Hello! I'm the owner of Fusubon.
When you're restricting carbohydrates, you often hear about ketones and the ketogenic diet, right?
Even if you have never tried carbohydrate restriction, you may have recently heard that soccer player Nagatomo is using the ketone body cycle.
In fact, the term ketone body cycle is slightly different from proper biological or medical terms such as the citric acid cycle.
Some people mistakenly believe that the citric acid cycle and the ketone body cycle are the same thing, so we will explain this point as well.
To understand this in detail, you need to have some understanding of metabolism, but first I'll give you a rough explanation in colloquial terms.
When glucose is in short supply in the blood, neutral fats are used as ketone bodies.
When the body goes without food for a long time, it first uses glycogen, a mass of sugar stored in the muscles and liver, as an energy source.
It is said that the amount of glycogen stored in the liver is about 100g, and that in the muscles is about 400g, but glycogen in the muscles can only be used by the muscles.
However, if hunger continues, a phenomenon called "gluconeogenesis" occurs, in which protein and muscle are broken down into amino acids and then converted into sugar.
The reason for this, which will be explained later, is that red blood cells do not have mitochondria and cannot even breathe without sugar.
At the same time, the body's ability to use fat as energy increases. At that time, the substances produced in the liver are called ketone bodies (a collective term for acetoacetate, beta-hydroxybutyrate, and acetone).
You may have heard of people who have been lost in snowy mountains or who have had to survive a disaster for several days, or even as long as a week, without food or water.
This means that your body uses fat for energy.
Of course, this is an extreme example. We also produce ketone bodies and use them as energy when we are hungry for long periods of time or while we are sleeping.
In the first place, fat is stored in order to be used as energy when we are hungry, so if we don't choose what we eat, we won't starve. In our modern Japanese society, if we eat normally, we don't use fat as energy. In order to use fat as energy, we need to reduce our sugar intake.
That's why you need to limit carbohydrates to lose weight.
That's roughly what it's like, but it's quite a leap forward.
To understand this, you need to understand metabolism, which we'll explain in detail below.
Living things use what they eat as part of their body
Cars burn gasoline to generate energy, but the gasoline never gets replaced by the car. On the other hand, living things replace the food they eat with their bodies.
Humans break down and absorb the food we eat using various digestive enzymes. During this process, various chemical reactions occur. These chemical reactions either require energy or produce energy.
If you just read this, you might think that "food = energy," but food is like burning gasoline, like a car.
Burning the energy used to produce explosive energy has a different meaning than when humans burn fat for energy.
It is well known that carbohydrates and proteins have 4 kcal per gram, and fats have 9 kcal per gram, but these are merely indicators of the maximum amount of energy that can be synthesized in the body from these foods. The amount that remains after use is not stored like gasoline for a car.
Also, even though cars use gasoline as a source of energy, that gasoline does not become the car's steering wheel, tires, or other parts.
On the other hand, everything we put into our mouths, except for dietary fiber, which cannot be absorbed, is not only excreted from the body as CO2 or water, but is also incorporated into the cells of the body. Dietary fiber that cannot be absorbed is necessary to feed intestinal bacteria and to regulate bowel movements.
There is a common saying that food "becomes your blood and your flesh," and this is exactly what happens when we eat. We should first understand that we are not simply extracting energy, but that during chemical reactions, substances are exchanged and energy is produced .
Animals use the energy produced during metabolic chemical reactions through something like an energy capsule called ATP (adenosine triphosphate) . Therefore, it can be said that humans eat a variety of foods in order to generate this ATP.
Food can be broadly divided into carbohydrates, proteins, and fats.
Carbohydrates = sugar + dietary fiber. If you understand how sugars, proteins, and lipids are broken down and absorbed in the body, you will understand how lipids are used for energy.
First, let me explain sugar metabolism.
Sugar metabolism
Chemical formula and structure of ATP
First, there are three systems that cells use to produce ATP.
