The Melanie Avalon Biohacking Podcast Episode #146 - Dr. Rick Johnson

TRANSCRIPT

Melanie Avalon: Hi, friends, welcome back to the show. I am so, so incredibly excited about the conversation that I'm about to have. Here is the backstory leading up to today's conversation. I historically have been very, very fascinated with energy generation in the body, energy processing, even down to the granular effect of glucose versus fructose versus sucrose. It's just been a little miniature obsession of mine, which is, well, I would say, it's a weird thing to be obsessed with, but if that's the case, then me and today's guests are both in on it. But in any case, back in 2020, I listened to Peter Attia's first interview with Dr. Richard Johnson. He is an MD, Professor of Medicine at the University of Colorado, and I was so excited because I finally was hearing somebody talk in the deep detail and nuance about fructose metabolism, like, I had been wanting for so long. And then what's really interesting is ever since listening to that, then I started seeing Dr. Johnson's name everywhere, because I realized when I've been reading all of these studies online, sometimes, they were his papers or he would be referenced in other papers, because his work is just so expansive and really revolutionary in understanding metabolic syndrome. Again, fructose, the obesity epidemic, so many things. Needless to say, that was 2020. He immediately went on my list of ideal guests to bring on the show. 

And then Rick was coming out with a new book called Nature Wants Us to Be Fat: The Surprising Science Behind Why We Gain Weight and How We Can Prevent--and Reverse--It. I think actually, his publicist reached out to me and I was so, so excited, because I've been dying to interview him. Got the book, dived into it, it's incredible, it is so comprehensive, it goes into so many things. Fructose, the obesity epidemic, this thing called the survival switch, hibernation in animals and what that means, uric acid, the polyol pathway, lots of key words, I'm sure we will dive deep into all of it. But I'm just really, really excited and I have 30 pages of notes. So, Rick, thank you so much for being here.

Dr. Richard Johnson: Melanie, thank you so much. It's really a wonderful thing to be on your show. As I mentioned, you've had so many experts on the show. I'm very happy to come up aboard and to try to share with you what I have learned from my research.

Melanie Avalon: Yes, I am so honored for you to be here. Actually, we were talking about this before, but Dr. David Perlmutter wrote the foreword to your book and I'll actually be bringing him on soon for his book all about uric acid, which you talk about as well in Nature Wants Us to Be Fat. So, all goes together, so many awesome topics. But to start things off, for listeners, who are not familiar with your work, would you like to tell them a little bit about yourself, what led you to your obsession with fructose? You talk about this in the book, but just in your own words, why are you doing what you're doing today?

Dr. Richard Johnson: Well, I tell you, I've been very interested in the causation of diseases. I trained as a kidney specialist. I began my career by studying kidney diseases and I realized that kidney disease is very much linked with high blood pressure. For years, it was thought that high blood pressure is a kidney problem in which the kidney has trouble excreting salt. In the process of studying the role of the kidney and high blood pressure, we realized that uric acid was playing a role in the pathogenesis or in the cause of high blood pressure. As we studied that, we began to realize that not only was uric acid important, but we began to realize, there are a lot of people with high uric acid. If you go back 50 years or 100 years, the prevalence of high uric acid was much lower. The uric acid levels have been increasing dramatically over the last century or so. Then that question was, "Well, what's driving the uric acid up?" There are many types of foods that do it, but one that is really good at doing it is sugar, and sugar contains fructose, and it's actually the fructose component that drives the uric acid up. So, we thought, "Well, let's see what happens if we give fructose to animals to raise the uric acid? Will they develop high blood pressure?" And they did. Then when we lowered the uric acid, we could lower the blood pressure. 

But then there was the twist, my friend, Taka Nakagawa, who was working with me said, "Hey, when we lowered the uric acid, we then just lowered the blood pressure. The animals didn't gain weight as much, they didn't gain as much fat. They seem to be protected from the effects of sugar." I said, "Well, that can't be. How could lowering uric acid affect weight gain in animals receiving sugar?" Because it didn't block their ability to eat sugar. They were still eating the sugar. At that point, we realized that there was something besides calories, the way that sugar was causing disease. This was in 2005. 2004, and everybody was thinking, it was all calories back then. That turned me on to realize that fructose was causing obesity, and so far through a mechanism that somehow involved this substance, uric acid, and that it wasn't classically involved with the calories, but with other things that fructose was doing. That led to hundreds of studies. Actually, it has been hundreds of studies. It's a sad statement of how old I am. We did lots of experiments, let's say that and we did those to try to figure out what fructose was doing, how it related to sugar, and so forth. That's how I got in there. So, I started as a kidney doc, and then switched into studying obesity and diabetes pretty early on. Now, 20 years ago. 

Melanie Avalon: Wow, that is incredible. So, with the uric acid studies, when you reduce the uric acid, was there any change in the animals, how many calories they took in at all?

Dr. Richard Johnson: No, it did not have as much effect on calorie intake. It had some, but not a dramatic effect. But it did block weight gain. It did reduce the food intake by some level, but it wasn't a dramatic effect. But later on, we wanted to understand how sugar causes weight gain. We began to do studies to try to separate calories from other mechanisms. We did figure out that sugar can cause obesity and sugar can cause obesity independently of eating too much calories. It increases the fat in you and it causes insulin resistance and diabetes, even if you reduce your diet, so that you're on a caloric-restricted diet. If you go on an actual diet, where you cut back on calories and you eat a high-sugar diet or a high-fructose diet, you can still induce features of fatty liver, metabolic syndrome, insulin resistance, and so forth, even though, you're on a diet. 

