Episode 273: Uric Acid And Fat Gain, Fruit & Fiber, Vitamin C, Oxidative Stress, Low Fructose Diets, Metabolic Flexibility, And More!

Intermittent Fasting


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Jul 10

Welcome to Episode 273 of The Intermittent Fasting Podcast, hosted by Melanie Avalon, author of What When Wine Diet: Lose Weight And Feel Great With Paleo-Style Meals, Intermittent Fasting, And Wine and Cynthia Thurlow, author of Intermittent Fasting Transformation: The 45-Day Program for Women to Lose Stubborn Weight, Improve Hormonal Health, and Slow Aging.

Today's episode of The Intermittent Fasting Podcast is brought to you by:

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To submit your own questions, email questions@IFpodcast.com, or submit your questions here!! 


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

Ep. 205 – Fructose – The Driver Behind Metabolic Disease with Dr. Rick Johnson

rick's Beginning

the surprising truth about hummingbirds

blood glucose metabolism in hummingbirds

fending off metabolic damage from excess sugar consumption

endogenous antioxidants

JOOVV: For A Limited Time Go To Joovv.com/ifpodcast And Use The Code IFPODCAST For An Exclusive Discount!

metabolic flexibility and the survival switch

seasonal weight


how fructose can block fat burning 

the polyol pathway; turning glucose into fructose

AVALONX SERRAPEPTASE: Get On The Email List To Stay Up To Date With All The Special Offers And News About Melanie's New Supplements At avalonx.us/emaillist, And Use The Code Melanieavalon For 10% On Any Order At Avalonx.Us And MDlogichealth.Com!

Nature Wants Us to Be Fat: The Surprising Science Behind Why We Gain Weight and How We Can Prevent--and Reverse--It 

is whole fruit ok? 

how fiber factors in

low fructose diet

vitamin c 

oxidative stress

Unripened Fruit

AMPK, AMPD and Metformin

Our content does not constitute an attempt to practice medicine, and does not establish a doctor-patient relationship. Please consult a qualified health care provider for medical advice and answers to personal health questions.


Melanie Avalon: Welcome to Episode 273 of The Intermittent Fasting Podcast. If you want to burn fat, gain energy, and enhance your health by changing when you eat, not what you eat with no calorie counting, then this show is for you. I'm Melanie Avalon, biohacker and author of What When Wine: Lose Weight and Feel Great with Paleo-Style Meals, Intermittent Fasting, and Wine. And I'm here with my cohost, Cynthia Thurlow, Nurse Practitioner and author of Intermittent Fasting Transformation: The 45-Day Program for Women to Lose Stubborn Weight, Improve Hormonal Health, and Slow Aging. For more on us, check out ifpodcast.com, melanieavalon.com, and cynthiathurlow.com. Please remember, the thoughts and opinions on this show do not constitute medical advice or treatment and no doctor-patient relationship is formed. So, pour yourself a mug of black coffee, a cup of tea, or even a glass of wine, if it's that time and get ready for The Intermittent Fasting Podcast.

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If you recently saw a documentary on Netflix called Seaspiracy, you might be a little bit nervous about eating seafood. Now, I understand why ButcherBox makes it so, so clear and important about how they work with the seafood industry. Everything is checked for transparency, for quality, and for sustainable raising practices. You want their seafood. The value is incredible, the average cost is actually less than $6 per meal, and it's so easy. Everything ships directly to your door. I am a huge steak lover. Every time I go to a restaurant, I usually order the steak. Oh, my goodness, the ButcherBox steaks are amazing. I remember the first time I had one and I just thought, “This is honestly one of the best steaks I've ever had in my entire life.” On top of that, did you know that the fatty acid profile of grass-fed, grass-finished steaks is much healthier for you than conventional steaks. And their bacon, for example is from pastured pork, and sugar and nitrate free. How hard is that to find? I'm super excited, because ButcherBox’s bacon for life is back and it's even better, because you get $10 off as well. Yep, right now, new members will get one pack of free bacon in every box for the life of your membership, plus $10 off when you sign up at butcherbox.com/ifpodcast. That's one pack of free bacon in every box for the rest of your life, plus $10 off. Just go to butcherbox.com/ifpodcast. And we'll put all this information in the show notes.

And one more thing before we jump in, are you fasting clean inside and out? When it comes to weight loss, we focus a lot on what and when we eat. It makes sense because these foods affect our hormones and how our bodies store and burn fat. But do you know what is possibly, one of the most influential factors in weight gain? It's not your food and it's not fasting, it's actually our skincare and makeup. As it turns out, Europe has banned over a thousand compounds found in conventional skincare and makeup in the US due to their toxicity. These include endocrine disrupters, which mess with your hormones, carcinogens linked to cancer, and obesogens, which literally can cause your body to store and gain weight. Basically, when we're using conventional skincare and makeup, we are giving these obesogenic compounds direct access to our bloodstream. And then in our bodies, studies have shown they do things like reduce our satiety hormones, increase our hunger hormones, make fat cells more likely to store fat, and more resistant to burning fat, and so much more. If you have stubborn fat, friends, your skincare and makeup maybe playing a role in that. Beyond weight gain and weight loss, these compounds have very detrimental effects on our health and they affect the health of our future generations. That's because ladies, when we have babies, a huge percent of those toxic compounds go through the placenta into the newborn. It is so, so shocking and the effects last four years. 

Conventional lipstick, for example, often test high in lead and the half-life of lead is up to 30 years. That means, when you put on some conventional lipstick, 30 years later, maybe half of that lead has left your bones. On top of that, there is essentially no regulation of these products on the shelves. That's why it's up to us to choose brands that are changing this. The brand that is working the hardest to do this is Beautycounter. They were founded on a mission to change this. Every single ingredient is extensively tested to be safe for your skin, so, you can truly feel good about what you put on. And friends, these products really, really work. They are incredible. They have counter time for anti-aging, counter match for normal skin, counter control for acne and oily prone, and counter start for sensitive. I use their Overnight Resurfacing Peel and vitamin C serum every single night of my life and their makeup is amazing. Check on my Instagram to see what it looks like. Tina Fey, even wore all Beautycounter makeup when she hosted The Golden Globes. So, yes, it is high-definition camera ready. They have so many other products, deodorant, shampoo and conditioner that I love, products for babies, and so much more. You can shop with us at beautycounter.com/melanieavalon or beautycounter.com/cynthiathurlow and use the coupon code, CLEANFORALL20 to get 20% off your first order. Also, make sure to get on my clean beauty email list. That's at melanieavalon.com/cleanbeauty. I give away a lot of free things on that list. So, definitely check it out. You can join me in my Facebook group, Clean Beauty and Safe Skincare with Melanie Avalon. People share their experiences, ask questions, give product reviews, and I do a giveaway every single week in that group as well. 