① The system known as "glycolysis" (anaerobic respiration)
② The cycle known as the "citric acid cycle" (TCA cycle, Krebs cycle)
3) The system known as the "electron transport chain"
There are three types:
The term "ketone body cycle" will not be used here. It's confusing, but let's try to understand it step by step.
To understand this, it is necessary to know "what kind of reaction" is occurring and "where" in the body (cells) .
So, starting from ①, let's take a look at where the reactions occur, what type of reaction they are (the substances obtained, the number of ATP, etc.).
Glycolysis (= anaerobic respiration)
First, I will explain the glycolysis pathway, which is found in most living organisms and is the most primitive energy-producing system.
The reason why they are called primitive is because ancient organisms did not have mitochondria in their cells.
We will discuss mitochondria later, but glycolysis is a system that can produce energy even without mitochondria (even without oxygen) .
Where the reaction occurs
First, it occurs in a place called the cytoplasmic matrix inside the cell. The cell has a membrane called the cell membrane, which contains the nucleus, mitochondria, etc. The picture above is a simplified diagram of a cell, and the reaction occurs in ① in the picture, that is, in an ordinary space inside the cell that is neither the nucleus nor the mitochondria.
Number of ATP and hydrogen obtained through glycolysis
In the cytosol, glucose (C 6 H 12 O 6) is converted into a substance called pyruvate (C 3 H 4 O 3 ) . The details of the reaction are omitted here, but this conversion produces 2NADH, 2 hydrogen ions (H + ), and 2ATP.
The NADH mentioned here may be unfamiliar and difficult to understand, but it's fine as long as you understand that NAD is a substance that is convenient for transferring electrons (called an electron carrier).
Hydrogen has the property of wanting to give up electrons. A representative element that tends to receive electrons is oxygen, while an element that tends to donate electrons is hydrogen.
(You may remember from high school chemistry that the right side of the periodic table has higher electronegativity.)
For now, all you need to know is that hydrogen H combines with NAD, and two protons (H + ) are produced when an electron is removed from the hydrogen.
In other words, 1 mol of glucose produces 2 mol of pyruvate, 4 mol of hydrogen ions, and 2 mol of ATP .
Glycolysis is also known as anaerobic respiration because it does not require oxygen to convert glucose into pyruvate.
Oxygen is required for the reactions that occur in the inner mitochondrial membrane, which will be described later.
The pyruvate made from this glucose is used in the next ② TCA cycle (a place inside the mitochondria called the matrix), and the hydrogen is used in ③ the electron transport chain (the inner membrane and intermembrane space of the mitochondrion).
It's amazing how the products made from glucose are used without any waste.
Citric Acid Cycle = TCA Cycle = Krebs Cycle
Next, we will explain the citric acid cycle. The citric acid cycle is also called the Krebs cycle after the person who discovered it.
It is also called the TCA cycle, which is an abbreviation for Tricarboxylic Acid Cycle.
Where the reaction occurs
It occurs in a place called the "mitochondrial matrix." This is similar to the cytoplasm, but it is a nondescript area of the mitochondria. It is the location ② in the picture above.
What is Acetyl CoA?
An easy-to-understand structural diagram of acetyl CoA
The two pyruvates produced in the glycolysis pathway in step ① are converted into a substance called acetyl CoA in the mitochondrial matrix. This is an unfamiliar term, isn't it?
Pyruvic acid is an unfamiliar term, but acetyl CoA is even less so.
However, this acetyl CoA will come up many times in the future, so even though it is a difficult word, it cannot be ignored. Rather, it is necessary to become familiar with acetyl CoA. It is pronounced "acetyl co-e", not "acetyl core".
I've never heard of it before and it's a little unsettling, but I'll get used to it so please bear with me for a while.
By the way, CoA is an abbreviation for coenzyme A. I think many people know about "coenzymes" from the supplement Coenzyme Q10.