Interestingly, in our studies, most of the weight gain from sugar is by making you hungry, so that you eat more than you normally do. There is a calorie component to how sugar works. Sugar does make you hungry, so, you eat more than you normally do. And that certainly helps with weight gain. If you're eating more and especially, if you eat foods that have a lot of calories like fat, if you combine sugar with fat, animals will gain weight very rapidly. Now, if you give them fat alone, they don't really gain weight that much, because most of them will control their weight. But you give them sugar that makes them hungry, so that you will eat more and then when you give them fatty diet, then it makes a difference. That's why a low-carb diet, if you're on a low-carb diet, you can eat a high-fat diet and you aren't going to gain weight, because you don't have the hunger. The low-carb diet's great. You don't have to calorie restrict, because you naturally calorie restrict because you're not hungry. But when you give fructose, you make-- an animal will become hungry. Interestingly, It takes a few weeks. If you just give sugar for one week to an animal, they control their weight. But if you give it to them for three weeks or four weeks, they suddenly get really hungry and we found that that was because they become resistant to leptin and leptin is this hormone that goes up when we eat and says, "Hey, you're full. Don't eat anymore." But people who are overweight tend to be resistant to the leptin and so they will continue to eat, even though, they have high blood levels of leptin. 

In fact, the way we test for leptin is we inject an animal with leptin. If they're resistant they'll continue to eat and if they're not resistant, they'll quit eating or really reduce their food. When you give them sugar or fructose after about a month, if you give them leptin-- an injection of leptin, they'll keep eating like nothing has happened. But if you give the leptin to a normal animal or an animal on a high-fat diet, they will reduce their intake. There's something special about the fructose that makes you hungry and then you eat more. But even if you put the animal on a diet, so it can't eat more. Even though, it may be hungry, you don't allow it to eat the food, you take away their foods, so they can't eat it, they will still develop metabolic syndrome. Interestingly, in our clinical trial-- not clinical trial, in our experimental trial where we did this, the animals that were on a diet, where we calorically restricted them, the controls lost about 10 grams of weight and the ones that got sugar, even though they were on the same exact number of calories, they gained 20 grams, but it wasn't statistically significant. It wasn't because it was a relatively short study. But when you take fructose, two things happen. One is, you get hungry and the other is, you reduce your metabolism. You're spending less energy, so if you give an animal fructose, they start sitting around more. They basically become couch potatoes, Melanie.

Melanie Avalon: To take things back a little bit for listeners, because we're using the word sugar and fructose. When you say sugar, are you referring to sucrose primarily, which would be fructose and glucose or you are using sugar as a synonym for fructose? Maybe you could listeners, sucrose versus glucose versus fructose, what those are?

Dr. Richard Johnson: Yeah, absolutely. I'll define it and then I'll be careful moving forward how I use those terms. Fructose is the sugar that is classically in fruit. We think of it as fruit sugar. And it's in fruit and it's in honey. These are things that we think of is good, right? And then fructose is also in table sugar and high fructose corn syrup. Table sugar is sucrose and it's what we call a disaccharide. What it is, is it's a fructose and glucose bound together. When you are eating sugar or table sugar, half of it is fructose and half of it is glucose. Then when you eat high fructose corn syrup, you're also eating a mixture of fructose and glucose. Glucose is usually a little bit less than fructose and the high fructose corn syrup in terms of the ratio. Fructose is typically 55% or 60% and glucose is typically like 45% or 40%. They do that because fructose is what gives sugar the sweeter-- is really responsible for the sweet taste. Glucose has a very, very mildly sweet taste, and so people like the sweetness, and it turns out they prefer to have something like 55 to 45 is the ideal amount that people tend to like. If it's too high, then it gets too sweet and people don't like it. If it's lower, they tend to want that 55, 45 ratio. 

Most soft drinks that have high fructose corn syrup have 55% fructose in it. But in fountain drinks, where you the people mix it slightly different, the fructose content can go up to 60% or 65% of the drink. For people, for us, when we go to the grocery store, most of the fructose we get, the vast majority of fructose the average person eats comes from added sugars. These are table sugar, sucrose, which has half fructose and high fructose corn syrup. What's terrible is that, high fructose corn syrup is a liquid and it can be mixed into foods easily. There are many, many processed foods that have sugar in them, or when I say sugar, I mean, table sugar, or high fructose corn syrup in them. And sometimes, it's subtle, where you can't-- When you think about-- when you eat it, you don't think there's sugar in it and then someone says, "Hey, it tastes a little sweet, did it?" Then you look at the package and it is. You're like, " Wheat Thins." When I was a kid, I loved Wheat Thins. I don’t know if you ever had those crackers. But if you taste them, there's just a tiny bit of sweetness to it. So, people do this.

One of the terrible things that we experiment and when I say, terrible, I don't mean terrible like terrible science, but something I was hoping I wouldn't see. And that was, when we knocked out the sweet taste in so that a mouse could not taste sweet. In fact, we knocked out all tastes. These are called tasteless mice. They can't taste anything. They still like sugar, they still like fructose, they still like glucose, they like it, ate and so, they get a dopamine response in their brain, even though, they can't taste it. Even if you can't taste the sugar, if it's there, maybe it's encouraging you to eat it. Not only that, those tasteless mice became fat, when we offered them sugar water or regular water. They're still sensitive to the effects of sugar. It just shows that it's not taste that's responsible for how sugar causes obesity. It isn't because it tastes good. You go back and eat more, that's not the mechanism. It's actually how it's metabolized, and it's linked with this uric acid, and that's how it works. So, yeah, bad news.

Melanie Avalon: You've also discussed in the book about how the cravings were also determined about if it was metabolized in the intestines versus the liver with the enzyme?

Dr. Richard Johnson: Yeah. This was also an exciting finding. One of the things we know is that when you eat sugar, even if you can't taste it, you end up by craving for it. Another question came is, is it craving a sugar, is that what causes you to become obese or is it not from craving? What we did was, we could create a mouse that could only metabolize fructose in certain organs, so we could knock out the ability for the mouse to metabolize fructose in the gut, or the liver, the brain. When we did that, we could figure out which organ is responsible for what effects. What we found was that the liver, which is the home of metabolism, the main organ that breaks down food, that's the place that drives whether or not you're going to get fat or diabetic. Because when we knocked out the metabolism of fructose in the liver, we could block how sugar or fructose causes obesity, we could block how fructose causes diabetes. If we could just block the metabolism of fructose in the liver, you can eat all the fructose you want, but you're not going to get fat. 