And lastly, if you're thinking of making Clean Beauty and Safe Skincare, a part of your future like we have, we definitely recommend becoming a Band of Beauty member. It's sort of like the Amazon Prime for clean beauty. You get 10% back in product credit, free shipping on qualifying orders, and a welcome gift that is worth way more than the price of the yearlong membership. It is totally, completely worth it. So, again, to shop with us, go to beautycounter.com/melanieavalon or beautycounter.com/cynthiathurlow and use the coupon code, CLEANFORALL20 to get 20% off your first order. And we'll put all this information in the show notes. All right, now, back to the show.

Melanie Avalon: Hi, friends, welcome back to the show. I am so excited for you guys for our conversation today because this is a super special episode of The Intermittent Fasting Podcast. We very rarely have guests on this show. If we have a guest on the show, it's because you know that we really, really love the work, and the thoughts, and opinions, and knowledge, and science of the guests that we brought on. I am so honored to be here today with Rick Johnson. The backstory on this is, I was first exposed to Rick's work a few years ago. I heard him on Peter Attia’s podcast and you guys know that we love Peter Attia. I was fascinated because I personally am very fascinated with the role of fructose in our diets. I know that's a very granular thing to be obsessed with, but I was so excited that there was somebody else who was really looking at the science of fructose metabolism. And so, I got his first book, The Fat Switch, and then fast forward, I really, really wanted to interview him, and then I heard him again much more recently, again on Peter Attia’s podcast because he has a new book out called Nature Wants Us to Be Fat: The Surprising Science Behind Why We Gain Weight and How We Can Prevent--and Reverse--It. I was like, “I've got to book him for the show for the Melanie Avalon Biohacking Podcast. 

Then his people actually came to me, his publicist or PR people asking to come on the show. I was so, so excited. That episode, actually, as of our recording right now is actually airing today on the Biohacking Podcast. But when this comes out, that will have been a few weeks ago. But I just so enjoy that conversation and since then, Rick and I have been emailing, and diving deeper into the science of everything, and I just knew I had to bring him on this show to share all of his incredible work with you, guys. I'm really happy right now. Rick, thank you so much for coming on the show.

Richard Johnson: It's an absolute pleasure really. [laughs] 

Melanie Avalon: I was just telling you this offline, but for Cynthia Thurlow’s other podcasts for listeners, she also recently aired an episode with Rick and said it was her most downloaded episode of the year. She interviews a lot of heavy hitters. So, that's pretty cool. This content is definitely resonating with people. Rick, for people who are not familiar with you, there might be some people who have listened to your other episodes, but for those who are not, what is your story? You're currently a professor of medicine at the University of Colorado, but what led you to where you are today with your fascination with fructose and this thing called the survival switch, and obesity, and just everything?

Richard Johnson: I went to medical school, trained to be a physician, and did my specialty in kidney diseases as well as internal medicine. But from the very start, I always was very interested in the “why” not just how to manage a person, but why were they developing diabetes, why were they developing kidney disease? And so, I began my career quite a few years ago, where I was both a clinician, as well as a researcher. I’ve got a lot of funding from the National Institute of Health to help me along the way and over the last [unintelligible [00:11:08] years, I've been doing research. It started off in kidney disease and then I became interested in high blood pressure because high blood pressure is linked with the kidney. From there, I discovered that there was a substance in our blood called uric acid and that substance was very strongly associated with high blood pressure. We actually found evidence that it might actually play a role in high blood pressure. Big surprise and I just kept following my nose along the way to try to figure out what was this pathway and then pretty soon, I became interested in, “Well, okay, if uric acid is so important, what's driving the uric acid up in our population,” because there's a lot of people with high uric acids.

The classic teaching was, it was from eating purine-rich foods, because high uric acid is associated with a disease called gout. It's associated with drinking beer, and eating a lot of meats, and stuff. But there's another food that dries up uric acid and its sugar. Table sugar or high fructose corn syrup contains fructose. Fructose is a carbohydrate, it's sugar in fruit. But if you eat it, it will generate uric acid. And particularly, if you eat a lot of it, you can really raise the uric acid inside your body and it turns out that that led me to some big discoveries, because the uric acid turned out to have a role in driving obesity and diabetes, and it led me to realize that fructose was really a culprit. Then from there, I started studying fructose and I found out that it wasn't just the fructose that we eat, but that our bodies can make fructose. This opened the door for what might be causing the whole obesity epidemic.

It was a long story. It took me everywhere. I did studies in hibernating animals, and I did studies in people, I did studies in genetically modified mice, and I did studies in indigenous tribes living in the jungle, I even did studies where we resurrected extinct genes. So, I've been around and really, it has been an adventure story, Melanie.

Melanie Avalon: I love it so much. And actually, to that point, your book, one of the things I really love about it is it reads like an adventure story, especially the very beginning where you're talking about, it's like a mystery of why did we become fat like as a society? You talk about really fascinating things that happen in animals. Could you tell listeners about the hummingbird for example?

Richard Johnson: Yeah. [laughs] Oh, we think that the hummingbird is this magnificent bird that's has the fastest metabolism of perhaps all birds. I think that it's flaps its wings, what, 250 times a minute. It has an incredible metabolism. You would think that that bird must be the healthiest bird in the world. But it lives off nectar and nectar is really sugar water, and that contains a lot of fructose. It contains fructose and glucose. When that hummingbird drinks this nectar, it is getting a very large amount of sugar. What happens is, during the day, that sugar is so strong that the little bird becomes diabetic. Its blood sugars go up to 500. Perhaps, the fattest liver of any bird, turns like glistening white. And so, by the end of the day, It's fat and diabetic. Then during the night, it will rest, and it will burn off the fat and the glucose, and in the morning it will be back to its normal state. And so, it's like intermittent fasting, [laughs] because a little bird gets really fat and then he fasts through the night. Interestingly, if they burn off all the fat and the carbs, then the he’ll go into torpor, which is a hibernation state, where they drop their metabolism, drop their blood temperature and all that, their body temperature. So, yeah. No, it's a very interesting bird.

