. Richard Johnson (00:50:23):

So you’re exactly right that this is what’s come out of our work. And I think that if you wanted to try to say that sugar was safe, you would pick people who have really good mitochondrial function and you give the sugar slowly and try to not activate the switch. And if you did it though, the way most kids are doing it out there, where they drink it really fast, then you’re going to see the problem. That’s it.

Dr. Casey Means (00:50:52):

I love it. So here’s the recommendations for research for the processed food companies where, have them be people who do lots of resistance training, have great mitochondrial function, give the sugar over very slow time period, make sure they’re really hydrated and give them lots of vitamin C. It’s like there are ways to show that this is not necessarily a big deal, but that is not the way that we’re eating these things exactly in our real life. We’re pairing processed food with sedentary behavior. We have all these other contributors of oxidative stress, like chronic low grade, psychological stress, et cetera. But it’s interesting to hear how you could kind of game the system with the research to show that it’s okay.

Dr. Richard Johnson (00:51:36):

Absolutely. And once you know how this works, honestly, you can read the papers and just go, “Aha, this is what they did.” I don’t know if you want me to go through that, but maybe a different-

Dr. Casey Means (00:51:49):

Maybe another episode.

Dr. Richard Johnson (00:51:49):

Another meeting, but we can go through how to game the system, which is done a lot. Good.

Dr. Casey Means (00:51:56):

Yeah, I would love to touch on, because I know our listeners are going to be interested in this, the concepts of salt and osmolality. A lot of people are not thinking about how salt contributes to obesity, but your book makes a really important case for this. Especially right now, there’s this movement, very pro salt movement that’s happening in the fitness and nutrition space about how important salt is for really cellular functioning, but it is a complex topic. And I think if you could just break down how salt and blood osmolality can lead to the switch and sort of drive obesity through mechanisms that I think are very not well-known. I’d love for you to just describe that sort of picture and maybe comments also on how people should be thinking about salt in their diet.

Dr. Richard Johnson (00:52:44):

Well, 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. And when you get dehydrated, your osmolarity goes up in your blood and osmolarity is a fancy term, but what it means is that the salt concentration and the blood goes up and that’s because you’re losing water. So when you get dehydrated, you’re losing water from sweating or from exercising or maybe from diarrhea or something. And what happens is, when you get dehydrated, the salt concentration in your blood goes up. And that is another trigger of the polyol pathway. So it will lead to fructose production. And we actually found that in animals, that if we dehydrated, they start making fructose. Now, mild dehydration, animals will be able to get around and look for food and water.

Dr. Richard Johnson (00:53:48):

But if you’re severely dehydrated, you’re out for it. But the way we can create mild dehydration in animals, a very easy way is to give salt. And when you eat salt, the concentration of salt goes up in your blood and it mimics like the effect of losing water. And so when you eat salty food and you get thirsty, it’s because the osmolarity has gone up in your blood that triggers thirst because your salt concentrations are high. And that actually is activating this pathway to make fructose. So we started thinking about this. We thought, well, geez everybody views salt as potentially a problem in blood pressure. And certainly I’ve studied it and I do believe that salt has a role in blood pressure in certain groups, 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 overweight over time.

Dr. Richard Johnson (00:54:48):

And it sort of has not been viewed very carefully, but there are quite a few papers and there’s an investigator, Jody Stookey, who’s done some really beautiful works showing that people who are overweight or obese also tend to be dehydrated and to be eating a lot of salt. And so in addition to things like sugar and high glycemic carbs, it made us realize that salt might be another mechanism to increase fructose production. And so what we did is we gave animals salt, and we did it over several months. And we found that when we gave them salt that over time, initially, it took a long time. Actually it took like four or five months. So it’s a slower process than with sugar. But eventually, they became extremely fat and diabetic and the whole bit, and all the switch was turned on in every way.

Dr. Richard Johnson (00:55:45):

And then when we looked inside them, we found that they were making a lot of fructose. And when we blocked the fructose, we could block the development of obesity. And so we realized that high salt diets are a potential way to trigger this obesity and the switch and the fast switch and cause obesity. We also went on and discovered that when the salt cut concentrations go up in the blood, that it activates a hormone called vasopressin. Vasopressin is a hormone that helps conserve water. And we said, well, okay. It conserves water by re-concentrating the urine, decreases water vapor loss through the lung, we believe. And so it’s thought to be a hormone that should protect animals from dehydration. And 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.

Dr. Richard Johnson (00:56:44):

And so we started thinking about that and we noticed that there was a literature pointing out that people who are overweight or obese have high vasopressin levels in their blood. And so we went on and 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 that people really didn’t know what that receptor was doing. And now we know that 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. And then that, of course, gave the idea that we might be able to treat obesity by giving people water. There’s a kind of a burgeoning literature that drinking water is healthy and that it can actually have a benefit on weight.

Dr. Richard Johnson (00:57:47):

And 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 about how much water we should be drinking. And 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, for example. It’s been shown that you can get water intoxicated. So please read my book before hydrating yourself too much. But if you want six to eight glasses of water a day, is a very good starting plan if you’re trying to lose weight and very healthy.

