Insulin and ketone bodies-the battle for brown fat Dr. Benjamin Bikman Chinese subtitles: Wang Zhuofeng Mark Wang Good morning! I am very happy to be here! Thank you very much Rod and Jeff for giving me this opportunity, Invite me to attend the conference and give a speech. For me, this type of meeting is "new"… I generally only attend very "pure" academic conferences. I am not saying this to offend you… And this kind of meeting is a good supplement to me.
For me, this is the first time… You can talk about "academic" and "application" at the same time. I don’t need to hide my other identity: the secret "low-carbon, high-fat" promoter On other occasions, I have to hide it! So, I am really happy to be here! And I’m even more happy that I can share with you The research results of our laboratory. I will try my best to be clear and easy to understand. The data I will show you We are preparing to sort out and will publish the paper soon. As Marianne mentioned (thanks to Marianne for the introduction) We are studying, Factors that affect the way fat in our body moves. What I want to talk about next will surprise you! I have no conflict of interest in a relationship to disclose I am a humble professor, and I don’t have much content about funding…
Many of us have seen this concept… If you haven’t read it, it’s probably a bit vague There are two main theories about why we are "overweight". One of them is widely accepted by society… "We are overweight because of an imbalance in calories." And another theory is that the "hormonal" (endocrine) imbalance, Especially the hormone "insulin". These two theories ("Karilu" theory or "endocrine" theory) Have calculated the energy intake, The energy release is also calculated. On the "calories" side, there are only two points: You either use energy or store it. And if you consume more than you use, the result is easy to predict…
Our body retains more energy and we become fatter. On the "endocrine" theory side, it will be a little more complicated… It is assumed here that our human body is not a simple "thermal machine". Energy needs to be "told" how it works, like a naughty child. And in this case, Among many hormones, "insulin" is definitely the most prominent one. And when insulin rises above the normal, baseline level, Insulin tells the body system, especially fat cells, Enlarge the inflow of energy and reduce the outflow of energy.
In this way, you can also expect If you pour water into a pool with a blocked leak, The system will "get bigger." (The same is true under this theory) Between these two different theories, There are some overlaps. Both will consider (and must also consider) "calories". So there is some overlap between the two theories, and many people are willing to admit it. On the calorie theory side, We only consider "use" and "storage" energy. This is very simple and straightforward from the perspective of "thermodynamics". Energy is either stored or used… Therefore, it should be possible to calculate an accurate account. But what I will show you, (This is why this topic is a bit controversial) The "endocrine theory" almost encompasses the entire "calorie theory", You can firmly believe in the "endocrine theory", And at the same time, you can follow those who are convinced "This is just a simple arithmetic game" people go to debate.
In fact, this is not the case. If "endocrine theory" can include "calorie theory", That means that "endocrine theory" can also explain The "storage" and "use" of energy. In fact, it is indeed possible, let me show you. Part of the mechanism is related to the characteristics of our fat cells. We have a lot of fat cells all over, I will talk about their detailed characteristics later, But first spoiler: the activity state of fat cells can be very different in different environments. We will talk about two variables. And when we talk about the characteristics of adipose tissue, I will show you "endocrine theory" How to change the way energy is used by controlling fat tissue.
Then, I will talk about the last mechanism, This is what we must consider when calculating calories. And we often ignore this. Okay, these are the protagonists of my story: The liver, it is important to all our metabolic processes. (This is beyond the scope of our discussion) Then there are two types of fats, which all humans have. "White" fat, and "brown" fat They look a bit like the one demonstrated here: When you dissect it, the colors are "white" and "brown". There are two more roles, you all should be familiar with: The hormone "insulin", and "ketone body". They are not a class of substances: "insulin" is a hormone (hormone) The "ketone body" is a metabolite. However, they have a very close relationship. Of course, I believe everyone here is familiar with this concept. Let's first look at fat cells. "White fat" is mainly used to store energy. The "brown fat" is used to regulate heat and temperature. In other words, If the "brown fat" is more active, it is just heating up and has no other use.