Coenzyme A is a coenzyme. What is a coenzyme? Many people may wonder, but in high school chemistry terms, a coenzyme is a catalyst. You can think of coenzymes = catalyst = vitamins. They are substances that help promote chemical reactions. The reason why vitamins are important for metabolism is because they play a role in promoting reactions. This is why vitamins are important when restricting carbohydrate intake.
Acetyl CoA was also known as "activated acetic acid" in previous study guidelines, so if you have studied high school chemistry, it may be easier to understand if you think of it as the OH part of acetic acid combined with sulfur S and coenzyme A (CoA), as shown in the illustration above. 
ATP and hydrogen produced by the citric acid cycle
When pyruvate produced by glycolysis enters the mitochondria, it is converted into acetyl CoA. This acetyl CoA combines with oxaloacetate (produced from pyruvate) to produce citric acid.
Citric acid → α-ketoglutaric acid → succinyl CoA → succinic acid → fumaric acid → malic acid → oxaloacetic acid + acetyl CoA → citric acid → ...
This cycle is called the citric acid cycle because it is the first step in the process. Oxaloacetate is the starting point, and some of the pyruvate produced by glycolysis is also converted into oxaloacetate. Oxaloacetate can also be produced from the amino acids aspartic acid and asparagine.
The complete reaction of this cycle is 2C3H4O3 + 6H2O → 6CO2 + 8(NADH+H+) + 2(FADH2) + 2ATP.
In other words, 2 moles of pyruvic acid produce 2 ATP and 20 hydrogen atoms.
Electron (hydrogen) transport chain
In old biology classes, this was called the hydrogen transport chain, but more recently it has come to be called the electron transport chain.
Where the reaction occurs
It is located in the inner membrane of mitochondria. This is location ③.
Number of ATP gained
The hydrogen produced by glycolysis and the citric acid cycle are used as energy and oxygen is used to produce water and ATP.
24H + + 6O2 → 12H2O + 34ATP
As we said, oxygen is used in mitochondrial reactions, and it is used in the electron transport chain.
We probably imagine breathing as taking in oxygen and exhaling carbon dioxide, but it's interesting that the order is reversed, with carbon dioxide coming out first in the citric acid cycle and oxygen being used in the electron transport chain.
If you look closely, you'll see that the amount of ATP obtained is far greater. 34 ATP is 17 times the energy of glycolysis. This is because hydrogen has been produced to donate electrons up to this point.
The amount of ATP produced in mitochondria , including that produced by the citric acid cycle (2ATP), is 36 ATP, so it is sometimes said that the amount of ATP produced by mitochondria is 18 times that produced by glycolysis .
It is often mistaken that sugar metabolism = glycolysis, but that is not all. Mitochondria are also used in the process of sugar metabolism. After glycolysis, pyruvate produced in glycolysis is used in the citric acid cycle, and hydrogen produced in glycolysis and the citric acid cycle is used in the electron transport chain.
If the body produces the energy it needs solely through sugar metabolism, it will no longer need energy from lipid metabolism, making it easier to gain weight.
Furthermore, if sugar is the only energy source, other problems can arise, such as excessive production of insulin and glycation, which can cause inflammation of blood vessels.
It may seem like glycolysis alone can produce enough energy, but humans have not always lived in times of plenty. For tens of thousands of years, we have survived without knowing when we would be able to get food.
Humans have survived by eating when they can, storing excess energy as triglycerides, and using it when needed.
Nowadays, we can eat it any time we want, so it is ironic that this same function is actually the cause of adult diseases such as obesity.
Next, let's look at fat metabolism.
About fat and lipid metabolism
Next, I will explain how fat is used as energy. Fat exists in the body in the form of neutral fat.
Neutral fats are broken down by lipase into glycerol and three fatty acids. Glycerol is then used for glycolysis or gluconeogenesis, which will be described later.
Here we look at the structure of fatty acids. 
Fatty acids have a carboxyl group (-COOH) at the end, just like acetic acid. Fatty acids that have a carbon-carbon double bond in the middle are called unsaturated fatty acids.
