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Are All Sugars the Same, and Which Should You Eat? | Cholsoon Jang PhD

Episode 82, duration 1 hr 07 mins
Episode 82

Are All Sugars the Same, and Which Should You Eat? | Cholsoon Jang PhD

Cholsoon Jang, PhD is an Assistant Professor of Biological Chemistry at the University of California Irvine School of Medicine. Dr. Jang obtained bachelor’s and master’s degrees from Korea Advanced Institute of Science and Technology. He then received PhD from Harvard University and completed postdoctoral training at Princeton University. Dr. Jang’s laboratory focuses on understanding how dietary nutrients are processed in the body and exert health-beneficial or detrimental effects. Dr. Jang received prestigious awards such as Pinnacle Research Award from the American Association for the Study of Liver Disease and Edward Mallinckrodt Jr. Foundation Award, and several research grants from National Institute of Health. Dr. Jang has published 92 papers in prominent journals like Nature, Cell, and Science, which are cited over 8500 times. Dr. Jang is regularly invited to speak nationally and internationally on his research in nutrient metabolism.

Are All Sugars the Same, and Which Should You Eat - Cholsoon Jang PhD

In this episode we discuss:
– What’s the difference between fructose and glucose?
– The factors that affect your ability to metabolize fructose.
– The problems with current nutritional research.
– Should you be eating sugar?

00:00:00 – Introduction

00:04:28 – The Chemistry of Fructose and its Abundance in Processed Foods

00:08:42 – Solid vs Liquid Fructose

00:12:58 – Fructose Tolerance and Digestion

00:17:14 – Fructose Metabolism in the Intestine

00:21:08 – Fructose and Skeletal Muscle

00:25:21 – The Influence of Food on Our Bodies

00:29:21 – Organ Cross-Talk and Metabolism

00:33:28 – Brown Fat Thermogenesis

00:37:31 – Circadian Clocks and Glucose

00:41:39 – Rest and Eating Patterns

00:46:05 – Exercise and Metabolic Disorders

00:49:58 – The Effect of Fiber on Fructose Metabolism

00:54:05 – Challenges in Microbiome Research

00:58:12 – Metabolites in Different Organ Conditions

01:02:39 – The Importance of Kidney Metabolism

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Dr. Gabrielle Lyon[0:00:02]

Welcome to the Dr. Gabrielle Lyon Show, where I believe a healthy world is based on transparent conversations.

In today’s episode of The Dr. Gabrielle Lyon Show, I sit down with Cholsoon Jang, PhD. We discussed his groundbreaking research on fructose metabolism while he was at Princeton, the difference between fructose and glucose, and where the holes are in the nutritional research landscape. Today, we discuss this and so much more..

Dr. Jang is an assistant professor of biological chemistry at the University of California, Irvine School of Medicine. Dr. Jang obtained a bachelor’s and master’s degree from the Korea Advanced Institute of Science and Technology. He then received a PhD from Harvard and completed post-doctoral training at Princeton University.

Dr. Jang’s laboratory focuses on understanding how dietary nutrients are processed in the body and exert beneficial or detrimental effects on health. His laboratory is incredibly unique. It takes a multi-disciplinary approach. Recent focus in Dr. Jang’s laboratory has included the synergistic or antagonistic effects between alcohol, fructose, and dietary fiber. I have to tell you, Dr. Jang’s work is extraordinary. He is a world-class researcher. He has published 92 papers in prominent journals like Nature, Cell, and Science, which are cited over 8,500 times. Dr. Jang is truly a thought leader.

As always, if you liked this episode, please take a moment to like, subscribe, leave a review, and share it with a friend.

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Dr. Jang, thank you so much, Dr. Cholsoon Jang. I’m so grateful to have you on the show. You are extraordinary, and a shout out to Dr. Alexis Cowan, who made the introduction. You received your PhD from Harvard. You did a postdoc at Princeton. You are now at the University of?

Dr. Cholsoon Jang[0:05:28]

California UC Irvine.

Dr. Gabrielle Lyon[0:05:29]

Wonderful. You are working as an assistant professor. You’ve done some extraordinary research. I still remember when you had a cell paper that came out, and it was called The Small Intestine Converts Dietary Fructose into Glucose and Organic Acids. That was this big, legendary paper, and I’d love for you to talk a little bit about your research, how you got interested in the gut microbiota, and, of course, your research on fructose.

Dr. Cholsoon Jang  [0:06:05]

Fantastic. Thank you very much. To answer your question about how I got into this fructose field, it was actually a funny story. I was interested in nutrients for a long time. Then I joined my postdoctoral fellowship lab in Josh Rabinowitz’s lab at Princeton University. I was trying to figure out what I wanted to study. I talked to Josh several times. Josh one day came from some conference and he said, hey, we got to study fructose because this is so popular everywhere, but I don’t think we really understand well, and we now have very good techniques to study this kind of nutrition, how they are processed in the body, how different organs and microbiome cooperate to digest fructose, where they go, and why fructose is connected to different diseases. That was a fascinating conversation with him. I just sat down and then figured out what’s known and what’s unknown in the literature. There are so many things known and unknown, and sometimes some things are controversial. I wanted to study that at the time.

Dr. Gabrielle Lyon[0:07:28]

This idea of fructose, for the listener, if you could explain what fructose is, the difference between high fructose corn syrup, and say, the way in which we in the nutrition field would think about fructose from fruit. I think that there’s a lot of discussion about this, and perhaps even some of the controversies in this field.