In this way, these two fats are very "antagonistic." "White fat" wants to store energy; And another kind of fat, "brown fat", wants to use energy. This finding is worth paying attention to, because in a typical "calorie" model, We think that the main energy use is muscle. But let me tell you, the body has a kind of fat cells, we all have, There is also a main intention, which is to "use energy". So, "white fat" stores energy, "Brown fat" is using energy. Babies have a lot of "brown fat". I already have three children, Interestingly, I found out that they just took a shower, When they were just born babies, they didn't tremble. Have you noticed? They don't shudder little babies. They don't need it. We need to rely on trembling, Rely on the trembling of the muscles to generate heat. And young children, especially babies, have a lot of brown fat. Those brown fat can keep their body temperature enough, So there is no need to "tremble".
Of course, when they grow up, brown fat begins to degenerate, From childhood to adulthood, there is a shift. Only a relatively small part of our fat is brown fat, And more is white adipose tissue used to store energy. So when we encounter cold temperatures, we start to tremble. In the field of scientific research, there is some controversy about the significance of it (brown fat) in the adult body. But let me solemnly declare: we have brown fat, and they are important. It is more active in some people, In other people, they can be more active through stimulation, Whether you "have more" or they are "more active", Your "metabolism" will be in a better state. Speaking of the topic of "brown fat", As a professor, I will assume that my students don't know much. I'm assuming the same here, please forgive me if you offend. "Brown fat" is very special, it looks brown, It's because it is full of something: mitochondria. Mitochondria are where the oxidative decomposition of nutrients (sugar or fat) occurs. We have discussed this aspect many times in this meeting.
But the mitochondria in brown fat have something special. All mitochondria have the ability to do two types of things. On the one hand, mitochondria absorb glucose, But it will only absorb just enough energy according to cell needs. Does it sound reasonable? Some physiological activities of cells require energy, Then it will only absorb just enough nutrients (here "glucose") Here we are specifically talking about brown fat. It only absorbs just enough glucose into the mitochondria from the outside, Used to do the physiological activities it needs to do. On the other hand, mitochondria have the ability to turn the absorbed glucose into "heat energy." Moreover, it will continuously generate heat. It's like you keep throwing pieces of wood into the fire. The tissue used to generate heat is called "uncoupling protein" (UCP1). All brown fat has a part of this protein. If I knew the previous speaker I will tell you about the "electronic delivery system" We can also discuss particularly complicated. I did not expect that we could be involved in such detail… I feel a little bit pitted… However, (brown fat fever) is a very useful physiological phenomenon.
Uncoupling proteins have an important position in the electron transport system. If the "decoupling protein" is active, it will generate a lot of heat in the mitochondria. But as you can see, If we want to make the fire more prosperous, Energy comes from glucose, so glucose will decrease. Because we use a lot for heat. It's like if we were to make a fire, wood would be used very quickly. And in mammals, in humans, if glucose starts to drop, Of course it will affect insulin. What about insulin? Of course, insulin will drop, and our demand for insulin will be less. No insulin is needed to lower blood sugar. Mitochondria are already doing this. And this series of physiological activities, More uncoupling proteins in mitochondria, Generate tiny heat. And we often don’t notice it, Not the kind that makes you hot enough to want to undress. However, this process can cause blood sugar to drop. Because we have a leaking pool, we can throw away blood sugar. Insulin will also drop. And our overall metabolic state will be more advantageous.
The body will not be so easily overweight. Nor is it that prone to diabetes, or insulin resistance. Come back to the "liver" There are a lot of nutrients flowing in the liver, Convert one nutrient substance into another nutrient substance. And the center of all this is "Acetyl-CoA" (Acetyl-CoA). I guess everyone is familiar with this concept. "Acetyl-CoA" is the core of many nutrient conversion pathways. Many nutrients will become "acetyl-CoA", "Acetyl Coenzyme A" will also be transformed into many nutrients. Including all (main nutrients), amino acids (proteins), glucose (carbohydrates) and fatty acids (fats). The change between "acetyl-CoA" and nutrition is mainly determined by the liver. Hormones are also involved in this process, and insulin is the most important of them. As a reminder, acetyl-CoA is a metabolite, Produced in the breakdown of glucose and fat. (Don’t forget this) If insulin is high, it wants to turn acetyl-CoA into fat. So no matter where acetyl-CoA comes from As long as insulin is high, it will cause a series of physiological activities, Turn acetyl-CoA into fat.