Melanie Avalon: With those huge spikes in blood sugar, which that blew my mind when I first read that, is it getting the effects of glycated hemoglobin? Does it have an HbA1c and things like that? How does it long term, how is it handling those spikes?

Richard Johnson: Well, one of the interesting things is, first off, there's not a lot of studies of hummingbirds long term. But what has been done suggest that they actually do all right, so that they're-- What happens is that they have such good mitochondria and they have this very good protective system to help protect the mitochondria from getting permanently damaged. They pair to not get diabetic complications. They've been able to survive diabetes without the complications. Again, no we can talk about what drives diabetic complications and all that kind of thing, but it's really interesting that these guys will raise their blood sugars to over 500. These are very high blood sugar levels, but they seem to be relatively protected. Although, I think more studies really need to be done, but the initial reports suggest that they're pretty protected even though they're very diabetic.

Melanie Avalon: Does that insinuate? This is completely theoretical and not real life at all. But if we could have a metabolism fast enough to burn off everything that we are eating or if we could literally exercise until we exercised off all of our excess calories that we could mitigate damage ourselves?

Richard Johnson: I think that that's true. There are people who have super mitochondria. There really are. There are people running around they tend to be the super athletes. Studies done in these super athletes, these professional athletes, like the guys that win the Tour de France, they have such wonderful mitochondria that they have what we call metabolic flexibility, where they can burn carbs and fat, intermittently going back and forth very freely without any problems. One of the things they have is they have a very high antioxidant system in their mitochondria that helps protect the mitochondria from damage. I have a friend who coaches in the Tour de France and he points out that a lot of these super athletes appear to eat sugar without a problem. Now, my belief is that if they pounded themselves with sugar and fructose that they would get into trouble over time but it is interesting. 

There's this naked mole rat. This is a little guy who burrows into the sand in South Africa. They live in these burrows where there's almost no oxygen, even though they have very low oxygen system. There's low oxygen there and it would normally kill most animals. They've developed a system where they can survive in that low oxygen state. One way they do that is they produce huge amounts of antioxidants in their mitochondria that protect them from the effects of hypoxia. It's interesting. There's a fructose story there, too, but I should probably bring that up later. But basically, if you can have super mitochondria, you can survive under a lot of stress and you can survive in the presence of sugar. I should say that these little naked mole rats make fructose to survive, but they don't suffer the consequences of the fructose because of this high-powered antioxidant system they develop.

Melanie Avalon: To clarify for listeners, because I think a lot of people hear antioxidants and they think exogenous antioxidants. So, they think antioxidants from fruits and vegetables and things like that. But these are antioxidants that our bodies are creating endogenously, right?

Richard Johnson: That's right. They're making it themselves. There's one called Nrf2. This antioxidant is strongly associated with living longer. I have a friend at the Karolinska, who studies this antioxidant. He can show that in many, many species that if you can maintain a high Nrf2 you can live longer. It's actually linked with sugar because if you eat sugar, you induce oxidative stress to the mitochondria. You can accelerate aging in animals by giving them fructose. And so, fructose does this by making the mitochondria put them under stress. That hummingbird is creating oxidative stress in his mitochondria and that would normally be associated with developing obesity and all these complications that would persist. But by keeping the antioxidant system high, which the hummingbird has genetically, by having that very high antioxidant system, he can protect his mitochondria. The super athlete has this incredible antioxidant system and the naked mole rat, which lives 30 times longer than a normal rat. It lives 30 years, whereas a normal rat lives two years. It's thought to be because of this Nrf2, this antioxidant system. 

But it's interesting, this Nrf2 system can be knocked down. One way, it can be knocked down is with fructose. I keep thinking, “Well, the hummingbird is eating all the sugar, he's got this high Nrf2. Can over time this be weathered down and knocked down?” That's why I'd like to see more studies done in the hummingbird and in the naked mole rat where they have this Nrf2. Because we know that if you take human cells and you treat them with fructose, the Nrf2 is knocked down and you get this oxidative stress, and you can accelerate aging. And so, it's a really interesting thing. The antioxidants in the mitochondria are really important at protecting the mitochondria from the complications of obesity, diabetes, and aging. And fructose is usually something that makes things worse and things like these antioxidants can protect against fructose. Some animals that are eating a lot of fructose or making a lot of fructose seem to do well, because they have a high level of these antioxidants. But like us, normally, we don't. But if you're super human-- [laughs]

Melanie Avalon: Jealous. 

Richard Johnson: Yeah, I’m jealous of those guys, too.

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Melanie Avalon: I'm so glad you're using these words, stress and you dropped in the word, metabolic flexibility, which is something that our listeners love hearing about and we talk about a lot in this show. I think a foundational question here. Because you're talking about activating the stressed out state and how that's a problem, what is that survival switch and how is it different from being in the survival state of fasting, which has a lot of benefits to it?

Richard Johnson: The very first major discovery we had was that there seemed to be this substance in our blood called uric acid. This uric acid is generated from foods we eat, but we also can make it. This uric acid, when it gets high, that can be associated with a disease called gout. You can get these uric acid can crystallize at high concentration and these crystals end up in the joints, particularly the big toe, and you get gout. That was noted a long time ago that gout is associated with being overweight or obese, and it's also associated with being diabetic, and it's associated with all kinds of conditions that aren't particularly what we would like to be. For a long time, it was thought that, “Oh, people who are overweight or obese are at increased risk for getting gout” and it's really the obesity that's leading to the gout. But in fact, our work started to suggest that uric acid might actually have a role in driving obesity. We found evidence that people with high uric acids where risk of developing obesity in and of developing diabetes. And so, that led us to try to understand what could raise the uric acid and it took us to fructose.

Fructose, when you give fructose to an animal, normally, animals regulate their weight just beautifully. If you overfeed it or it will gain weight, but then you stop over feeding, it will come back to normal weight. If you fast, it will lose weight because you're taking away its calories. But then as soon as you let it eat again, it will go right back to the weight it wants to be. Most animals want to carry a little bit of fat, but not a lot of fat.