Dr. Cholsoon Jang[0:07:52]

Fructose is really similar to glucose. Everyone knows about glucose, and they actually have the same chemical formula. The only small difference in the chemistry or chemical structure of glucose is aldose sugar, and fructose is ketones sugar. So there’s only one difference in terms of chemistry. Fructose is abundant in fruits and vegetables, and nowadays, everywhere. It’s just all the processed food, like Coke, sugary drinks, cakes, and chocolate. We love this sweet taste; it’s really present when you eat fructose, which is why it’s so abundant now.

Historically, fructose was very expensive because you had to isolate it from sugar cane or sugar beet. It was really expensive, and only the rich people could eat fructose in the tea. They isolate, and then they drink the tea in the UK a long time ago. But then there’s a revolution in technology; the industry or revolution basically invented a method to generate fructose from glucose by using just one simple enzyme called glucose isomerase. They can now generate tons of fructose from glucose, and mostly they use corn because corn is so easy to get. They basically incubate the corn syrup with this enzyme to convert glucose to fructose, and then now they can get this high-fructose corn syrup, which is composed of about a one-to-one ratio of glucose and fructose.

Dr. Gabrielle Lyon  [0:09:48]

That’s so interesting. From what I understand, the goal of your lab is to understand how nutrient metabolism across organs and the gut microbiome can go awry and potentially cause disease. You guys have focused a lot on diseases linked to nutrients such as fructose, alcohol, fiber, and fat content in the scope of cardiovascular disease, diabetes, and what they used to call NASH. I think they now call it something else. What do they call it now?

Dr. Cholsoon Jang[0:10:29]

Metabolic dysfunction-associated fatty liver, so it’s MAFLD.

Dr. Gabrielle Lyon  [0:10:34]

They just wanted to make it more complicated, now graduated from NAFLD and NASH to something else. Can you talk a little bit about your research now? And what are some of the high-level understandings of fructose? Is it really a problem? At what dose is it a problem? I know that in some of the rodent models, 40% of their carbohydrates are fructose. But what about humans? Humans will say, well, now they’re saying, is fruit bad for me versus, say, a processed food that has, again, high fructose corn syrup? How is it different? What is the dosing? What is some of the research that you guys are doing as it relates to the general population?

Dr. Cholsoon Jang[0:11:21]

Our lab is now mostly interested in, basically, how fructose, like you asked, is toxic, and why there is a difference between the solid form of fructose and the liquid form of fructose. People think fruit is good because it has fructose, but it also has other nutrients, vitamins, and fiber, which we think is true. But nowadays, actually, fruit is getting more and more sweeter because we like sweet fruit. So basically, they are selected. That’s why even some people, especially lean people, who consume a lot of fruits actually also get fatty liver because they think only the fruit is very healthy, and if they consume a lot, that can cause fatty liver. They are surprised when they visit the hospital. Oh, wow, I always just eat fruit. Why do I get fatty liver? The dose is actually very hard to understand because it is so hard to measure how much we eat fructose. You can check the label on Coke or other foods, but I don’t remember actually how much I ate this morning, for example. All this data is based on this questionnaire from the people, and it’s really hard to measure.

There are actually some human studies people try to understand. They give different doses of fructose to people, and they try to understand what the dose causes, but another issue is that we have different capacities to clear fructose. Some people are really good at clearing fructose from the intestine and the liver, so fructose doesn’t really pose a big problem. But some other people have problems with digestion, and some fructose actually causes this damage in the liver or even spills over to the colony microbiome, which causes microbiome dysbiosis, which can also cause inflammation. It’s hard to say, but this dose is good for everyone. It really depends on the people.

My lab basically studies this using different mouse models, and then we generate different genetic mouse models by feeding fructose into their drinking water or converting fructose into chow. As you mentioned, the mouse study has been using this really high fructose in the chow, 40%. The reason why is that the mouse metabolism is 10 times faster than that of humans, so to induce some disease, you need to give a lot of fructose to mice. but probably it’s natural for humans. Nowadays, the statistics say about 20% of carbohydrate intake is from fructose, and this is in the United States and some South American countries. but maybe it’s much less in Asia or Europe, so that’s another difference.

Dr. Gabrielle Lyon[0:14:33]

That’s interesting. If we were to think about that, 20% of the carbohydrate is in the form of fructose, and probably the majority of that is not in the form of fruit bound with fiber just because of the overall fruit consumption. Is fruit the only place that we find fructose in nature?

Dr. Cholsoon Jang[0:14:59]

Fruit, vegetables, and honey

Dr. Gabrielle Lyon[0:15:02]

How would somebody know their fructose tolerance?

Dr. Cholsoon Jang[0:15:09]

When you have fructose intolerance, which means you cannot really absorb fructose by the intestine, then actually, fructose goes to the large intestine. Because of osmotic pressure, the water comes into the intestine when there’s a lot of fructose in the colon, and then you really feel bad. You have a gut problem.

Dr. Gabrielle Lyon[0:15:35]

Nobody wants to sit next to you, guys. That’s exactly what happens.

Dr. Cholsoon Jang  [0:15:42]

Yeah, exactly. It’s similar to lactose intolerance in that regard. You have an uncomfortable feeling, so they cut out fructose. But compared to lactose intolerance, fructose intolerance is much more rare in the population.