Produce more fat in the liver. If, on the contrary, insulin is lower, the situation is different. In this case, acetyl-CoA will produce ketone bodies. Insulin is a powerful hindrance to ketogenesis. Let me clarify one more point, (Insulin hinders the effect of ketogenesis) There has never been a "resistance" effect. Even people with deep "insulin resistance" Insulin can still effectively hinder ketogenesis. But if the insulin is low, (People with good insulin sensitivity usually have low insulin) Ketogenesis will occur, and we will begin to produce ketone bodies. Let’s look at these two key roles (insulin and ketone bodies), What effect will it have on the behavior of "fat tissue". These are bubbles that represent fat. The first question I tried to answer in my lab was: What effect does insulin have on adipose tissue? On the one hand, if we increase insulin, How will "ketogenesis" and "ketone body concentration" change? The answer is yes, it will fall. (Everyone is a good student^_^) So, our first study is to increase insulin content in mice We immediately found out (let me tell you slowly) Let’s look at fat weight gain first, Within 4 weeks of increasing insulin.
Like humans, mice have different fat storage locations. Perrenal fat is a typical visceral fat, Belly fat is typical subcutaneous fat, The interscapular fat is where the real brown fat is stored in rats. And humans (not highlighted in my previous picture) Brown fat is also stored near the thoracic spine. You will find that when the insulin of the animal body is high, Their "visceral fat" and "subcutaneous fat" will grow, But it has no effect on increasing "brown fat". Those places where "brown fat" is stored did not increase. The “belly fat” of mice is equivalent to the “subcutaneous fat” of humans.
This type of fat is often the largest adipose tissue in the human body. And in the human body, research has proved that Subcutaneous fat, generally considered white fat, Under certain circumstances it can become more like "brown fat", So there is a more active metabolism, Because they start to consume more glucose to generate heat. I also marked it on the previous picture, This process is called "decoupling".
During this transition, the "decoupling" activity in mitochondria is increasing, There is no longer a correlation between the energy required by the cell and the energy expenditure. Then, we studied the effect of insulin on the physiological processes of mitochondria. In the middle two pictures, we are looking at the extent of oxygen consumption by mitochondria. This is the purest form of "metabolic activity", The extent to which mitochondria use oxygen. You will see that in the white fat, Insulin has almost no effect on mitochondria. Very little breathing activity, Mitochondria and white fat use very little oxygen, And insulin has almost no effect on it. In the upper right picture, you can see UCP1 (Uncoupling Protein).
This is the amount of UCP1 (uncoupling) protein we measured, And you will see just a blank picture from left to right, (Plus insulin) has no effect on it, It’s very rare, almost unpredictable, The addition of insulin has no good or bad effect on it. The opposite of, When we studied the effect of insulin on brown fat, we found that You can take a look at the black bar graph in the figure below compared to the white bar graph, Insulin reduces the amount of oxygen used by mitochondria.
And this is what happened in "brown fat", The original characteristic of this tissue is the high rate of mitochondrial respiration. If you look further to the right, You will see that the animals in the control group have higher decoupling protein activity. And a little bit to the right (add insulin), The degree of activity is greatly reduced. When we add insulin to animals, the activity of uncoupled proteins in brown fat is almost completely eliminated. Then we tested the metabolic rate. We put animals in a closed space for measuring metabolic rate, And measure their energy consumption. We found that 4 weeks ago, the metabolic rates of the two groups were comparable. After 4 weeks, insulin caused a significant drop in metabolic rate. I will show you the evidence about the human body later. We still have a lot of data and will publish it soon, But these few books show that a "shift" has occurred.
The behavior of brown fat began to look more and more like that of white fat. And we also see a change in the whole, The entire metabolic environment will promote "storage" and inhibit "use". All thanks to insulin. Now, let's discuss the opposite problem. What happens if we raise the "ketone body"? If you want to increase the ketone body in mammals, how to regulate insulin? I have to turn it over (let the insulin drop) We also did experiments with mice. If you want to know the difference between humans and mice, This is indeed what we should always remind ourselves, (I myself, as a scientific worker, of course will always pay attention) Take a look, what to do with the mouse to get it into the "ketogenic state": 1% carbohydrates. We must be aware of this: When we experimented with a (low-carb) high-fat diet, Really, in different mammals, this means different things. We use a very high-fat ketogenic diet to put animals into a ketogenic state.