Melanie Avalon: Can I ask you a quick question?

Richard Johnson: Yeah. 

Melanie Avalon: Doesn't it go back to the weight that correlates to the season?

Richard Johnson: Yes, yes, it does. Usually, in the spring animals and the summer animals will really regulate their weight well. But as winter comes and food becomes less available, animals will start to increase their weight in the fall, in preparation for winter. The biggest case, of course, are animals that hibernate. There're some animals that they can't find enough food during the winter that they will actually hibernate and they will drop the metabolism, they'll go into a burrow or something, and they'll just basically go to sleep, and drop their heart rate, they drop their temperatures, and they won't eat, they won't drink, they won't pee, anything like that for maybe three to six months. The bear can hibernate for four to six months. During that time, it's not eating or peeing or anything. It lives off its fat during that time. The fat doesn't just provide energy, but when the fat’s broken down, it produces water. There's this really interesting thing. We don't think of fat as a source of water. Normally, most of us don't. But fat is a source of calories and it's a source of water. When you eat food, you're making calories you eat are turned into energy. Most of the time, we think of energy as this thing, ATP is what we call it in science. This is basically a chemical that activates processes and generates energy. This ATP is what we usually call our immediate energy.

But there's also a stored energy and that's fat. When you're eating calories, they usually are either burned as active calories like ATP or they're stored as fat, and then the fat is later burned to generate energy when you're not eating any foods, so the fat becomes that source of energy, when there's no food around. These animals, all animals like to have a little fat because they want-- In case, if something happens and they don't get any food for a while, they can basically generate the energy they need from their fat, but they also generate water from their fat. Fat becomes a survival tool for animals in the wild. It led to my Nature Wants Us to Be Fat, because these animals would like, for example, if you're a burden, you're going to migrate 10,000 kilometers. You want to have enough fat, so that you can burn it, and get the water and energy you need, so, you don't have to try to find food when you're halfway over the ocean. Because if you're a land bird, that's not a good thing to be.

Anyway, so, what happens is, these animals will gain weight dramatically in preparation. This is the cool. They do it in preparation before they know there's no food around. Beginning in the fall, for example, the bear will start gaining eight to 10 pounds a day and it does that by eating huge amounts of food. Normally, I told you, animals regulate their weight. They have a sensation of when they're full and so, they won't keep eating. But they lose that sensation of fullness in the fall. Suddenly, they will keep eating, and they will eat huge amounts of food, and they'll get fat, and then they'll survive with that fat when they hibernate. So, there's a little bit of evidence that people also tend to gain weight during the winter months, as you probably have read. 

Melanie Avalon: So, do we gain during the winter, do we gain leading up to the winter?

Richard Johnson: Well, that's a good question. For the animals that hibernate, they will keep gaining until they actually hibernate. When they hibernate, they're obviously not eating it off. We tend to keep eating into the winter, [chuckles] as well as during winter. Actually, we're pretty much eating too much all the time if you look and so the problem is, it says, if we have activated this switch to gain weight in a 24/7 pattern. But this was one of the questions that we had. What happened is, we realized that these animals were gaining weight in the fall and they weren't just gaining weight, they were eating more, they were hungry, they were thirsty, and they also became insulin resistant. They develop these features, we call metabolic syndrome. They're foraging for food, and they're eating too much, and they're getting fatty liver, and the fats are going up in their blood, as well as in their adipose tissue, and they're gain insulin resistant, and we go, “Oh, my God, this is what we call abnormal. This is what we call metabolic syndrome.” We consider this almost a disease among people, right? But if you're a bear, this is normal. This is what you want. It's a survival pathway, because if they didn't do this, they might get into trouble. 

When there's no food around, it's late then to store fat. We realized that this whole process was really a survival switch, and that it was turned on, and it was something that animals do to help them survive. This was the first big discovery that really in our group was that there was the survival switch. The metabolic syndrome, what we call-- When people come in and they go, “Yeah, my hemoglobin A1C is high, my blood sugar's a little high, I've got high triglycerides in my blood.” This is part of a syndrome. You have activated the switch. That's what's going on. This was the first big thing. Then the question you had was, “Why would insulin resistance be a survival switch? Why would that be part of a survival switch?” It causes diabetes. Diabetes is associated with increased risk for death. Why would an animal want to be prediabetic? The interesting part is that the brain loves glucose. It’s his favorite fuel, okay? Glucose is its favorite fuel. It will use ketones as well, but it loves glucose, says, it's ideal fuel. Glucose is regulated by insulin and Insulin is the hormone that goes up in our blood, drives glucose into tissues. There're certain tissues that are particularly insulin responsive and the big one is muscle. When you become insulin resistant, there's less glucose going into the muscle, so the glucose begins to collect in the blood and the brain doesn't really require insulin at least for much of the brain. 

It's a way of shunting the glucose from the muscle to the brain. If the animal could think about survival, if it really could do that, it would want to have the glucose that it has be preferentially use for its thinking, rather than for its muscle, because if you can't think, you're not going to do well out in the wild. Insulin resistance is really a way to help an animal when it does not have enough food around to help preserve the glucose, mainly for brain function. There's a scientist that I've worked with who studied starvation and things like that, and when you starve, not only does your insulin levels go down, but you become relatively insulin resistant as well. It's all meant to help when there's no food around, you want that glucose primarily to go to the brain.

Melanie Avalon: The big paradigm shift here are also a debate in a chicken and egg question is, it sounds some people will say, you become overweight or obese and that causes metabolic syndrome. But this sounds more metabolic syndrome has a purpose to make us overweight and obese?

Richard Johnson: Yeah, metabolic syndrome is really another name for a collection of signs and symptoms to help you survive a period of time when there's no food. If you want to maximize how to help yourself during a time when there's no food, you want to have the metabolic syndrome because you want to be insulin resistant, you want to have high fats, and your blood and your liver and everywhere, so that you have enough fuel to survive when there's no food around.

Melanie Avalon: So, what's happening when we practice intermittent fasting? Is that stimulating all of this because we're in a “starvation state” during the fast?