Dr. Gabrielle Lyon[0:16:01]

Interesting. You’d mentioned it in this paper, which I strongly recommend to everybody. We’ll actually link it in, and we’ll do a small summary of this: The Small Intestine Converts Dietary Fructose into Glucose and Organic Acids. This came out in Cell Metabolism in 2018. It really was a popular paper. What was something that you really brought to light on this paper that you felt was not addressed or known in the past?

Dr. Cholsoon Jang[0:16:39]

That was my first paper when I studied fructose. It was an interesting finding because before that paper, in textbooks, everybody says fructose is metabolized only by the liver based on gene expression. There is a gene called ketohexokinase, which is a really essential enzyme for fructose catabolism. If you don’t have that enzyme, you basically eat fructose, and all the fructose goes to the urine because no organ touches the fructose because you don’t have this enzyme. That’s shown by the knockout mouse model and also by the Pfizer drug. Pfizer actually invested some money to generate this ketohexokinase inhibitor because they hope they can give this drug to people, and then people take this drug, and then this enzyme is suppressed, and then even though you eat chocolate or soda, it can just go to the urine because it cannot do anything.

Dr. Gabrielle Lyon[0:17:44]

Would it potentially affect NASH, or nonalcoholic fatty liver disease?

Dr. Cholsoon Jang[0:17:50]

Right, that’s how they—

Dr. Gabrielle Lyon[0:17:51]

Wow. Did it ever come to market?

Dr. Cholsoon Jang[0:17:55]

I remember it being in clinical trial phase II or maybe even III, but I don’t actually remember what’s going on now.

Dr. Gabrielle Lyon[0:18:02]

Instead of just cleaning up our diet, they are providing a medication to limit the absorption of fructose.

Dr. Cholsoon Jang[0:18:11]

Yeah, the catabolism of fructose. The paper that you mentioned was basically about the finding that fructose is digested by the intestine first, even before it reaches our liver. If you think about the enzyme, this ketohexokinase, it is known to be expressed in the intestine and the liver, but the liver level is much higher compared to the intestine, and there are some expressed in the kidney. But if we think about it, then based on these enzyme levels, people think, okay, it’s the liver that catabolizes all these fructose. But if you think about what organ first sees the fructose when you eat, it’s actually the intestine. It’s the first organ.

It doesn’t matter if the liver expresses a high level. If the intestine expresses that certain level of enzyme and then clears this fructose before the liver. You have to remember the order of the organs that are exposed to these types of nutrients. The reason it’s interesting is because the intestine, we think, is like a passive organ. They just don’t do anything. They just take up the nutrients and then deliver them to the other organs. But now we show that the intestine is actually an active, metabolically active organ in terms of fructose. They catabolize fructose and then convert fructose to glucose and other metabolites. It’s different for glucose because the intestine doesn’t really catabolize glucose. They just take it out and then deliver it to the other organs.

Dr. Gabrielle Lyon  [0:19:51]

Wow, it’s really interesting. Do you think that would give us some indication as to the amount of glucose, fructose, and amino acids that we are designed to eat? And I say designed loosely, but from a percentage of calories. Again, with rodent models, we can define certain things. We can say this percentage will come from fructose, and this will come from glucose. Do you think that there is potentially an ideal? I realize it’s hard to say, but is there potentially an ideal percentage? With someone who has a normal functioning intestine, would it be feasible to say that 10% or 5% of our carbohydrates should come from fructose? Do you think that there’s a way in which we could design a diet based on some of these mechanisms that we’re seeing?

Dr. Cholsoon Jang[0:20:47]

I mean, that’s a million dollar question.

Dr. Gabrielle Lyon[0:20:53]

Do you mean you don’t know the answer?

Dr. Cholsoon Jang[0:20:55]

I don’t know the answer. To be honest, we can survive without eating any fructose because glucose is sufficient to provide energy and other things. The reason why humans have been exposed to fructose for a long time is because, in ancient society, we were not agricultural people. We basically harvested fruits and vegetables, and then we just ate them. It’s good, actually, evolutionarily, because fructose is different from glucose in that it’s catabolized. But it’s also really highly stored as a fat, especially in the liver. That’s why when you eat fruit in the fall, you can store these carbons as fat, and then you can survive in the winter. With glucose, you can also generate glycogen and store it in the liver and muscle, but fructose is more converted to fat because, as I said, the liver is the organ that really likes fructose and then converts fructose to other metabolites. That’s quite interesting if you think about how glucose and fructose are different.

Dr. Gabrielle Lyon[0:22:28]

I think you mentioned skeletal muscle, and oftentimes, I hear people say that they will eat fruit post-trainingorpre-training, and skeletal muscle doesn’t utilize fructose. I think that’s somewhat important to highlight.

Dr. Cholsoon Jang[0:22:47]

Yeah, exactly. I think so because fructose has a very rich systemic load. It’s catabolized first by the intestine, and then only a portion of the liver and liver basically suck out almost 100% of fructose because of this really high enzyme expression. Almost 0% of fructose actually reaches the systemic blood, so it doesn’t really reach other organs like the brain or skeletal muscle.

Dr. Gabrielle Lyon[0:23:17]

Isn’tthat interesting that fructose seems to be, would you say,the fuel source for the intestineand again, I don’t know exactly what it’s doing in the liver other than being stored?