Conversely, if there are no saturated fatty acids, they are called saturated fatty acids. We will explain the characteristics of various oils and fatty acids (such as essential fatty acids) in another article.
When the carboxyl group (-OH) is replaced by sulfur and a coenzyme (-S-CoA), as shown in the diagram below, it is called acyl-CoA .
Acyl CoA binds with carnitine and enters the mitochondria. (L-carnitine is not necessary in the case of medium-chain fatty acids such as coconut oil.)
After that, it separates from carnitine and leaves the mitochondria.
When acyl-CoA enters mitochondria, acetyl-CoA is produced from the acyl-CoA. The reaction at that time is called β-oxidation.
β-oxidation is when the carbon next to the carbon that was originally a carboxyl group in acyl CoA is called α, and the carbon next to it is called β, and the second carbon is oxidized to produce acetyl CoA, which is why it is called β-oxidation.
Although the remaining part is slightly shorter, it has the same shape, so it is still called acyl-CoA and undergoes repeated beta-oxidation.
At the same time, NADH and FADH2, which are used in the electron transport chain, are also produced. Acetyl CoA is used in the citric acid cycle.
The role of amino acids and amino acid metabolism
Amino acids have two main roles.
① They become the raw materials for proteins, enzymes necessary for metabolism, nitrogenous compounds, hormones, information molecules, and polymeric compounds that support structure. ② They are metabolized and become an energy source.
In step ②, this is done using the citric acid cycle, which has previously been discussed in sugar metabolism and lipid metabolism.
Amino acid metabolism
It may seem complicated, but all you need to understand is that there are 20 types of amino acids that participate in the citric acid cycle at some point, or that can produce pyruvate or acetyl CoA .
What is gluconeogenesis?
Before explaining ketone bodies, let's talk about gluconeogenesis.
Simply put, gluconeogenesis is a reaction that occurs mainly in the liver when you are fasting, and converts pyruvate made from amino acids (glycogenic amino acids) and lactic acid into glucose, and glycerol separated from neutral fats into glucose.
During glycolysis, there is a reaction that converts glucose into pyruvate, but since ATP is used to convert pyruvate back into glucose, this may seem like a waste of time.
This occurs because cells without mitochondria cannot function without glucose, and glucose is a minimum requirement as it is used as a material for nucleic acids and electron carriers.
Specifically, pyruvate enters the mitochondria and is converted to oxaloacetate by an enzyme called pyruvate carboxylase.
Oxaloacetate cannot leave the mitochondria, so it is converted to malate by malate dehydrogenase.
In the clockwise direction of the citric acid cycle, amino acids that join just before malate leave the mitochondria at the malate stage and are used for gluconeogenesis.
Malate that leaves the mitochondria is converted back to oxaloacetate, and then converted to phosphoenolpyruvate → 3-phosphoglycerate → 1,3-bisphosphoglycerate → glyceraldehyde-3-phosphate → ... → glucose.
What is important from now on is that oxaloacetate in mitochondria is being converted into malic acid and is in short supply.
Ketone bodies are produced in the liver
Now we can finally talk about ketone bodies. Acetyl CoA binds with oxaloacetate and the citric acid cycle begins, but when there is little glucose in the blood, there is a shortage of pyruvate made from glucose. Ketone bodies are also used in the reaction of converting oxaloacetate back into glucose through gluconeogenesis, so there is a shortage of oxaloacetate in the liver, and there is an excess of acetyl CoA derived from fatty acids.
The remaining acetyl CoA is used in the liver to synthesize ketone bodies (acetoacetate, β-hydroxybutyrate, and acetone). Acetoacetate and β-hydroxybutyrate are water-soluble and are transported from the liver to other tissues by dissolving in the blood.