Interestingly, when we knocked it out of the liver, the animals still loved sugar. They can eat all the sugar they want, but they wouldn't gain weight. It was the liver that was responsible for the whole thing. But it wasn't responsible for the craving, because the animals that we knocked it out of the liver, they still love sugar. Then we knocked it out in the intestines and they reduced their sugar intake dramatically. It was like, they didn't really care for sugar anymore. We think that the craving is linked with the gut, and that there's a gut-brain pathway involved in craving, and the liver, though, is the place where the action is. Yeah, kind of interesting. [laughs] Yeah, when you combine a little bit of research like this kind of stuff, and you also do studies in people, and try to do things like in nature and so forth, you get a lot of insights. So, these are-- we were able to better understand how sugar works.

Melanie Avalon: So, does that suggest that, in general, our cravings are primarily determined by our intestines and our taste is actually just an avenue to find the things that will get rid of those cravings rather than cravings originating from our taste itself?

Dr. Richard Johnson: Yes, I think taste is a secondary mechanism. This is really interesting. There're five tastes. Two of them are bitter and sour and those two tastes are there primarily to protect you from eating things that could hurt you. But there are three great tastes that are all tastes that people love. And some people love one taste more than another. So, some like sweet, some like salt, and some like umami. 

Melanie Avalon: I love umami. [laughs] 

Dr. Richard Johnson: I love umami. The good news is, okay, there's bad news and good news. It turns out that sugar is the number one and when I say sugar, I mean, fructose-containing sugars. That's the number one way to become overweight. The sweet taste is trying to drive you to pick out sweet foods that might have fructose in it. The sweet taste receptor is there to help you find those foods. Now, you will become addicted to the food even if you can't taste it, but it is true. If you knock out the taste, they'll eat less. They'll eat less, but they still prefer it to water. If you give them water or sugar water, they'll prefer the sugar water even if they can't taste it. But they will reduce the amount they drink, but they still get fat equally, amazingly. If you give them artificial sweeteners, they don't care for the-- You knock out the sweet receptor, they don't care for artificial sweeteners anymore. Artificial sweeteners are primarily driven by taste.

Melanie Avalon: That makes sense, because with artificial sweeteners, it's not actually fulfilling the guts craving, like the intestinal craving, but it's tricking the taste to make the gut think it's coming, but since it doesn't come, it makes sense that you wouldn't have that effect.

Dr. Richard Johnson: The bad news about artificial sweeteners is, they keep you hooked on the liking of sweetness. The biggest problem with artificial sweeteners is not that they cause obesity. One of them may cause a little insulin resistance, but we've done many experiments with artificial sweeteners. They don't cause obesity, but they do make you seek sweet foods. In that process, you can't completely get rid of your craving for sweets. That biology is fighting you now. You'll end up still wanting sweets. So, it's hard in the long term not to have some sweets here and there that you would not necessarily feel the urge for if you weren't on those sweeteners.

Melanie Avalon: Going back to the other piece, blocking the fructokinase in the liver, does the organism not experience the metabolic effects, because it's literally blocking the calories or is it something beyond that? Because if you're blocking the fructokinase in the liver, then you're just literally not getting that fuel source, right?

Dr. Richard Johnson: Yes. The liver does seem to drive a lot of things even in the periphery. The part that amazed me was that it blocked accumulation of fat in the adipose or fat tissues. I was pretty sure it would block the fat accumulation in the liver, because it's in the liver. We know that if you blocked that fructose metabolism in the liver, you block the development of fatty liver and that made sense to me. But what was interesting was that it blocked the fat accumulation in the periphery. There's a communication. Exactly, how this works we haven't totally figured out. It's our next series of studies is to understand communication from the liver to the brain, from the liver to the fat. But we see all kinds of evidence that it's affecting all these peripheral mechanisms. The liver seems to be like the conductor and it's working through the liver, it's working in the peripheral tissues as well. We'll have to figure out exactly how that works. Uric acid is likely involved to some extent, because it is produced heavily in the liver and then it gets in the circulation. So, there's some data to suggest that that's one of the cues driving that. I don't think it's the only one it's involved.

Melanie Avalon: So, it's blocking the fat generated from the fructose or it's blocking fat in the meal in general going into adipose tissue?

Dr. Richard Johnson: Ah, so, this is a big question, Melanie. You asked really a great question. A long time ago, people were thinking that, it was known for a long time that if you gave fructose to people, that triglycerides go up in the blood 30 minutes later-- or four hours later, I'm sorry, it's four hours later. The conception was that those triglycerides were coming from the fructose itself, so that when the fructose is broken down components of other breakdown products that then get turned into fat. There are some breakdown products of fructose that do go into fat but it was a very small amount. It couldn't account for this big rise in triglyceride. The really fantastic discovery was done by my partner, Miguel Lanaspa and he was studying how fructose works and what he found was that when you eat fructose, there's this thing called oxidative stress that occurs. There's a burst of chemically reactive oxygen that's produced in the liver cell and that affects the mitochondria. It's driven by the uric acid. Remember, we knew that the uric acid was involved and that oxidative stress stuns the mitochondria. What it does is it sets up for fat production from precursors of fat that do not have to necessarily be from the fructose. It stimulates other glucose and other things present, and fatty acids and so forth. It stimulates them to start making fat. The fat doesn't actually come from the fructose. It comes from the other nutrients that are there. So, it turns out that fructose itself is like glucose. It's just sugary that it's a type of sugar, not table sugar, but a type of sugar in the global sense. 