Dr. Cholsoon Jang[0:23:32]

That’s an interesting question. We haven’t measured how much fructose is used by the intestine for energy production. But based on our calculation, we think the intestine really doesn’t use fructose as an energy source. They basically break down and then convert fructose to other metabolites. The liver is the organ that takes up this fructose, stores it as fat, converts it to fat, and then delivers it to other organs, such as adipose tissue. But when they have too much fat stored in the liver, that causes fatty liver.

Dr. Gabrielle Lyon[0:24:18]

It’s really interesting. You’d mentioned earlier that, as we’re eating fruit, we think fruit is healthy. Again, it’s probably healthy, and to what level? Yes, but the foods are modified to become sweeter. If you think about it, if you go and eat a blueberry off of a bush that you just found in nature, I’m not saying that one should do this, but it’s pretty bitter. It does not taste sweet at all, compared to the foods that we are eating here and now. There’s this quote that says all disease begins in the gut. Would you agree with that statement?

Dr. Cholsoon Jang[0:25:00]

It’s an overstatement, for sure, but it means a lot. We are exposed to everything, but especially food, which we basically take out and then go into our bodies. I trust that. it’s true.

Dr. Gabrielle Lyon[0:25:22]

Hippocrates said that. I don’t know, pretty smart guy. I think that much of your research has validated this theory. That much disease begins in the gut. When you think about it, it really is influenced by the things that we are putting in. What factors might individuals consider as it relates to fructose consumption? Again, we mentioned that there wasn’t a particular dose, but sometimes people will say, should you consume liquid calories? What are your thoughts on that?


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Dr. Cholsoon Jang[0:28:56]

As far as I can tell, if you want to consume some fructose, I think the solid form is much better than the liquid form, and there are two reasons. One is pretty strong epidemiological evidence. So people study based on questionnaires: how much solid fructose do you consume per week or in liquid form? Then they see that there’s actually a pretty good correlation between the liquid form of fructose consumption and a lot of different metabolic disorders. But solid form doesn’t really show that correlation. People think, oh, maybe the soda is the bad one compared to chocolate or cake. That’s pretty consistent with our results because when you feed mice fructose in the drinking water versus solid fructose, the drinking water is much worse because, again, the intestine should have some time to catabolize fructose and block the fructose spillover to the liver. If you drink soda, the absorption is too quick. It’s liquid, so you basically take 100 molecules, and then you can process only 10 molecules at a time, then 90 molecules, bypass the intestine, and it goes to the liver, and the liver sucks out this 90 and then generates a lot of fat. But if you eat chocolate or cake and then slow, you also eat fruit, which has fiber, so you have to chew. You cannot just drink orange, and then the intestine has sufficient time and capacity to digest fructose so that the liver doesn’t really see much fructose. I told this to my mom because she really likes fruits. I just told her, don’t just grind fruits.

Dr. Gabrielle Lyon[0:30:53]

No smoothies. Smoothies potentially take away that mastication, and they don’t allow for slower absorption. You were probably thinking as you started to do this research that smoothies were the worst invention cloaked in health, aside from junk food.

Dr. Cholsoon Jang[0:31:15]

Yeah, I think it’s actually a bad idea to just grind the whole fruit and drink it because you want to chew it instead of drinking it.

Dr. Gabrielle Lyon[0:31:25]

Here’s just a question I’m curious about. If you were to say someone should have, and I realize that we’re just speaking hypothetically, would you rather have someone have a glucose drink, say a Gatorade, or a fruit smoothie?

Dr. Cholsoon Jang[0:31:46]

Glucose drinking—that’s interesting. We drink glucose, but usually we eat glucose. I guess the big difference between glucose and fructose again is that the intestine can actually take up glucose quite well. Glucose actually doesn’t really accumulate in the liver. The liver doesn’t take up glucose much unless there is very high glucose in the blood. That’s the difference. Glucose goes to the muscle and other organs, adipose tissue, brain, so it’s maybe less toxic.

Dr. Gabrielle Lyon[0:32:25]

I would agree with you. Again, we’re just talking as friends here, trying to think about whether people will always say either or, potentially, just thinking about these things. One of the things that I would love for you to say is that this idea of your research gives credence to the body as this holistic type of system. I certainly would love your perspective on the holistic nature and the inter-organ crosstalk between systems.

Dr. Cholsoon Jang[0:32:59]

That’s another topic my lab is interested in because, when I first studied this fructose, I realized, wow, people study only the liver, and now there is a crosstalk between the intestine, liver, and gut microbiome. I realized we should study every organ at the same time, not just focus on one organ because they’re always connected through the blood system. They constantly take up and then release different factors, such as proteins and metabolites, and then signaling molecules. That’s why whenever we do our animal work, we try to harvest as many organs as possible and then look at them and see what changes. Sometimes, there are surprising changes in different organs we completely did not expect, like when the spleen shows up with something. Sometimes the brain shows something. That’s why we are fascinated by this concept of inter-organ communication.

Dr. Gabrielle Lyon[0:34:00]

Anything particularly, my community is always interested in skeletal muscle?

Dr. Cholsoon Jang[0:34:06]

The muscle is a big organ. Just in terms of the whole body, muscle is the biggest organ, and then skin, probably. There are a lot of studies done on muscle, so people know quite well, I guess. When you study fructose, we usually don’t really look at muscle, except when we expose animals to chronic fructose because that causes insulin resistance in muscle.