Richard Johnson: Okay. When you quit eating, you're actually not necessarily activating the switch right away. Because you have fat already, everybody has some fat. When you fast, you begin by burning the glycogen and fat that you have. A normal animal, if it starts fasting will not activate the switch. When the animal that gets really fat like the bear, and he gets really fat, and then winter comes and there's no food around, and that's usually the time when they can't find any more food, they'll hibernate, and they switch into a fat, they switch into a burning phase. First, they burn the glycogen, which is the carb stores, and they disappear within a day or two, and then they will burn the fat, and it is a very healthy thing. They're not foraging, they're not hungry, they're sleeping and they're just burning the fat, and they get rid of the fat. Then in the spring, they may have just a tiny bit of fat left and many times, they won't have any fat left and that may actually help stimulate them to wake up actually. Then they wake up and they're back to normal.

When you're intermittent fasting, most people who are intermittent fasting have some fat stores and they have-- Everybody has some fat stores and some glycogen, right? If you intermittent fast, you are burning the glycogen and you're burning the fat. When you're burning the glycogen and fat, everything is fine. You're not in trouble, you're not in trouble. But as soon as the fat burns away, then you know what they have to burn? The protein. That's the only thing. Yeah, the muscle. One of the first things that's released is uric acid and that is like an alarm signal and it turns on the switch and they start foraging, they’re looking for food, and they're desperate. But now, they've turned on the switch in a situation where there really are starving. They've done studies with penguins. The emperor penguin is this magnificent bird. It is. I want to go to Antarctica and see one of these guys. Apparently, there was a penguin that was six feet tall ones.

Melanie Avalon: I was going to say, how tall are they? Yeah, they're tall.

Richard Johnson: These are four feet, I think three to four feet or so three feet, maybe. But there was a penguin that was six feet. That's the penguin, but it's extinct now, unfortunately. The colossus penguin. But anyway, the emperor penguin is this huge penguin and it will get fat in the Antarctic before it nests. The emperor is one of the few birds that nest during the winter. It's nesting during the winter in the Antarctic. It has to store-- It does the same thing. It gets usually fat. Usually fat. It almost doubles its weight. Its liver gets really fat. Birds get particularly get fatty liver. Then it wattles in inland and then the male actually does the nesting, because the male is a bigger bird, so, it can carry more fat. And so, it can survive longer than the female in the winter. When it's nesting, the male will sit on the egg because it knows that it may not that winter’s a long time down there and it can take a while. It wants to have enough fat and so, the male has more fat, so it can last longer. But sometimes, the male doesn't have enough fat. If it runs out of its fat while it's burning the fat, it completely feels good. It just sits there, it's not in distress, same thing is true with people who are fasting. 

If you're just burning the carbs and the fat, it's generally not a stressful situation from the standpoint of survival. But once the muscle starts breaking down, the penguin will desert. It will leave the egg, and will try desperately to get back to the coast to get some food, and it will start making sounds, calling sounds and foraging. It's like a stressful period. If it doesn't get food, it will die. What's interesting is that what heralds, that shift is a rise in uric acid because uric acid is released and is generated when muscles breaking down. That was actually a clue to us that uric acid might be a survival factor and so, it was interesting that fructose raised uric acid. Then we started studying, “Well, why does fructose raise the uric acid and what's the uric acid doing?” What we found is that when you give fructose to an animal, it creates a pseudo starvation state. What happens is, when you eat fructose, inside the cell, the fructose causes this drop in phosphate. And phosphates are critical for energy production, phosphate is part of ATP. ATP, the P part is a phosphate. The way the ATP works is that it donates a phosphate to generate and drive chemical reactions. That's how energy is activated really. What happens is when you eat fructose, there's this acute fall in phosphate inside the cell. When that happens, the ATP levels fall. The breakdown of ATP gets turned into uric acid and then the uric acid keeps the energy levels in the cell low for a prolonged period of time and it does so by causing oxidative stress to those energy factories that are making ATP. It causes oxidative stress to these mitochondria and that suppresses the mitochondrial function. 

Now, again, if you're a super athlete, that's not going to happen. Your mitochondria are strong enough to weather. Your hummingbird, it's not going to happen. Because at least, acutely, you can weather that storm. But for most of us, when that mitochondrial stress occurs, it suppresses the mitochondria, keeps the ATP levels low, and that activates an alarm system. Basically, the animal thinks to itself, “You know what, my energy levels are low. I'm in trouble.” Normally, if my energy levels are low, my fats going to kick in and start being broken down to provide that missing energy. But what fructose does is, it blocks the burning of the fat at the same time. It's suppressing the ability to break down the fat. When the ATP levels fall, the only way to replenish it is to eat more. You can't use that fat, because the fructose is blocking your ability to burn the fat. And so, what happens is you become hungry and you start eating more, and then more food comes in, and again you've got this shunt going on. More of the calories are going to stored fat rather than to ATP. The ATP levels will continue to stay low for a while, and then eventually, you'll correct it, but at the expense of eating a lot more food. So, it's this brilliant system. 

Basically, when you eat fructose, your body thinks it's starving. It will continue to stimulate processes to store fat, to become insulin resistant, but you're actually not starving. It is pseudo starvation. Because you have fat on board and it's only getting bigger, more from this. It's a way to get the animal instead of regulating this weight so perfectly, I'm going to stay skinny. Now, suddenly, you're gaining weight. When people are young, when you're 20 years old, and you're out running on the beach, and you have all the energy in the world, you can drink that soft drink and it's not going to really have a big effect. You're not going to see sudden weight change or anything like that because your mitochondria are pretty healthy and it takes repeated insults, repeated times. But in this world, where 70% of processed food has sugar in it, where soft drinks are everywhere, where they're putting all this kind of foods around, and this high fructose corn syrup is being added to everything. We're being hit hard ,15%, 20% of our diet is from these added sugars. And so, we're chronically activating this switch. Some of us do it better than others or worst-- [laughs] look at it. And so, some people gain weight a little bit easier than others, some are still doing pretty well, and you can battle it by exercise, you can battle it by willpower, but this is a biologic process. So, it's hard to have the willpower chronically when there's a biologic process saying that you're hungry, this looks good. So, this is what's going on.

Melanie Avalon: Basically, when we're eating sugar, and high fructose corn syrup, and things like that, it's really ironic. Because we're taking in calories, we're taking in energy, but it's stopping our body from actually burning energy, so, our body needs to eat more, which is ironic.