It can be broken down to make energy and it can be turned into fat and glycogen. But fructose activates another process that tries to stimulate fat, not even from its own molecule, but from other things present. It stimulates hunger, which makes you want to eat other foods. It's not just sugar that you want to eat, it does cause craving of sugar or sweet, but it also makes you eat more food, even if you can't really taste it. This leptin resistance kicks in, that makes you hungry. Fructose is a different beast. We've fell into the big mechanism by which it works. It's interesting because it's a nutrient. Nutrients provide calories and calories give us energy. When we get energy, it's either an instant form of energy, what we call ATP, which is made largely by mitochondria and other mechanisms. It makes stored energy and stored energy is like fat or glycogen. Whenever you eat, it's used to drive biologic act, how we live, and move, and act, and think. We need calories for that. Some of the calories are converted to instant energy, and some is converted to stored energy. What fructose does is, it creates an alarm signal, because it drops the instant energy by 10% or 20%. What it does is, it tells the animal that that there's some kind of alarm going on that you don't have quite enough food. So, that's what seems to trigger food intake, fat accumulation, everything is like, "Uh-oh, I'm running low on my stores." 

One of my friends called an insurance plan. Fructose stimulates an insurance plan. It isn't really. It's triggered by starvation, but it's not starvation. It's just a drop in the energy in the cell that makes the animal feel it doesn't have enough things-- enough fat stored away. When that happens, it stimulates more fat storage and it does that, even though, you already may have fat. It tricks you. You actually may have all this energy available. You have this fat and glycogen that are stored energy, but when it drops the immediate energy, it tricks you into thinking that there's not enough energy around, so you make more fat. It's a way to increase your fat. All animals, all of us have some body fat. We didn't have any body fat, we'd be really in trouble. But everybody has some body fat. What this does is when you eat fructose, it wants to increase your body fat no matter where you start. If you're at 10% body fat, it wants to make it 15%. If you're at 15%, it wants to make you 20%, so forth. Fructose is an insurance plan aimed at increasing your fat stores, while glucose is the immediate fuel. It's there to really make immediate energy that you can use right away. So, the two sugars look very similar in composition. One is there to make immediate energy and one is there to make stored energy.

Melanie Avalon: I have a question about that. I want to clarify one thing before that. When you were talking about how fructose does not itself create a lot of fat stores from the fructose rather it's how fructose affects the metabolic health of the cell and then it starts creating fat from other things, but you mentioned it creating fat from glucose. But since glucose is also a simple sugar, does glucose easily become fat or is it mostly just fatty acids that are becoming fat in the context of fructose?

Dr. Richard Johnson: You can make fat from glucose for sure. Fatty acids are a major way, of course. But yes, you can make fat from almost any kind of caloric source. So, there're pathways to do it. So, yeah.

Melanie Avalon: The glucose to fat storage conversion is that easier to do more likely than fructose itself to fat stores?

Dr. Richard Johnson: Not necessarily. I'm not an expert on this. You certainly can create fat by eating glucose, and then it enters the Krebs cycle or citric acid cycle, and then some of it can be diverted with the acetylcholine towards fat. For sure, you can generate fat and glucose, when you stimulate insulin, it will actually help increase fat as well. Glucose, when you eat it, the insulin also tends to try to block the degradation of fat in the periphery. There's definitely a carb-fat pathway that is very important and there's also a fat-fat pathway. Proteins maybe make fat a little bit less. But yeah, you definitely can make fat from both carbs and fat. When you give fructose, you increase fat and it turns out that we probably should talk about one way that when you eat glucose, another way glucose can increase fat is that it can be converted to fructose in the body. So, that's a whole new story. There's this big controversy going on in the scientific world about whether when you drink a soft drink, there's fructose in it, and there's also glucose in it. The question was, is one of them the dominant player in causing the obesity epidemic? And glucose, as we mentioned stimulates insulin and insulin and that combination increases not only the storage of glucose as glycogen, but the conversion of glucose to fat. The thought was that a lot of people were thinking that it's the glucose that's key is really a problem of high glycemic foods. Foods that when carbs that you eat that make your blood glucose go up, that triggers the insulin response that then can drive the fat production.

Certain foods, when you eat certain carbs will raise the glucose level in your blood substantially. Those foods are things like bread, rice, potatoes crackers, cereal, chips, they tend to have a high glycemic index, which means that when you eat them, there's a spill over into the blood of glucose and the blood glucose, which is normally 90 might go up to 120 or 130 following a meal or even higher following a meal with a high glycemic carb. And then that would trigger insulin and insulin could help drive the glucose into being stored as fat or as glycogen. That's been a major hypothesis. I think Gary Taubes has really talked about that, David Ludwig and there's evidence in support of that. But what we found out was that when you eat glucose, when the glucose levels go up, high glycemic foods, again, are culprits that some of that glucose gets converted to fructose especially in the liver. And now, I told you how important the liver was for fructose. When you're drinking glucose solutions or eating a lot of high glycemic carbs, the glucose goes up in the liver and in the blood, and that triggers the production of fructose. Now, you have another mechanism that could drive obesity, not just insulin, but fructose. So, what we did is, we gave glucose to mice that couldn't metabolize fructose. They had a normal insulin response and they love glucose. But instead of getting fat like really control rats, who became the normal rats fed glucose became quite fat, and they became prediabetic in the whole bit. But they had high fructose levels in their liver and when we block the fructose, we found that we could significantly reduce the development of obesity. They still became a little obese, but they were protected from insulin resistance and they were protected from fatty liver very well.