Dr. Gabrielle Lyon[0:34:39]

In skeletal muscle?

Dr. Cholsoon Jang[0:34:39]


Dr. Gabrielle Lyon[0:34:42]

Is that because of the fatty acid byproducts that are deposited in skeletal muscle, or whether it’s ceramide or diacylglycerol?

Dr. Cholsoon Jang[0:34:54]

Exactly. Lipotoxicity, that happens in the liver muscle, too.

Dr. Gabrielle Lyon[0:34:59]

That’s from fructose, potentially?

Dr. Cholsoon Jang[0:35:02]

Yeah, some are, but not all, because initially, fructose causes this insulin resistance in the liver, and then now, the glucose or other carbohydrate also accumulates in the systemic blood, and muscle takes up more. I think that’s how it causes the systemic effect. I wouldn’t say fructose alone contributes to this.

Dr. Gabrielle Lyon[0:35:29]

Really interesting. Anything that you found quite striking with this inter-organ crosstalk, whether it was with the spleen or the intestine, as it relates to fructose or anything? Your lab is extremely comprehensive. You even have a recent paper on quantitative analysis of metabolic fluxes in brown fat and skeletal muscle during thermogenesis. Your lab is quite comprehensive from a metabolomic perspective.

Dr. Cholsoon Jang[0:36:07]

That paper is a collaboration with David Guertin at UMass. He’s a really famous guy in the field of brown-fat thermogenesis. We have a special technique called arteriovenous metabolomics. Basically, we try to measure what’s going into the organ and what’s coming out of the organ. We took the blood samples from the arterial blood and the venous blood and then compared them, so that you basically compare the input and output of the organ instead of just measuring the level in the blood. If you compare input and output, we can tell what organs take up and release.

We applied that technique to the mice, especially in the cold exposure condition, because the cold exposure, as you know, induces thermogenesis, especially in the brown adipose tissue in the human body we have here around shorter, and it is highly popular in that it can prevent metabolic disorders like diabetes, obesity, and so on, because you burn energy to generate heat. We try to understand whether brown fat or even muscle is important because muscle is also important when you shiver. When you are cold, you shiver, and then that generates heat in the muscle, so we try to understand what’s going on there.

Dr. Gabrielle Lyon[0:37:42]

There were several specific mechanisms that were identified in this study. It looked at fat utilization and divergent fuel utilization profiles, which I thought was interesting, such as cold exposure versus pharmacological agents. It was a very well-done study. We’ll link to it. We’ll do a summary for everybody; it’s quite fascinating, also the amino acid composition of brown adipose tissue and that they can increase consumption of amino acids during thermogenesis except for glutamine, which I thought was fascinating.

Dr. Cholsoon Jang[0:38:26]

We still don’t know why brown fat doesn’t really use glutamine. Instead, they release glutamine. Maybe they tried to get rid of this nitrogen. Because when you break down other amino acids, you can accumulate nitrogen, and glutamine is one of the best ways to get rid of the nitrogen. That’s maybe one way for brown fat to be removed. In that paper, we basically quantitate how much glucose, lactate, or other amino acids and fatty acids can be burned by brown fat or muscle. Because before, people thought they used glucose. They use lactate, but we don’t know the percentage or how much they use.

Dr. Gabrielle Lyon[0:39:11]

Do you think that will provide translational information to humans? Obviously, calories are important, and I think a lot of your work is really from the perspective of how do we make the world healthier? A lot of your research translates to this, and your lab translates to this. Do you think that once we have an understanding of how much is utilized in particular environments, whether it’s cold, etc., we’ll be able to combat some of these diseases that we’re seeing?

Dr. Cholsoon Jang[0:39:48]

Yeah, I think certainly, hopefully, in the next few decades, some people will study more about this kind of biology in humans because, obviously, this is a mouse study and there’s a gap between mice and humans. But we think a lot of this interesting biology is similar between mice and humans, so hopefully this intrigues people like clinicians and other people who can recruit patients and then study this. That’s our dream, basically. They can show this work in humans too, so that’s got to be translated.

Dr. Gabrielle Lyon[0:40:31]

So fascinating. Something else that you published recently, actually 2023, and this was Liver and muscle circadian clocks cooperating to support glucose tolerance in mice. People talk a lot about circadian rhythm circadian clocks and say that they’re a defining feature. But this is interesting—this idea of specifically liver and muscle circadian clocks.

Dr. Cholsoon Jang[0:41:07]

That is also a collaboration with Paolo’s previous lab members. Paolo was one of the biggest figures in this field, the circadian rhythm. Unfortunately, he passed away three years ago, right after I arrived here. But they basically made a lot of different genetic mouse models, and they disrupted circadian rhythm in specific organs. They also restored some circadian organs. For example, they disrupt the whole body’s circadian rhythm and then restore it only in the liver, only in the muscle, and see what’s happening. That was a fascinating study, which we found very interesting, like the different metabolic changes across organs when you have only the liver circadian rhythm intact versus muscle. We also think the main message from that paper is that diet is one of the most important factors that can normalize our circadian rhythm, even if you have some disruption in certain organs.