Richard Johnson: That's exactly how it works. It's like tricking the system and it turns out when we started studying this, we realized that glucose is actually, really there as an immediate fuel. It's really meant to make ATP, it's not meant to really be a storage mechanism. Fructose, though, is the carb that's really trying to aim at storing energy, as opposed to immediately using energy. Now, I know you're going to say, well, but I know that eating bread, and rice, and potatoes, and French fries, and they don't have fructose in them, but they're fatty. We know that from low-carb diets how powerful bad carbs can be. This was a challenge. This was a challenge to me. Because when I was originally doing this work, and we were giving fructose to animals, and they developed metabolic syndrome, and then we could see that a lot of animals were eating fructose to create metabolic syndrome as a survival mechanism, it seemed the answer was going to be easy. We just had to avoid foods with fructose. I even wrote a book, The Sugar Fix back in 2008. It was one of the first books to say, “The problem is fructose. It's not anything else.” I had a lot of people write me, email me, tell me, “Oh, my God, when I quit eating sugar, I lost 25 pounds, I feel great. Thank you so much.” 

Then of course, you can't completely stop eating sugar. I don't recommend that either. It's a birthday or something, I'll eat sugar. Anyway, the idea was to really limit sugar. Then I had these people contacting me and saying, “I'm sure sugar is important, but I have to cut out all carbs. I really have to cut out starch and especially, high glycemic carbs,” carbs that release glucose into the blood like potatoes, rice, cereal, chips. I knew that they were right because I knew that when I ate bread it seemed like I would gain weight. There's not a lot of sugar in bread, there's a little. Then I said, “Okay, well, buy bread that doesn't have much sugar at all.” I found that I still. There was something about bread and me that was making me gain weight. Then we started trying to figure it out and then we had this really major insight. It was not our discovery. People had already discovered that the body can make fructose. There's only one way you can only make fructose from glucose. There's a specific enzyme. Normally, that enzyme is pretty quiet. When we're born, we do not really have that enzyme anywhere, except in certain regions of our kidney. But otherwise, it's really not around and we call it the polyol pathway. But it was known. Gosh, it was known when I was in medical school that in diabetes, the body can make fructose and this polyol pathway is turned on. It was known that once you become diabetic, you can make fructose even if you're not eating it.

There are studies showing that particularly when diabetes was out of control that you can have high fructose levels in your blood, in your urine, and we've confirmed that sense. Then the question was, “Well, how does it work?” It turns out that the enzyme that makes fructose gets turned on when you're starving, it makes sense. It gets turned on when you're dehydrated. That makes sense because fructose will make fat, fat can be a source of water and it can be turned on when glucose levels in the blood are high in diabetes. That made sense because when the blood glucose goes up, it makes the blood concentrated and what happens is, it makes you thirsty. So. it's another way to create dehydration. We said, “Uh-huh. But what about high glycemic carbs?” When you eat bread, the glucose gets released. We call it high glycemic carbs, because certain foods, when you eat it, the glucose level will go up in the blood right after you eat it. Let's say, you have a blood sugar of 80, and you eat some bread, your blood sugar might go up to 120. It may just go up that fast with just eating a slice or two of bread. That's because when the bread is broken down, it releases glucose very rapidly, and some of that gets into the blood, and it makes the blood concentration go up. So, it's a transient or temporary diabetic state. You're not diabetic when you eat bread, but your glucose shoots up. And so, you have transient, temporary high glucose or hyperglycemia and that turns out to be enough to activate the switch. 

What we found was that high glycemic carbs get turned into fructose in the body. If you block that and we did it in laboratory mice, but we did it beautifully and knocked it out. When that happens, those animals are incredibly protected. They don't get fatty liver, they don't get insulin resistance, they still gain a little weight, but it's a healthy obesity. It is driven by insulin, but it's not actually the mechanism that where you get fatty liver and insulin resistance. it is not from the effects of insulin itself. It's from the fructose. And so, it turns out that high glycemic carbs are bad. They're really bad, but it isn't really just from stimulating insulin. It is because they get turned into fructose. And now, there was just recently a study showing that when you eat glucose, you’re making fructose in the body. It's been shown in humans now. I'm feeling pretty confident that this is a major mechanism. That's why low-carb diets are so great because you are restricting sugar, which is fructose, which contains fructose. You're restricting high fructose corn syrup, but you're also restricting high glycemic carbs. You're restricting the main way that the body can make fructose because it uses glucose. If you restrict foods that make a lot of glucose it's going to work. So, that was like, “Wow, that explains the low-carb diet.”

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Melanie Avalon: For listeners, you'll have to get Nature Wants Us to Be Fat, because he goes deep into all of the technicalities of all these studies that you've conducted and they're just really, really fascinating. And so, just for listeners so they can get the full resource. So, big question. Fructose, we keep saying fructose sugar, high fructose corn syrup. Does this apply to whole fruits as well?

Richard Johnson: Oh, great question. Again, we're studying this right and I'm going, “Oh, my gosh, if this is correct, then I shouldn't be eating an apple or a banana.” I love fruit and fruit is healthy. There are 200 papers out there plus it shows that if you're eating natural fruits, you tend to do well. But there's an interesting thing. It was noted 20 years ago by the pediatricians that fruit juice was not the same as natural fruits. They actually did studies and they found that if children drink fruit juice that that was associated with obesity. The pediatric societies came out and said, “Hey, you got to limit how much fruit juice you're drinking, especially if you're giving it to children,” because they can get obesity from it. It can stunt growth, it can do all kinds of things, but particularly, the obesity and the diabetes were strongly associated with fruit juice. What was the difference? Well, it turns out that when you eat a natural fruit, one fruit has 46 grams of fructose, typically, some have a little bit more, but that's much less than drinking a soft drink that has 30 grams of fructose. We're talking a big difference in the amount. So, that's one.

The second thing is, when you eat a natural fruit, there's fiber in it and fiber slows the absorption of the fructose. That's important because the way the fructose drops the energy in the cell it is like a chemical reaction. It's not based on just the amount. it's based on the concentration. If the fructose hits there and it's at a high concentration, the energy falls a lot and the switch is turned on a lot. But if you get only a little bit of fructose there, the energy just falls a little bit and it's not going to create the same thing. It's going to be a much milder activation of the switch. The switch is really like a dimmer. It's not like on and off. When you drink a soft drink, you're drinking a ton of fructose, 30 grams, and you're drinking it in about five minutes or less. Some people just guzzle it. You get this big wave of fructose that hits the liver and big activation switch. But when you eat fruit, especially you're eating it with a meal, and there's all this fiber, and everything slows the absorption, you're only eating a small amount, you don't get the same dose. You don't get the same concentration.