Then we did a study with soft drinks and showed the same thing. What we think is that the main mechanism by which soft drinks cause obesity is through the fructose content. It's not just the fructose that you drink, but the glucose is being converted to fructose as well in the liver. It's the fructose that's driving a lot of the obesity and fatty liver. There is some being driven by insulin. When I discussed this with Gary, he pointed out that fructose makes an animal insulin resistant and prediabetic, and it's the fructose that does it. But once you become insulin resistant, your insulin levels tend to be high in the blood. Although, the insulin resistance in the fat is to glucose not other mechanisms. When you become insulin resistant, glucose can't get into the fat tissue, but the insulin is still working on the fat tissue and blocking the degradation of fat. So, fat accumulates. Even with the fructose pathway, insulin turns out to be playing a role in the obesity, but it's not working, because glucose is stimulating it. It is working, because fructose is causing insulin resistance. The insulin levels go high and then the insulin blocks the fat from being burned in the fat tissue. We've got a couple-- 

This is really deep science. But the bottom line is, sugar, which contains glucose and fructose can cause obesity, metabolic syndrome, fatty liver, and it's primarily the fructose that's responsible. But the fructose can come both from the diet, but it can also be made in response to high glycemic carbs. Melanie, this really points out how important carb restriction is low carb diets, keto diets in terms of blocking this mechanism. If you really want to lose weight, intermittent fasting is a great way of removing your exposure to these carbs. And a low-carb diet or keto diet would be another way to reduce the exposure to not just the fructose we eat, but from high glycemic carbs that can convert fructose in the body. So, what you've championed really makes a lot of sense to me.

Melanie Avalon: So, is that the polyol pathway, the glucose to fructose conversion?

Dr. Richard Johnson: There's only one way that animals can make fructose and they make it through a thing called the polyol pathway. Sorry, for the complicated name. But this polyol pathway converts glucose to fructose and it can be activated a number of ways. The number one way is by a high glucose. In diabetes, when you have a high glucose, you're making fructose. Almost everybody who has diabetes, especially, if it's not well controlled, they're making fructose. When you eat a high glycemic carb is like trying to create a transient diabetic state in your liver, because the glucose levels go up high and that converts the glucose to fructose. I mean, it activates the polyol pathway and it converts the glucose to fructose. This is the main way that we make fructose. But interestingly, this pathway can get turned on in stress. In a heart attack, it was shown that in the heart, you start making fructose. Can you believe that? When there's low oxygen, you can start making fructose. it is like being turned on in situations of survival. If you're dehydrated, if you get dehydrated, fructose production can increase inside of you. But usually, these are small amounts with just mild but the dehydration pathway may be much more important as a mechanism for stimulating fructose. We learned about that when we realized that most people with obesity have an elevated hormone in their blood called vasopressin, which is a marker of dehydration. It's uncanny if you just measure vasopressin, the blood tests called copeptin. But if you measure it in a population, people who are overweight almost always have a high copeptin. If you're lean and you have a high copeptin, you're quite at increased risk for developing obesity or diabetes. What makes the copeptin go up is if you're dehydrated. 

There's a scientist named Jodi [unintelligible [00:41:28], I think you should invite her on your podcast. She's really an unbelievable character, who has championed studies looking at how well our population's hydrated. Most people are not drinking enough water. It's especially true for people, who are overweight or obese. It's depending on what kind of measurement you use. It can be five or 10-fold higher risk for dehydration if you're overweight or obese. This is something you might say, "Well, how can that be?" Well, it turns out that to become dehydrated, there're two ways you can do it. You can drink too little water or you can eat too much salt, and both have the same effect on your blood. When you drink too little, the salt concentration goes up in your blood and that triggers thirst and the condition we call dehydration. When you're dehydrated, if you're losing water like vomiting, or diarrhea, or sweating, as you lose water the salt concentration goes up in the blood and it creates thirst, stimulates this vasopressin hormone, and you are dehydrated. But if you eat salty food, really salty food, which we love, I mean, salted popcorn, God, much of my kid's life, when I was a kid, I was trying-- making popcorn, and going to the movies, and eating popcorn, and getting really thirsty from it. Then we drink soft drinks to quench our thirst. Of course, soft drinks are not quenching. They actually dehydrate you more and so you're still thirsty. You drink more and more soft drinks, and you eat more and more popcorn, and you're raising the salt concentration in your blood, and that activates this polyol pathway.

The polyol pathway makes fructose and then fructose as it's metabolized sucks the water out of the blood into the tissues as it makes glycogen. Fructose will rapidly make glycogen and fat. It's interesting, Melanie, whenever I would eat popcorn, the next day, I would gain two pounds. I always thought it was water but it may not be it. I think it's likely glycogen. What happened was I just activated this massive glycogen deposition into my liver, which is not great. But yeah, if it was just water, you'd expect the weight to come down the next day. But it tends to come down slower when you eat that kind of salty food. You have to go back to your low carb, low salt, or intermittent fasting type of diet. The big thing we found was that salt can be a cause of obesity. When we gave animals salt it took a lot longer. With sugar, it's quick. Not the first few weeks. It's not a two-week thing or a three-week thing, with sugar if you're giving it to a mouse or something, it takes to two or three months. But if you give salt, you have to wait twice as long. Four or five months before they really start becoming fat. So, there's a different process. And salt is slower and more secret is like a stealth mechanism for obesity.

Melanie Avalon: You're talking about all of these different markers or factors that correlate to metabolic syndrome and obesity. We talked about the high uric acid levels, we're talking about the dehydration, and all within Nature Wants Us to Be Fat, you talk about how it relates to this, basically, the survival switch, which is creating a state in our body that would be preparing for hibernation. In animals their body activates all these pathways, so that they can store up all this fat, and then when they're hibernating, you talk about how hibernation mimics metabolic syndrome. A question about that. These animals that are hibernating or migration, you talked about how it happens with birds that are migrating, which was so cool. I had no idea about that. Those situations with animals who are hibernating and birds that are migrating and the similarity in their bodies to metabolic syndrome. Oh, and also the hummingbird. Is their form of "metabolic syndrome" all five things, the abdominal obesity, the triglycerides, the low HDL, the blood pressure, and the high fasting blood sugar or is it a little bit different?