Dr. Gabrielle Lyon[0:42:19]

Can you speak a little bit about that? Again, these are rodent models, and rodents are nocturnal. They will certainly continue to feed an ad libitum-fed rodent, which would be considered an obese model. What can we learn? Or how can we think about that statement? That food seems to be a very significant way in which we can entrain our circadian clock. What does that impact have on our metabolomics, the metabolism of glucose, etc.?

Dr. Cholsoon Jang[0:42:53]

The problem with mouse studies in circadian rhythm is that they are nocturnal, and they don’t just eat all the time instead of three meals per day. During the circadian rhythm, at a certain point, our body is very good at taking nutrients and then processing them. But other times, maybe they just want to take a rest, and then they don’t want to touch the food. But if you constantly eat, nowadays, in modern society, we are always exposed to readily available foods that we just eat whenever. I have a lot on my desk, too, and you can eat any time. That can cause problems because our body is basically not really working that way. We want to have a certain time when we have to eat, and then a certain time when we have to take a break. I guess that’s the point that I want to make. For example, don’t eat too much at night because at night, you are supposed to take a rest.

Dr. Gabrielle Lyon[0:44:20]

Interesting, right.


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Would you say that there’s a particular timeframe in which humans should eat? Is it an eight- to nine-hour window? it’s interesting. Obviously, it’s complex, and it does have this misalignment between liver and muscle. I don’t know how one could do that to humans. But do you think that there is a way in which we can entrain our circadian rhythm, and should we be doing that in a structured, non-chaotic way?

Dr. Cholsoon Jang[0:46:29]

I think we can certainly train our bodies, and that’s why intermittent fasting or those different diets can work in humans. I guess maybe the timing is important, but we can control it. for example, some people can eat only at certain times, and then they basically fix that time for a long time, then the body basically gets used to it and they are fine. But then if you just keep changing your dietary habit, you’ve tried all, and then you eat sometimes at night, sometimes not, then there could be problems because that disrupts your whole body’s system, and that’s the bad one. Do you agree?

Dr. Gabrielle Lyon[0:47:24]

I do agree. I’m excited to see how we can begin to incorporate that more. I absolutely agree with you that we should have structured feeding times. Probably, some people will do earlier feeding windows versus later. I’m very interested in these muscle clock genes. I don’t know if we know much about them or their influence, as it translates to something significant for humans. But again, it seems as if that would be extraordinarily fascinating to look at. Do you have any thoughts about these muscle clocks, the regulation of glucose metabolism, and these muscle clocks? Do you think that we’re there yet? I know that there’s this oscillation of these transporters.

Dr. Cholsoon Jang[0:48:20]

To be honest, I don’t know much about that clock in the muscle specifically because, again, we were focused on a different way of communicating. I don’t know the answer.

Dr. Gabrielle Lyon[0:48:37]

But it will be very interesting to see as things really begin to evolve. I realized that it’s not studied directly, but do you think that exercise factors into these discussions of inter-organ crosstalk and clock genes? Do you think that there is a role and a place for that? I know that out of Rabinowitz’s lab, when you were there, they definitely focused on exercise, etc. Do you feel like that really plays a role?

Dr. Cholsoon Jang[0:49:08]

Yeah, for sure. Exercise is maybe the best way to treat all these diseases—metabolic disorders, and so on—and cardiovascular disease. If you think about how that works, I studied exercise during my PhD in the Zoltan Arany lab, and there was basically the exercise layer—genes that are turned on in exercise like PGC-1alpha and fatty acid oxidation genes, and so on. Then in Josh’s lab, he basically tried to put the mouse on the treadmill and then tried to figure out what nutrients are used by the exercise and mostly other organs. I don’t know how exercise changes the circadian rhythm of the muscle. Some people already exercise in the morning versus at dinner time. Still, I’m not sure whether it’s really translated into humans, but probably. It should also be coordinated with the diet, whether you eat before or after exercise. Sometimes people eat a lot after exercise because they feel–

Dr. Gabrielle Lyon[0:50:21]

Maybe that’s not the best thing, but who knows?

Dr. Cholsoon Jang[0:50:24]

Yeah, who knows?So fascinating topics.

Dr. Gabrielle Lyon[0:50:28]

It is. Just touching on this, there’s a lot of this cold therapy. Again, it’s difficult to say population interventions, but do you think that there is a place for some of these fitness trends that we see, whether it’s heat therapy or, in particular, this cold therapy that we saw in this rodent paper on brown adipose thermogenesis? Do you think that there’s a role? If so, what does that look like?

Dr. Cholsoon Jang  [0:51:03]

You mean the people who are exposed to cold are healthier?

Dr. Gabrielle Lyon[0:51:12]

Yeah, or potentially, maybe have better metabolic regulation. Again, who knows? But I do think that this paper that you partnered with in this lab is very interesting. I’m not sure if you’ve thought about that. Or if there was something on your mind regarding cold therapy, etc., that might not be a fair question, but I’m just curious, and you could say no, we’re not even looking at that.

Dr. Cholsoon Jang[0:51:47]

I know I’ve seen these people who are actually doing this cold therapy in California and also in New York City. They say this is not FDA-approved or certified. But still, I saw that some people actually got pretty good benefits from that. But I’m not sure it could be beneficial for everyone.

Dr. Gabrielle Lyon[0:52:12]

What are some of the studies that you’re currently looking at in your lab and working on?