Many of you probably understand, Why a high-fat, low-carb diet is "ketogenic". But here, let me pretend that some of you don't understand. (Let me be a good professor^_^) This is a study on the human body's intake of extremely single nutrients. (Translator's note: It should be a study of mice, the speaker made a mistake.) Pure fat, pure carbohydrate, pure protein. You can see how insulin behaves in different situations. "Protein" causes a small amount of insulin to rise, But this is also related to the protein category, Just as different carbohydrates have different reactions.
Protein has only a small amount of insulin boost effect, The effect of carbohydrates on increasing insulin is very significant. You can hardly see the effect of fat on insulin, Because it only vibrates near zero. So if you only eat pure fat, As a reminder, in most cases, we generally don’t (We are different from this group^_^) We will not eat pure fat.
But if you eat pure fat (some people eat that way, no problem) But if you eat pure fat, it will not affect insulin. Therefore, the low-carb and high-fat diet is to "maintain low insulin levels." You are providing "calories" to the body, but not causing insulin to rise. Therefore, this way of eating is called a "ketogenic" diet. This is the experiment we conducted on these mice. These are very new data. New data from the past few weeks. We extract the subcutaneous fat of the mouse, And studied the mitochondria. You will find that the black bar graph is an animal on a ketogenic diet Compared with animals under a standard diet (white bar graph) Mitochondria in subcutaneous fat have changed. These mitochondria are more active and use more oxygen.
And the position in the picture below, you can vaguely see UCP1 (uncoupling protein) activity increased. Originally, in the white fat in the subcutaneous fat, the activity of the uncoupling protein could not be detected in the animals under the standard diet. But suddenly, we saw these activities begin to show up. The protein begins to manifest (become a decoupled protein). This may be the cause of the increased respiration in white fat. This is turning white fat into more brown fat. We continue to study further (this is what just happened) We cultivated some adipose tissue in a petri dish. We want to distinguish: Does this phenomenon only occur in fat cells? Or does it need to interact with other tissues in the body? We cultivated fat cells in a petri dish, And add exogenous ketone body (β-hydroxybutyric acid) to increase the value of ketone body. Remind everyone that all laboratories that have cultivated fat know that Without insulin, fat cannot grow. We are cultivating primitive early cells, (Fibroblasts, they have the potential to transform into various cells.) The way we turn it into fat, Just add insulin. We have to train for a period of time after adding insulin, Then remove the insulin, Then add the ketone body and see what happens.
The control group will be placed in a general solution medium. I will not elaborate on all the environmental conditions here, (Of course, if any of you are interested, I would be more than happy to share.) Let us say here for the time being, these are the respiratory function of mitochondria. As you can see, overall, The black column, the fat added to the ketone body, compared to the ordinary solution, Has a very significant improvement, The amount of oxygen used by these cells has doubled. In other words, when the ketone body is elevated, the behavior of the fat cells changes.
They start to use more energy (in this "decoupling" state) And their tendency to store energy weakens. So, we are changing (fatty) behavior. Because there are ketone bodies and low insulin, We begin to change the way the body uses energy. This is very important when we calculate "calories". So far, we summarize: These two molecules, insulin vs. ketone body, Will cause our fat cells to have the opposite behavior. When insulin is in charge, what does it want to do with fat? It wants to make fat become very, very "white" and enter a "storage" state. Instead of "using" energy, it wants to reduce energy use.
On the contrary, when the "ketone body" in the body is the master, Our fat will become more "brown". Fat cells will be in a more "waste" state. And all of this is because we affect the mitochondria in the cell. When the mitochondria are more "coupled", it uses only the energy the cell needs. After turning into brown fat, it suddenly begins to "wasted" energy to heat up. It’s like we keep adding wood to the fire, Because we want the fire to burn more and more. This phenomenon occurs when the "decoupling" protein is the master.