Dr. Richard Johnson: There is a little variation. It's not exactly the same. For example, bears, they become hungry, leptin resistant, they start foraging, they put on fat, they block burning the fat, and they increase the fat production. They do almost everything. But no one's really measured their blood pressure to see if their blood pressure goes up. That's not been proven that the blood pressure goes up.

Melanie Avalon: Or their HDL?

Dr. Richard Johnson: Yeah. And also, I don't think there're studies looking at the HDL. If you give fructose to a mouse, they do show all the whole things, the HDL falls.

Melanie Avalon: Even the HDL? 

Dr. Richard Johnson: Yeah. 

Melanie Avalon: Oh, wow. I was wondering if the HDL was the thing that might be a little bit different.

Dr. Richard Johnson: Well, in the rat, it's been certainly reported that fructose drops HDL, increases VLDL and triglycerides. 

Melanie Avalon: Oh, and the fructose.

Dr. Richard Johnson: Yeah. It can do the whole thing. But in these animals in the wild, there's some variability. It turns out, birds, they get almost all of the same things. They get insulin resistant, fat. They get a very, very prominent look fatty liver, which is more than you see in the mammals. But it's interesting birds lack this uricase just like we do. When it comes to the uric acid pathways. We're a little bit more alike the bird in terms of the fact that it doesn't have uricase and we don't have uricase. Uricase is an enzyme that degrades uric acid and most mammals have it but we lost that gene years ago, and probably to help us survive by enhancing this sugar pathway, the fructose pathway. But anyway, there is the survival switch. Most of the animals show pretty much majority of the same features. Some of them have not been studied and there may be some exceptions. It's a pretty consistent story that these animals will before they hibernate, or before they migrate, or before they nest, they have to rapidly increase their weight. Some of them seem to do it by eating fructose and then others, we don't really know the mechanism, but we think it's because they somehow activate fructose production in their body, but that's something we want to prove. We haven't actually proven it yet. But bears, yeah, bears, for example, will eat a lot of fructose in the fall. We did do a study in hibernating bears and they do get high blood levels of fructose when they're preparing for hibernation.

Melanie Avalon: Because I was thinking a lot about that. If the fructose signaling is required to start this preparation for hibernation. So, evolutionarily, what would have come first? How did we evolve to instigate this hibernating pathway? Did we eat the fruit first, and the fruit made us fat, and then that was a happy chance that made us be okay for winter or did we learn to gain weight and then associate it with fruit? I'm not articulating this well. I'm curious. So, for example, with the animals that are not eating fructose, but they're still turning on the survival switch and hibernating, why take that extra step to make fructose when they could just store the fat? Why would you even go that route?

Dr. Richard Johnson: Yeah, you're asking a really good question that I can't totally answer. But it seems like very early on in evolution, there was a distinction made between the kind of nutrients and the biology of their effects. It seems to me that glucose was really designed as being the immediate energy that animals use to do things in the immediate sense. Fructose seems to have been a fuel that was used to preferentially store calories. It seems like Mother Nature figured this out. For example, a lot of trees will-- fruits will ripen in the fall. The fruit will ripen in the fall and that's when the sugar content goes up. The trees time the fruiting of the tree to a period of time when the animals want to have fructose to store the extra fat in preparation for the fall and winter. There seems to be a timing. And then in turn, when the animals eat the fruit, they disperse the seeds to help the tree. It's like a symbiotic thing. There's even a fish I've commented on this in other podcasts. There's a fish called the Pacu that lives in the Amazon. When the Amazon floods--

Melanie Avalon: Eats the fruit.

Dr. Richard Johnson: Yeah, it eats the fruit out of the tree and the trees have a time. I read these papers going all the way back to the late 1800s. It's really interesting, but it's been noted that the timing of the floods, the times with the fruiting, and the ripening of the fruit, and the fish, everything's there perfectly. Then the fish eats the fruit, gets fat from it, because they eat so many. They get a big dose of fructose, because they're really eating a lot for their body weight. And then they get this fat and then they quit eating. The Amazon recedes and when it recedes back to its regular wherever they can go months with eating very minimal food and they kind of wait until the flood again, and then they go out there and get more fruit. There seems to be some a long-standing relationship that has developed between how these animals survive in nature. We've disrupted that. This is one reason I like intermittent fasting is, is intermittent fasting sort of goes back to the way nature wanted us, where we would put on a little fat than you need to burn it off? When you hibernate, you actually remove the food, you no longer have the food available, and then your body transitions into a point, where it's burning the fat. So, there's an argument that intermittent fasting is a great way, has evolutionary basis to it.

Melanie Avalon: Well, that actually brings me to a huge question I have for you. I'm excited. You brought that up. I actually first thought about this, not in your most recent interview with Peter Attia, but that first one that I listened to in 2020, and it's something that you touched on as well in this interview, which was the role of fructose in the cells and how its energy depleting. I don't think you mentioned this in the interview, but in your book, you talk about how it's converted to, is it ADP and AMP? My question is and how this relates to fasting is, the benefits of fasting, calorie restriction-- and/or calorie restriction are often attributed to AMPK. So, AMP activated kinase. How is that different? Because when I first heard you talk about fructose creating an energy deficit in the cell, normally, that's what we want is an energy deficit. So, how is that not activating AMPK, how is that not a good thing?

Dr. Richard Johnson: Okay. So, let's go through that. It's a complicated question. If it's okay with you, well, I like to do is take you through how the fructose works and its relationship with AMPK, okay?

Melanie Avalon: I'm so excited. I'm ready.