Dr. Cholsoon Jang  [0:52:20]

We have two topics. One is how dietary nutrients interact with each other. Usually, we focus on only one at a time. We study fructose. We study fat. But now we study how interaction happen between fructose and fiber, when you eat together, which one wins? If fructose is bad and fiber is good, which one wins, and when do we adjust the different ratios of these two? We also tried to see whether the order matters. For example, when you feed fructose for a long time and then give fiber to those mice, can we see the fiber reverse the fructose effect or the opposite? When you feed fiber and then give fructose later, which one wins, basically? Maybe fiber already makes your body quite well and healthier, so then the fructose cannot now really make belly fat. That’s what we are trying to figure out.

Now we actually saw good news: fiber wins. When I say fiber, it’s inulin. It’s inulin fiber, which is a polymer of fructose. The mice get inulin and fructose together, they’re healthy. If you give fructose for a long time and it induces fatty liver, then give fiber plus fructose, so continuous fructose exposure, but then add fiber to the diet, it actually reverses the fatty liver to the normal liver. It’s really fascinating.

Dr. Gabrielle Lyon[0:53:58]


Dr. Cholsoon Jang[0:53:59]

It looks like insulin is all about a change in the microbiome. It seems totally microbiome-dependent because if you treat antibiotics, the effect is gone—actually even worse. It looks like somehow microbiome changes happen through this fiber, and then they signal off to the liver or intestine, and then they switch the metabolism of fructose so that they don’t really accumulate fat anymore. It looks like what we see is fructose now being converted to amino acids instead of fat, so we tried to find what molecules do this.

Dr. Gabrielle Lyon  [0:54:39]

That is fascinating. If you were to think about what wins, I really like how you mentioned that, and some of your earlier research was on the gut microbiome. How important do you think that is to our body composition in general and our overall state of disease?

Dr. Cholsoon Jang[0:55:00]

The gut microbiome is important, in my opinion, because it’s also a giant organ if you think about the number of cells or enzymes they have. The mass is big, and it’s also closely linked to diet, for sure. Some people are skeptical about the microbiome because some joke about it. Is there anything that is not related to the microbiome these days? But everything is now related. I think it’s actually true because it’s one of our organs, to be honest. It’s a big organ. The effect of the microbiome on many metabolic aspects of our body is certainly true.

Dr. Gabrielle Lyon[0:55:54]

Yeah, and unusual. When we think about it from the perspective of how do we live longer, how do we live more healthy, and how do we live disease-free, the influence on the gut microbiome Obviously, from a medical perspective, we are new to this. Even for the clinician who has been dealing with it for the last 10 years, I would still say it’s a newer field and so interesting, especially when you think about it as its own organ system.

Dr. Cholsoon Jang[0:56:31]

There are so many unknowns about the microbiome. We are really beginning to understand the microbiome.

Dr. Gabrielle Lyon[0:56:38]

So you’re working on that in your lab?

Dr. Cholsoon Jang[0:56:40]

Yeah, maybe one-third of our lab is working on the microbiome because obviously, it’s related to nutrients. It’s so directly related.

Dr. Gabrielle Lyon[0:56:50]

What is one of the challenges that you see in research right now related to your field? You had mentioned that when people are studying, for example, individuals—I’ll just throw this out there. When individuals are looking at, I don’t know, protein, they might just use a whey protein isolate versus a food that has its own complete nutrient, quote, food matrix. I’m curious, from your perspective, as you’re going in there trying to advance the science, what are maybe a few areas of struggle or an area that needs improvement?

Dr. Cholsoon Jang  [0:57:40]

I think the challenge here is that we need more active collaboration between scientists like me, biologists, and nutrition scientists. I studied nutrition, but I’m not a nutritionist, so it’s important to communicate with them to make sure what we basically use for studying in mice is actually really translation in humans. For example, you cannot just give tons of fructose or only specific fiber because it’s such a simplified version of our diets. I think that’s one thing we should do for sure in the next decade: active collaboration, maybe a big meeting that summons all these nutrition scientists and basic scientists to work together.

Dr. Gabrielle Lyon[0:58:36]

That would be incredible. You do see there’s a divergence—I would agree with you. It’s so complex, and it’s such a new field; the newness to it is probably, again, just a much newer science. You mentioned that one-third of your lab is looking at the gut microbiome. What about the other two-thirds?

Dr. Cholsoon Jang[0:59:02]

Another one-third is working on developing new technology, and another one-third is working on organ interaction. We use large animals too, like pigs. We have pigs in our lab because pigs are really great in terms of being similar to humans much more than rodents are. Pigs are big, so we can take many different samples. As I mentioned, this blood sampling from different organs shows that venous blood is really possible in pigs, not really mice, so that’s what we’ve done recently.

Dr. Gabrielle Lyon[0:59:41]

You’re being very humble, and I know Dr. Alexis Cowan is going to listen to this episode. You mentioned that you’re working on some techniques in your lab. What you’re not saying is that you’re really working on techniques that could revolutionize the field—the work in metabolomics, non-radioactive stable isotope tracing, and bioinformatics analysis. So there is no need to be humble here; I would love to hear, and the listener would love to hear, because you are extraordinary. I’m so grateful for your time. I don’t take it lightly. I know that the listener or the viewer will not take this lightly. You’re doing really important work to advance the field, so thank you. But please mention a little bit about these innovative techniques and what you’re doing there; I’d love to hear it, and then I’m going to come back on the last one-third.