There's another thing. The intestinal lining can inactivate about four or five grams of fructose. It turns out that the fructose in vegetables gets inactivated. You can eat vegetables. Sweet potatoes can have a little bit of fructose in it, but it's not going to make you fat because your intestines going to inactivate it. Now, if you coat it with brown sugar. [laughs] There's a way to beat everything. You can make it worse. Just keep in mind. It's like the dose and the dose is what happens in the wild. The bear doesn't eat 10 berries and then a nut. It's eating thousands of berries and grapes at a time and I mean it. There're some studies that show that they can eat 10,000 berries in 24 hours. [laughs] But anyway, so fruit. We decided to do a study in people. It's good enough to talk about this, but let's do it. We gave overweight ladies, a low-fructose diet and that included low fruit, low everything man. Anything that had fructose in it, it was limited. One group got that, but one group got the low-fructose diet, but we added back natural fruits. There really wasn't a low-fructose diet. It was really a low-added sugar diet, but they couldn't drink fruit juice and stuff like that. It turned out that even though the people got natural fruits, they still improved their metabolic syndrome and they tolerated it better. They felt better on the diet. So, I think that natural fruits are good. I think it's possible to overdo it. If you're eating a huge amount of fruit in front of the TV, you're probably going to activate the switch.

Melanie Avalon: Would a fourth factor in the fruit be how we talk about-- how we lost our ability to synthesize vitamin C, actually as a mechanism to encourage weight gain. So, would the vitamin C and the fruit also help mitigate the effects?

Richard Johnson: Yes. There's this really interesting thing. We have to take vitamins. When we take a vitamin is because we used to make that stuff, but we don't make it anymore. Vitamin C, humans, our ancestors could make vitamin C, but we lost the ability to make that vitamin C. We have to get vitamin C or we can get a disease called scurvy. One of the great discoveries was James Lind, surgeon, who was on a ship and all these guys were getting this terrible aching joints, and bleeding joints, and bleeding gums. They had scurvy and he gave them some lemons, and oranges, and he could cure it. Later figured out it was the vitamin C. So, people go, “Why would we have lost vitamins?” The ability to make vitamin C, there's no advantage to being vitamin C deficient. In fact, you're going to get scurvy. Why would that happen? And so, it's been a mystery why we would lose vitamin C. One of the things about vitamin C is, it's an antioxidant. Antioxidants are supposed to be good. So, why would you lose an antioxidant? You would think you might live shorter if you didn't have that or shorter time. It's been a mystery. But when we were studying this, we realized that vitamin C turns out to be an antioxidant and it's involved in the survival switch. Remember how I told you how mitochondria that are really healthy have a lot of antioxidant activity? They can block the oxidative stress induced by fructose. 

When you give fructose to an animal, you create this oxidative stress to the mitochondria and it's driven by the uric acid. But the oxidative stress suppresses the mitochondria and reduces the amount of ATP produced, so that the energy that comes in gets converted to fat. What happens is, it's a way to suppress the oxidative stress, suppresses the ATP production, so that the calories are converted to stored energy instead of to instant energy. Oxidative stress is actually a survival tool to prepare you for winter. It's actually to help you store fat. It turns out that the mutation for vitamin C occurred at the time of the dinosaur extinction. This huge asteroid, Chicxulub it was called, came sailing in from the heavens, and smashed the earth, and caused a major extinction. All the dinosaurs basically died except for the birds, which was sort of a dinosaur like thing. It creamed the animals and the primates got creamed. There were a lot of primates. At least, there were some primates we think genetically. But for some reason, some of those primates survived and it turns out, it was that most of those primates, the lemurs also survived, and they did not get this mutation. But all the other primates, there was a common ancestor. And they somehow this one guy lost his vitamin C through a mutation and it provided a survival advantage. The survival advantage was that it led to a greater oxidative stress to those mitochondria from just even a small amount of fructose. And so, it allowed you to store fat more easily. 

The way we prove that was we took mice, and we worked with them, and we got genetically altered mice that were vitamin C deficient just like we are. You have to keep them on a low dose of vitamin C or they will get scurvy. Now, we had him on a low dose of vitamin C just to keep them from getting scurvy. But now, we give one group a high dose of vitamin C and the other group we give a low dose. We have two groups of mice. We have a mouse group that has a high vitamin C and we have a group that has a low vitamin C, and then we gave them sugar. Actually, we gave them high fructose corn syrup. Both groups, all animals love high fructose corn syrup. We put it in their drinking water, they were happy, and it activated their switch, and they started eating more. They don't just get the calories from the sugar water, they’d become hungry and they eat more chow and they eat more, they got fatty liver, they became prediabetic, the whole bit. But the group that had the low amount of vitamin C got a lot more fatter. They got almost 40% more fat. And so, we could show that the vitamin C mutation could help these animals survive when there wasn't much-- It would help them survive if there wasn't much fructose around. But if we give them more fructose, then they actually become fatter than their controls, because they're getting more damage to their mitochondria, so they can survive. 

It turns out that fruit, when fruit is first immature, the seeds are immature. The fruit falls, there's going to be no germination, the seeds aren't going to be able to make a new fruit tree. It's high in vitamin C at that time. Animals won't gain much fat by eating it. They tend not to go after immature fruit. But as the fruit ripens, the sugar content goes up and the vitamin C content goes down. It's almost like the plant knows that the plant wants the fruit to be eaten when the seeds are mature, so that it can promote a new tree. By making the fruit ripe would load vitamin C, the animals know that they're going to get more fat from eating it. They learned this evolutionarily. It isn't they know this, but this brought into the evolution of how these animals work. What's happened is vitamin C, when the fruit that-- we tend to like fruit that's less mature, we like the tart fruits, we like the fruits that don't have as much sugar. We don't like the right mushy fruits that a lot of animals would go after. We want it when it's tart, high in vitamin C. When we're eating natural fruits, the fruit has fiber, and potassium, and vitamin C, and all these things help counter. So, that is why natural fruits are good, even though they contain fructose. But things like fruit juices and sugar, why they're so effective at activating the switch.