This is a fundamental change in how fat uses energy. Especially how to increase the use of energy, just to generate heat. What I said here is all related to this set of views: When the "insulin" and "ketone bodies" in our body alternate with each other, One is high and the other is low. Because under normal circumstances, the two will not be high at the same time, The two will not be low at the same time. (But in recent supplements, this can be discussed in depth) But in simple terms, the above point of view is the core point here. I will sum up later. There is one more important point, I want to say, As I mentioned before, if we only consider the "heat model", Energy is either used or stored. But in fact, there is an important part here, which is always overlooked. Even if we, this low-carbon and high-fat community, I didn't pay much attention to it (I think). Maybe someone has it, but I don't think it is enough.
That is, the concept of "waste". I think "wasting" energy is very different from "using" energy. What do I mean by that? We are thinking about the earliest model, We looked at two theories about "obesity", The "calorie" model, and the "endocrine" model. I have explained to you, In the "endocrine" model, we have a very special place for energy use. That is "brown fat".
Mitochondria are "decoupling" and are only used to generate heat. Use glucose to support our "fire." And in the "endocrine" about obesity, We have another concept, We have another energy outlet. This is the "ketone body" itself. You may already know this, and some people can already infer it. If the body’s insulin is low, We will convert acetyl-CoA into ketone bodies. Remember, where did acetyl-CoA come from? (This is an important point) It comes from nutrients, mainly fat and carbohydrates. We cut the fat cells into small pieces. Each piece is "acetyl-CoA", Then turn "acetyl-CoA" into "ketone body". We are equivalent to turning "fat" into "ketone body". And when we are in a "ketogenic state", how to deal with these ketone bodies? Will be excreted through breathing. anything else? We will pee it out. This can be a meaningful feature~^_^ According to the degree of a person’s "ketogenic state", (Exhale, ketone bodies in urine) 5-20 times more than normal.
Pay attention to the significance of this: We waste a section of fat directly! Released in the environment! Can you find the meaning? Very incredible: we exhale/urinate segments of fat. I am not talking about the kind of nephritis syndrome. The doctor may think it is a waxy cylinder, but I am not talking about those. I'm talking about "ketone bodies", segments of fat become "ketone bodies". We waste them. This only exists when calories are calculated in the endocrine model. This is why you can have some (energy intake) swing space, You can consume some excess energy, but still lose weight faster than others.
Because we have this swing space, we can waste energy. This is not counting the part that I demonstrated to you before, "improving energy use". All the data that I showed you, from my laboratory, It's all about this model. I attach great importance to the question that has been in everyone's mind: How much does this have to do with the human body? (I attach great importance to this issue) Let's first take a look at the hints given to us in the existing research. This is a study a few years ago, from the laboratory of Dr. David Ludwig. Let people eat three diet plans with different nutrient ratios. (Low fat, low glycemic index, low carbon) You will find that the ordinate is similar to the ordinate I showed you.
Ours is the metabolic rate of mice, here is the metabolic rate of humans. You will find that the highest metabolic rate is the lowest carbohydrate group. The total calorie intake of these groups is the same. However, the low-carbon group has the highest metabolic rate. Perhaps this confirms the increase in energy use, The increase in "decoupling" will increase the amount of oxygen used, This is what is measured when measuring metabolic rate. The following research is very interesting-you can see it by looking at the title.
They divided people into two groups. One group intake is the classic "low fat, calorie control" diet. The other group has a "low-carb, no calorie control" diet. In other words, (low-carbon group) you can eat as much as you like. What's interesting is that in the end the two groups of people ate the same (calories). (Almost less than the amount) As you all know, we will automatically control the amount of food, People don’t eat crazy and unlimited food often. We will naturally control ourselves. In this study, the calorie intake is the same for the two groups. Even (low-carbon group) you can eat as much as you like. The important point is that the group that was told you can eat whatever you want, The actual amount they eat is statistically the same as the other group. But they lost more than twice as much fat as the other group! (In the process of research) But (by common sense), this shouldn't happen. The author also specifically mentioned this point. They eat the same calories, But the amount of fat loss in one group was 2.5 times that of the other group.
(Less more) You should eat less, but they don't. There is more evidence that In this process, there may be some "extra" energy usage, Or some degree of waste. Let’s look at it the other way around, These studies are looking at "lowering" insulin response, So what if insulin is "upgraded"? This study found two groups of people with the same weight, Type 2 diabetes, corresponding to the same weight without diabetes. In the beginning, the diabetes group had a higher metabolic rate. There are many reasons for this phenomenon, One of them may be that insulin (in the diabetic group) is relatively low compared to people who are also overweight but do not have diabetes.