Dr. Cholsoon Jang[1:00:33]

Sure. I guess another major challenge in our field is that we think we know all the metabolites in our body, but for sure it’s not true. People keep discovering new metabolites, especially those made from the gut microbiome and some other organs, especially in certain conditions, not just normal conditions. When they’re stressed out, when they’re exposed to cold, or when they’re exposed to certain different yeast states, the organs produce certain metabolites because these metabolites exist only in certain conditions. That’s why we don’t really see them usually. Our lab tries to develop techniques to identify those metabolites, what they are, whether they have any functions in the body, and why they have to be generated in the body. That’s what we do these days. Some people also argue that we already discovered all the important metabolites, which is probably true, that in the glycolysis TCA cycle, all this central carbon metabolite is probably the most important metabolite. But there are probably also other new metabolites coming from the gut microbiome, and those things should be discovered so that we can target them. That’s what we do.

Dr. Gabrielle Lyon[1:02:08]

Do you think that we can greatly influence these metabolites?

Dr. Cholsoon Jang[1:02:12]

To influence those metabolites, we also have to figure out enzymes—what enzyme may make this and what enzyme breaks down these metabolites. That’s another challenge; identifying the enzymes is super hard.

Dr. Gabrielle Lyon[1:02:28]

What I’m hearing you say is that we still have quite a bit of work to do in the field. It’s really fascinating. The last piece of what you’re doing, which I find very fascinating, is that organ crosstalk. Again, think about it, even in medicine. We look at the cardiovascular system; we have cardiologists, we have endocrinologists, etc. pulmonologist, which looks at the lungs, and we do look at these systems in the context of the whole body, but not really. It really is in isolation; that’s why you get a referral. That’s why you have multiple teams. Maybe that will always be that way, but we have very little knowledge of the interface of all of them together. I’m so curious as to the work that you’re doing to advance that and what you’ve discovered. Is there one aha moment, one crazy discovery?

Dr. Cholsoon Jang[1:03:30]

Organ crosstalk is, for sure, a frontier of metabolism. You know about this Cori cycle, which is this really popular, most famous organ. The Cori cycle is between two organs, the liver and muscle, and involves glucose-lactate exchange. For sure, it cannot be just one cycle in the body. Our lab basically tried to find hundreds or even thousands more cycles of this crosstalk between different organs. We have some evidence that, of course, there is a lot more going on than just one with this Cori cycle. For sure, glucose lactate is the most important, maybe in terms of metabolism, but we basically do not really understand the whole body-level crosstalk between organs. We’re basically unbiased. We are just unbiased and comprehensive. We’ll try to figure out everything, hopefully, in the next 10 years.

Dr. Gabrielle Lyon[1:04:52]

Chop, chop. You’ve got to do it. You guys have a lot of work to do. Where are you starting? I know that liver primary care is really of interest to you, probably because of your original research in fructose metabolism. Do you think that muscle just by being 40% body weight may be influential if you were to think about, from a metabolomic perspective, where is the disposal going? Or are you more interested in, say, adipose tissue?

Dr. Cholsoon Jang[1:05:26]

We are nowadays more interested in kidneys because–

Dr. Gabrielle Lyon[1:05:30]

Ah, interesting.

Dr. Cholsoon Jang[1:05:31]

Yeah, it turns out the kidney is a really active metabolic organ. We always thought the kidney was just another passive organ that took up garbage from the blood and released it into the urine. That’s true, but the kidneys also generate a lot of amino acids during fasting. The kidney is one of the organs that generates serine, glycine, and other urea cycle metabolites and then provides them to the body.

You mentioned muscle, and muscles use creatine and phosphocreatine for energy. If you think about it, creatine is made from the liver, but the liver needs this glycocyamine metabolite to generate creatine. This glycocyamine is only made by the kidney. If you have a failing kidney, you cannot make glycocyamine. You cannot make creatine. The muscle would suffer because of the creatine deficiency.

The kidney is so important. We found so many things coming out of the kidney, and so many things are taken up by the kidney, but not all go to urine. They basically use them to do something. The kidney is also very heterogeneous, if you think about the structure. The cortex and medulla are quite different, and that’s actually a headache because it’s hard to dissect in mice. Once you dissect, it’s too slow, and there are all these metabolite changes. That’s why it’s important to use other new techniques like imaging mass spectrometry to identify the metabolite and then measure flux in the intact organ instead of dissecting it.

Dr. Gabrielle Lyon[1:07:14]

That’s fascinating. I had, quite frankly, never thought about the kidney in that way. I had never thought about the health of the kidneys in relation to the health of the skeletal muscle. Certainly, it’s metabolic demand, which is interesting. I’m excited to hear, read, and see some of your research. Thank you so much for your time. I don’t know if there’s anything else that you would like to mention. Really, really interesting.

Dr. Cholsoon Jang[1:07:45]

Yeah, I really appreciate your input and the questions. That reminds me of what’s important to study. This has been a really good conversation. I really enjoyed it. Thank you.

Dr. Gabrielle Lyon[1:07:59]

Me too. Thank you so much. We’ll link to your lab site, to your Twitter. Again, I am so grateful, Dr. Jang, for your time. The goal is to bring the experts who are in the trenches doing the research to the forefront so that we can learn directly from you. Again, thank you so much.

Dr. Cholsoon Jang[1:08:21]

Thank you. Have a nice day.

Dr. Gabrielle Lyon[1:08:23]

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