Dr. Casey Means (00:58:48):

That’s a great practical tip and really fascinating physiology. It’s such a simple intervention. There was a study that you cited from Germany and the book that showed that just by putting water fountains in schools, they could get students to each drink one glass of water more per day. And then it led to a 30% reduction in the risk of children becoming overweight. I mean, this is so simple and we know the mechanism now. I’m excited for everyone to have that one in their back pocket.

Dr. Casey Means (00:59:18):

What about thinking about a healthy level of salt intake per day? I guess the question is, does it really matter how much salt you’re taking in if you are hydrating appropriately to keep the concentration at the appropriate level? Does it matter about how much, like you said, with marathon training, how much training you’re doing? It’s sort of hard to find tune out the biofeedback that we don’t really have yet. I think it’ll be great when we have an osmolarity monitor on us. But how can we like think about salt intake, especially in the context of fitness and training?

Dr. Richard Johnson (00:59:53):

Well, one of the things that comes out of this is that it’s really the balance of salt and water that one eats that governs your salt concentration in your blood. And it also how much you’re exercising and whether you’re in conditions where you’re losing water. But we did an experiment that I think was really pretty cool experiment. This was done by my collaborator, [Maynooth 01:00:17] can be in Turkey. What he decided to do with us was to give salty soup to volunteers. And one of the great things about soup is you can mask how much salt is in there because of the flavor of the soup. So he made a fairly salty soup that would raise the salt concentration, just a little bit in the blood, but it was enough to raise the salt concentration in the blood. And when he gives this, the vasopressin went up in the blood, which we know is driving obesity.

Dr. Richard Johnson (01:00:49):

So it’s showing that the switch is being activated and also the blood pressure shot up as the immediate response associated with activating the switch. So then he randomized it. So one group got the salty soup with no water and another group got… Actually, we had three groups, we had different amounts of water. And what we found is that as we increased the water with the soup, we could block the vasopressin response and we could block the rise in blood pressure. So 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. And so if you can block that by drinking water at the same time, you can actually neutralize the effect of the salt. So 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 (01:01:51):

Amazing. Okay. Very, very helpful. We are running out of time. I have so many more questions I want to ask you. We may need to have a follow-up conversation because this is just so amazing. And I think maybe one thing we could leave listeners with, because really the latter third of the book is the actual plan for how to take everything we know from these dozens of experiments you’ve done about the survival switch and put it into a plan that doesn’t activate the survival switch so that we can basically optimize these pathways to be lean and healthy in our modern world. But some of what you talk about there, aside from just foods is we ultimately need to get our mitochondria functioning better and keep our mitochondria healthy and active and all of these things. So maybe you could leave people with one tip, maybe around exercise or something else of just how we can really do a simple behavior or action that keeps our mitochondria on track.

Dr. Richard Johnson (01:02:49):

Sure. So 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. So 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. And 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 it’s not any exercise, it’s a specific type of exercise where you exercise what we call zone two.

Dr. Richard Johnson (01:03:53):

But what you want to do is you want to exercise just enough that you can talk, but it’s a little difficult to talk while you’re exercising. And that actually gets you right into that range, that zone two range. Some people are on medication that affects heart rates and things like that. So it turns out that exercising the heart rate is not as effective as doing it the way that I’m telling you. But like walking or cycling or like that can really make a difference. You have to go a certain amount of time, at least 45 minutes at 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 (01:04:41):

Yes. Well, that is great. I think for people not on beta blockers or other medications that are going to affect heart rate, I think a general rule, you can look online for zone two heart rate. So basically taking your age and figure out percentage of your max heart rate and then shooting to do that for a fairly long period of time. Probably what, 30 minutes to an hour, would you say?

Dr. Richard Johnson (01:05:07):

Yes.

Dr. Casey Means (01:05:08):

But this is good news because this is not super intense exercise. This is, like you said, walking, maybe fast paced walking if you’re young. So that’s great and very doable. And that’s one of the things I love about your book is that everything in it is actually pretty doable. The diet is not restrictive.

Dr. Casey Means (01:05:26):

The exercise is fairly gentle. The water, drinking water. But there’s a molecular basis to all of it and experiments to that every single recommendation up. It’s really a tour to 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 the unfolding of this mystery of this detective case. And every experiment follows up, prior your 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. Thank you. Thank you for this book. Thank you for what you’re bringing into the world.

Dr. Casey Means (01:06:22):

I think the public health implications of this type of knowledge are monumental in the multi trillions of dollars worth of impact because obviously metabolic disease is underpinning so much of our morbidity and mortality and costs in this country. So thank you for your work.

Dr. Casey Means (01:06:37):

Thank you for sharing with us. And everyone, go get Nature Wants Us To Be Fat. And where can people find you?

Dr. Richard Johnson (01:06:44):

Drrichardjohnson.com is my website. We’re also going to have this website, naturewantsustobefat.com. So the same as the title of the book.

Dr. Casey Means (01:06:53):

Thank you.

Dr. Richard Johnson (01:06:54):

You bet.