But what happens when people with diabetes start insulin injections? Their metabolic rate began to drop drastically. (They discovered this) When people with type 2 diabetes start to inject insulin, their metabolic rate drops. This also proves that some "transitions" have taken place (in the body). The last study I want to show you, There are also clues to support this view.
And it's in humans (I like this research very much). Don't be scared by (so many numbers). This study is tracking type 2 diabetes, Start insulin therapy from the beginning (month 0). Let's take a look at a few key contents. How does the insulin dose change in 6 months? Do you see what happened? The overall trend is that insulin doses are increasing. This also reflects a physiological phenomenon: Too much of a certain thing will cause its sensitivity to decrease. In other words, high insulin causes insulin resistance. The insulin resistance of these type 2 diabetic patients will become more and more serious. There is only a 6-month process here. In just 6 months, how has their weight changed? They gained 20 pounds of fat. This is common in type 2 diabetes patients who are injected with insulin. 20 pounds gain. And finally, (the results are very interesting so far) How much food did they eat? (At least how much was "claimed" to eat?) (I admit that using "claims" as data is problematic) (Food calories) are falling. So, there is only one indicator, insulin amount, or calorie intake, Comparing with the weight gain.
There is only one (is insulin). Finally, let us make a concise summary. There are two theories about why we gain weight. Calorie theory, and endocrine theory. In both theories, energy needs to be stored or used. But in endocrine theory (which can explain calorie theory at the same time), There is a third option, which is that energy can be "wasted". It is not "waste" in the broad sense, but wasted from people. In a state of low insulin, The evidence I have seen before shows that There will be a change in the behavior of our adipose tissue. Fat will become more "decoupled" and more like brown fat.
At the same time, the behavior of white fat is relatively small. This means that if fat does not behave as white fat, It is less likely to store energy, and the tendency to store energy becomes smaller. On the contrary, because adipose tissue is more "decoupling", It's more like brown fat, and uses more energy. But this is not because we do more work, do more exercise.
Why do we use more energy? Yes, it is used to heat up! This is the function of brown fat to regulate heat. Finally, what’s not related to "brown fat" (I have to mention it too), When insulin is low, ketogenesis will increase, There are these small pieces of nutrients, which will be wasted from the body, Through breathing, urination. All these factors add up, let me sum up very down-to-earth: The "calorie" theory can be included in the "endocrine" theory. But you will find that I don't want to be too absolute. Maybe there is something else (we didn't think about it), so I left a small piece outside the circle. As a scientific worker, my job is to find the truth. I admit that there may be some variables that I haven’t considered yet, I haven't found it yet, or we don't know yet. So here, I will leave room. Respect for the unknown. Overall, I believe that this series of events, The transformation of our fat tissue behavior, the transformation of the way we use energy (wasting energy), (By excluded ketone bodies) I believe that these are all we need to remember, When we are talking about the benefits of a low-carb and high-fat diet on the metabolic state of the human body.
This kind of overall metabolic environment in the human body, Allow us not to care about every calorie. We can tell people, tell ourselves, Eat when you're hungry, don't eat when you're hungry. We don’t need to count calories. Because if we eat a little more, The body is ready to deal with this situation. Although this topic was raised in our current historical environment, I also want to say that this is not a new concept. We already know this knowledge. Many of you are familiar with these concepts. If you have heard the previous lectures, you should be familiar with it. This is not a new concept. This concept has been around since we started to study "why do we get fat".
in the future, What we are doing now is to cooperate with medical institutions for "gastric bypass surgery", The first step is to look at the insulin after fasting, and other related indexes, and the correlation with insulin sensitivity. There are also behavioral characteristics of subcutaneous fat and visceral fat. Just like the experiment we did on mice, We will measure the respiration of uncoupled proteins and mitochondria. In other words, how does fat behave? More like white fat or brown fat? Then, we will study how humans enter a ketogenic state. Cut fat through living tissue to see how it behaves. I admit that the human body data is still insufficient. I believe that there are clues to support our philosophy. We will solve the mystery soon. I hope you can ask me questions during the break. (I love questions very much.) Again, I am very grateful to participate in this seminar, thank you!.