Dr. Richard Johnson: [laughs] Fructose lowers the ATP level on the cell, but not to zero, not to alarm that the cell is going to die, but it drops it 10%, 20%, which is like a warning. It drops it only 10% to 20%. The way it does that, it first consumes some ATP as the fructose is metabolized. It consumes the enzyme that metabolizes fructose does it so rapidly that there's this immediate drop in energy associated with metabolism or breaking down of fructose. It costs calories to make calories or to costs energy to make energy. Some energy is used up as the fructose is burned. There's this immediate drop. That immediate drop triggers because there's a fall in not just ATP but also phosphate. And that triggers an enzyme that is called AMP deaminase. That enzyme sweeps away AMP. When the ATP is used, it makes ADP and AMP. And then normally, the AMP would then be remade back to ATP. There's this normal shuttle where ATP goes to ADP and AMP and then they get remade back to ATP. But when you-- when you drop the phosphate in the cell, it activates an enzyme that takes away the AMP and makes uric acid. It's specific to fructose. So, glucose doesn't do that. 

Now, you don't have enough AMP to reconstitute ATP. At the same time, you're removing the AMP and making the uric acid. And then the uric acid goes into the energy factories themselves that actually localizes to the mitochondria and brings with it an enzyme that causes oxidative stress. You get this big oxidative stress in the mitochondria that slows down the mitochondria and it slows down both the fatty acid oxidation and the Krebs cycle or citric cycle. It makes the mitochondria make less ATP. Coming out of that, the energy instead of being made into ATP, it tends to be shunted into fat. Fat is a stored energy. Instead of making immediate energy, it's just that the stored energy. One of the ways that the uric acid also works in addition to working on the mitochondria is it inhibits the AMP kinase. There's a thing that's activated that helps burn fat, it burns fat and it burns glucose, basically and it's called AMPK and low AMPK characterizes diabetes. Things that increase AMPK can be used to treat diabetes. A stimulating AMPK is a good thing, because it causes burning of fat. When the uric acid goes up in the cell, it blocks that. You end up not being able to burn fat so well, and glucose levels go up in the blood as well, because it ends up stimulating this thing, where you start making glucose. The liver starts pouring out glucose. What's happened is when you eat fructose, you are resetting the energy to a lower level and you're inhibiting AMP kinase. 

Now, when you are starving and you have zero energy, you need to activate AMPK to make ATP, because you don't have enough to survive. Even though, you may have no fat, you'll try to burn whatever fat you have, you'll try to burn whatever glucose you have. You're trying hard to make ATP when the level gets really low. When we eat fructose, we're preparing for starvation, not actually being in the extremes of starvation. When you're in the extremes of starvation, you want to activate AMPK to help you survive. But when you're trying to store fat, you actually want to inhibit AMPK to help you store fat, and to raise glucose levels, and so forth. That's the difference. When an animal hibernates, and we did this study, the enzyme that is storing fat we call AMP deaminase. Its levels fall and AMP kinase goes up, and the AMP kinase then allows the animal to burn the fat while it's hibernating. When you're fasting, you're actually stimulating AMP kinase. So, that's good, because it helps you burn fat. AMP kinase is a good guy if you're wanting to lose weight and if you're wanting to gain weight, it's a bad guy. You want to inhibit it. So, does that help? 

Melanie Avalon: Basically, when you're taking in the fructose, it creates a little miniature, we're going to be starving soon, let's store energy compared to if you're actually starving or actually fasting, your body's like, "We have to generate energy." So, it starts burning energy. 

Dr. Richard Johnson: Right. So, immediate energy is what you need, if you're about to die. But if you get a warning sign that things are not good, you think can happen in the future, then you want to store energy.

Melanie Avalon: What if you combine those, what would be stronger? If you're fasting, you're actually starving, but then you have like a little bit of fructose. What would that do?

Dr. Richard Johnson: We've actually done some studies on this and then there's a beautiful paper in the literature on this, too. When you're starving, it's interesting. Or, even on a keto diet, your uric acid may go up, even though you're burning fat. Uric acid is supposed to block the burning of fat. When you're starving, the process to burn fat becomes stronger than the ability of uric acid to block it. We think the uric acid is actually helping, still bring-- raise glucose or to increase glucose up from the liver. We do think that it's still kicking in to help, but it's not-- When you're truly starving, the AMP kinase pathway just takes over and is stronger. You can actually show that. There's a paper that took starving animals and they had a high uric acid. When they gave them fructose, the fructose was turned completely into glucose. It went the other way. The fructose became an immediate fuel. Of all things that with starvation, uric acid tends to go up, because what happens is you use to start breaking down muscle. The way it works with starvation is once you run out of fat and glucose, you start breaking down your muscle using that as an energy source and that rapidly leads to death. But at that stage, uric acid goes up in the blood from the breaking down of muscle. The uric acid may actually be helping to drive glucose up. 

But anyway, so, if you give any kind of energy in a starving animal, it doesn't matter. So long as it's a calorie. The animal will use it to try to make ATP. It reroutes the system. Starvation is such a critical, near fatal, and sometimes, fatal event that animals will do everything they can to take any source of calorie and try to use it to survive. But the way we eat fructose, we're using it more as a warning sign. It creates a warning sign that we could that we could be in trouble. So, it's preferentially using this pathway that will lead to fat accumulation and inhibition of AMPK.

Melanie Avalon: I think a really practical takeaway from that and I'm not advocating going on severely restricted diets, but I think that dismantles the myth. There's this idea that if you are eating too low calorie of a diet, you'll enter starvation mode and they'll reach a point, where you won't lose any more weight. But it sounds like if you actually are, again, not advocating this as a dietary approach, but if you actually are starving, you are going to burn fat. That pathway is going to overtake the storage promoting pathway.