Melanie Avalon: Well, again, listeners, if you get Nature Wants Us to Be Fat, it has an entire outline of a diet to follow, because I bet listeners are probably thinking, “Oh, no. What do I eat now?” It's a really, really helpful resource. I want to be really respectful of your time. Can I ask you one last super granular question that I apologize in advance to listeners, because it's going to be so granular? [chuckles] It's based off of what we were talking about recently with some email exchanges. 

Richard Johnson: Yes, please go ahead. 

Melanie Avalon: I had asked Rick about fructose’s effect on AMPK in the cells. And listeners might actually be familiar with AMPK, because we do talk about it a lot on the show is a pathway that's activated from fasting, and how it creates a lot of benefits in the fasted state by signaling the need for energy, and a lot of benefits from that. Okay, so, here's my question. In one of the studies that I was reading and I sent you the quote from it last night, but it was saying that “fructose actually activates both AMPK in the cell and AMPD2 specifically, which is like counteracts AMPK and has the opposite effect of AMPK. I'm probably completely bastardizing this but in layman's terms, that was my takeaway is that it actually stops fat burning and counteracts the beneficial effects of AMPK. Okay, here's my question. One of the other studies you had sent me was talk-- No, I think it was the same study. It was talking about metformin, and how metformin can actually block AMPD2. So, if you were to and this is hypothetical, and I don't even know if this practically could happen. But if you took in fructose, and then you took in a compound like metformin, and if you could block AMPD2, would that actually be all beneficial then, because then you'd be stimulating AMPK from the fructose, but you wouldn't be getting the AMPD2, so, you'd be just getting the benefits?

Richard Johnson: Well, this is pretty heavy question, but let me just say a few things and I'll try to get to that answer. I think you're onto something. But let me just begin by saying that AMPK is this wonderful pathway that when you activate it, it burns fat, and it keeps glucose levels down, and it gets inhibited in diabetes, and it's inhibited. Our group show that it's inhibited by AMPD and by uric acid and AMPD is the enzyme that makes uric acid in the fructose pathway. So, it turns out that fructose activates AMPD and AMPD makes uric acid and they counter the effects of AMPK. There's this ying-yang, where AMPK is considered the good guy and AMPD is what drives fat. And so, we would love to make an AMPD inhibitor and metformin is a weak one. If metformin it stimulates AMPK and it weakly inhibits AMPD and this is probably one reason why metformin has been found to be so beneficial. But if it could really knock down AMPD big time, it could be a huge winner. When we knock down AMPD, we can even cure genetically induced obesity. It's just amazing. We can block addiction for sugar and it's just a very powerful pathway.

Melanie Avalon: In theory, there could be a drug that could do that. If that happened and then you took in fructose, would you get benefits then, because you stimulate AMPK, still? 

Richard Johnson: You probably would, you would because one thing that can stimulate AMPK is a drop in energy in the cell. Fructose drops the energy in the cell, but then the AMPD pathway and the uric acid generated inhibits the AMPK. When you give fructose, you can show that AMPK goes up to some extent, it's actually induced, but then it's inhibited by the uric acid and the AMPD. The net effect is that AMPK is kept low. Now, in a true starvation state, the AMPK can override the AMPD. If you're in a true starvation state where there's no fat around and things like that, you are very minimal. AMPK will be activated. But anyway, you're right. These two players, AMPD and AMPK, the balance of that is so important in intermittent fasting, and low-carb diets, and anything. AMPK should be viewed as pretty much a good guy and AMPD is its evil counterpart, [laughs] unless you're preparing for starvation, then you want that AMPD man.

Melanie Avalon: Well, thank you for entertaining that. I was reading all the studies and I was like, “I have to ask,” and apologies to listeners for the random rabbit hole. Well, this has been so amazing. We only barely touched on just a tiny bit of everything that's in your book. Listeners, go get Nature Wants Us to Be Fat. It's amazing. You will learn so many things. And Rick, I can't thank you enough for your work. I'm so excited to see what the future holds with all of your studies. Are you writing another book right now?

Richard Johnson: I'm thinking of writing another book. I haven't started, yet, but I'm very interested in writing a book about discovery processes just because I've been involved in quite a few and like, what's the art of discovery? Because it's interesting how there're different approaches to discovering things in it.

Melanie Avalon: Does it often start with asking why, like, you were saying in the beginning?

Richard Johnson: Yeah. Well, one thing that's for sure involved with almost every discovery process is just you got to be passionate and curious. For sure, those two are characteristics that are constantly seen. But there's a lot of serendipity and all kinds of things that are involved. There're certain tricks that I think can help that I might be able to write about them. Not necessarily that I have done, but that other people that I've seen others do, too, because I've been doing research since the mid-80s. And so, I've been around and I've been around some wonderful people, I've seen Nobel laureates, talked to them, and over the years, I've just been very curious to know, “What is it? Why did that guy discover that?” I'm interested in, “What was the thinking that led to that?” Not so much what the science of the discovery is, but like, “How did he figure that out and what was the technique?” So, I'm interested in that part.

Melanie Avalon: I love that. I really hope you write that because I would just eat that up. I would love to bring you on in the future if you do and talk all about that. Well, thank you so much. This has been absolutely wonderful. Again, listeners, there will be a full transcript in the show notes because I know we went deep into everything. But this has been so amazing and hopefully, we can talk again in the future.

Richard Johnson: Thank you, Melanie. That was just wonderful. Your knowledge is so strong. It's just really wonderful talking to you.

Melanie Avalon: Oh, thank you. You're amazing and I will talk to you soon. Bye.

Richard Johnson: Bye. 

Melanie Avalon: Thank you so much for listening to the Intermittent Fasting Podcast. Please remember, everything we discussed on this show does not constitute medical advice and no patient-doctor relationship is formed. If you enjoyed the show, please consider writing your review on iTunes. We couldn't do this without our amazing team. Administration by Sharon Merriman, editing by Podcast Doctors, show notes and artwork by Brianna Joyner, transcripts by SpeechDocs, and original theme composed by Leland Cox and recomposed by Steve Saunders. See you next week.


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