Dr. Richard Johnson: Yeah. The way it works is that the fat and the glycogen that we've stored, they are preferentially used when we're starving. Eventually, when they go get used up, then the muscles are broken down and that's really the very end stage and that's when people really die rapidly. There is a very, very strong mechanism when you starve to drop your energy metabolism. If you're not getting enough calories, the body tries to respond by reducing how much it will spend. It's not like hibernation, but there's a real move to reduce-- to slow your metabolism, especially when you're at rest. That can be quite significant. What happens is that people, when they start losing weight, they find they have to eat less to stay at the same weight. Let's say, you normally eat 1,800 calories a day and now, you want to lose his weight. You lose 10 pounds, but your body adapts to that by trying to lower its metabolism. Now, to eat this to stay at the same weight, this new weight, you have to eat less calories a day and this can make it very difficult. The way that you can get around that is, if you can improve your mitochondria. 

The mitochondria are your energy factories and they make ATP. As we get older, they work a little bit less well. As we get overweight, chronically being overweight, also wears them down. What you need to do is to try to keep the energy factories strong. There are certain foods that do that. Vitamin C is good for that, by the way, dark chocolate is good for that. But the best way is to have an exercise program and to try to exercise and what we call Zone 2, where you raise your heart rate enough, so that you are getting the muscles working, but you're not going into exhaustion very quickly, and you don't build up lactic acid in your blood. The classic teaching is to exercise until you have trouble talking. As soon as you-- if you can still talk while you're exercising, but just barely, that's perfect. If you can't talk, you're probably going too fast. And if you can talk easily, you're probably exercising too slowly. Get on a stationary bike, or whatever, walking, or jogging. But that's what they recommend. Then by improving your mitochondria, then when you lose weight, you can still eat your 1,600 calories a day without having to worry about regaining the weight. 

Melanie Avalon: I have so many more questions, but I want to be super respectful of your time. But one last question I could ask would be, because you touched on the vitamin C, because I think listeners might be a little bit nervous right now about fructose and fruit, and fruit is high in vitamin C, and some other nutrients that possibly might counteract these issues. All of these studies on fructose, do we find any of this with whole fruit?

Dr. Richard Johnson: Yes. I've done studies on whole fruit, both clinical studies, as well as we've done research studies on the components and fruit. Natural fruits, whole fruits contain substances that block fructose effects but it's when the fruit is not super ripe. Fruit contains vitamin C, and it contains potassium, and it contains flavanols, and all of these are substances that actually block some of the effects of fructose, so does fiber. It's like the plant doesn't really want the animal to eat the fruit when it's tart. They want to wait for the fruit to ripen so the seeds are maturing and can seed well. When the fruit is in the early phase and immature fruit, it tends to be very high and stuff that's very good for us. And then as the fruit ripens what happens is the vitamin C content goes down and the sugar content goes up. By the time it falls off the tree, when the animals start eating it, it doesn't have much vitamin C anymore or flavanols and it is mainly fructose rich, and then they eat a lot of them, and bingo they can activate this pathway to gain weight. But we thank God. We tend to like tart fruit, we tend to like fruit that is often high in vitamin C. These flavanols like luteolin and quercetin, David Perlmutter has pointed out that some of these flavanols not only block fructose, but they block uric acid, they can lower uric acid. 

We've actually done studies. If we give vitamin C, we can reduce the effects of fructose to gain-- to cause obesity in animals. If we can do something similar, I've given potassium, so some diuretics that are used in hypertension are known to cause metabolic syndrome as a side effect, and they tend to raise uric acid and lower potassium. If we lower uric acid or raise potassium, we can block the effects of these diuretics to cause metabolic syndrome. Since fruits have a lot of potassium, I'm thinking that's probably a protective mechanism as well. There's a lot of good things about fruit. When we did a diet in people in Mexicans, who are overweight, where we put them on a low-sugar diet with fruit supplements, so we put them on a low-fructose diet, they were basically low fructose for added sugars, but they could get natural fruit, and the other group was just low fructose across the board. What we found was that when they had natural fruit supplements, they liked the diet more, and they lost weight just as well, and they had improvement in their metabolic syndrome just as well.

Eating natural fruits are good. I don't think you want to eat a bowl of grapes at one setting, you don't want to eat lots of fruit at the same setting. But a natural fruit is a great way to go, I would recommend one with each meal. A nice apple or something like that would be a good thing to do. Also, there's the amount of fructose in the fruit and some fruits have very little fructose, some have more. In my book, I talk about which ones tend to be better. Figs, in particular, are very rich in sugar. It's not all fruits are good, but anyway, there's a science to this. So, I think if you're interested in and you want to read more about it, you can do so in my book.

Melanie Avalon: Yes, listeners. Get Nature Wants Us to Be Fat. We only briefly, barely touched an echo of everything that is in this book. Thank you so much for your time. I've been looking forward to this for so, so long. It was incredible. The last question I ask every single guest on this show and it's just because I realize more and more each day how important mindset is. So, what is something that you're grateful for?

Dr. Richard Johnson: Oh, I'm grateful to be able to have the opportunity to do research and to take care of my patients. I was very lucky that I chose this path to become a doctor, and I'm still a clinician, and practicing physician. I'm very grateful for being able to try to help people, both my patients and to do research, where we can try to understand the causes of disease. I'm grateful that COVID is finally ending.

Melanie Avalon: Yeah, it's a nice thing. Well, thank you so much. I am so, so grateful for your work. I'm just in awe of everything that you're doing. It's incredible. I can't wait for listeners to get your book. If it's okay with you, I feel I'm probably going to email you some other questions I have. But thank you so much. Any links you want to put out there for listeners to best follow your work?

Dr. Richard Johnson: Okay. Well, I do have a website. It's drrichardjohnson.com. We post lots of little stories there. So, that would be a good site for us.

Melanie Avalon: Awesome. Well, I'll put that in the show notes. Again, the show notes are at melanieavalon.com/fructose. And thank you so much, Rick. This was amazing. I'm just so happy. Thank you for coming on the show. 

Dr. Richard Johnson: Thank you, Melanie. 

Melanie Avalon: Bye.

Dr. Richard Johnson: Yeah, bye.