Ketone bodies are reconstituted as acetyl-CoA in non-hepatic cells
How ketone bodies are used
The transported acetoacetate is converted to acetoacetyl-CoA and succinic acid by the enzyme succinyl-CoA transferase, which is produced from ketoglutarate in the citric acid cycle.
Acetoacetyl-CoA is broken down into two molecules of acetyl-CoA by thiolase.
Ketone bodies cannot be utilized not only by cells without mitochondria, but also by the liver, because the liver does not have the enzyme with the complicated and long name (succinyl CoA transferase). Ketone bodies are utilized by tissues other than the liver. Succinic acid, which is made from acetoacetate and succinyl CoA, is also used in the citric acid cycle.
You may wonder why water-soluble acetyl-CoA is converted into ketone bodies and then transported as acetyl-CoA again, but since acetyl-CoA cannot pass through the lipid bilayer of the cell membrane, it is thought that it is converted into ketone bodies, which are small molecules.
By the way, of the ketone bodies, only acetoacetate is used for energy production. β-hydroxybutyrate is converted into acetoacetate and used for energy metabolism, while acetone is not an energy source and is excreted through exhalation.
The misconception that glucose is the only energy source for the brain
Since the brain's source of energy is glucose, I will explain why we still recommend consuming sugar.
There are two main reasons. One is that when your blood sugar level is low and it rises, you actually feel happy and energized.
Another plausible explanation is that there is a blood-brain barrier, which fatty acid molecules are too large to pass through, meaning that only sugar can be used as an energy source.
The euphoric feeling that occurs when blood sugar levels rise can become a problem if repeated.
Regarding the former, when you eat a large amount of carbohydrates, your blood sugar level rises sharply. This causes a lot of insulin to be secreted, but the insulin secreted does not match the blood sugar level before the meal. The pancreas does not have the ability to regulate to that extent, so if anything, excessive insulin is secreted.
This will cause your blood sugar to go down even lower than it was before you ate. When you have low blood sugar, you start to feel tired and sleepy, and if you eat something sweet at that time, your blood sugar level will rise sharply, giving you a sense of euphoria and making you feel very energetic. However, after some time has passed, your blood sugar level will drop again, and you will fall into a state similar to drug addiction, where you will have to eat something sweet again.
This is why sugar is said to be addictive. It would be fine if this cycle didn't have any side effects, but it is known that extreme fluctuations in blood sugar levels can cause inflammation in the endothelial cells of blood vessels, and if you continue to secrete large amounts of insulin, it can weaken the pancreas and lead to diabetes, which weakens the ability to secrete insulin.
I think everyone has experienced this feeling of energy when blood sugar changes from low to high, when you eat something sweet (even when you are not exercising), and when you feel energized. When you eat sweet chocolate as a snack, when you eat something sweet after running a marathon, etc., although the situation may be different, many people will agree with their own sense that sugar is an essential nutrient for the brain.
When you're fasting, your brain uses ketones for energy.
As I have explained at length up to this point, when you are fasting, the brain does not directly use fatty acids as energy, but uses ketone bodies produced in the liver as energy, so the fact that fatty acids cannot pass through the blood-brain barrier is not an issue at all.
Ketone bodies and ketoacidosis
Diabetic patients cannot take in glucose because their insulin secretion is weak, so their body uses glycogen or produces glucose through gluconeogenesis to create energy, but since this cannot be absorbed into cells, a large amount of ketone bodies are produced. This causes the blood to become acidic, putting the body in a dangerous state.
However, this is the case for people who are unable to secrete insulin, so it is not a problem for people who can secrete insulin normally.
Ketone body levels when restricting carbohydrate intake
If you are unsure, you can also use a blood glucose measuring machine to check your ketone levels.
As a rough guide, if you have about 0.5 mmol/L of ketone bodies, you can say you have a ketotic body type. The unit of ketone bodies is often μmol/L. Micro is 10 to the power of -6, and milli is 10 to the power of -3, so 1000 μmol/L is 1 mmol/L. In a state of ketoacidosis, the ketone body value is 5000 μmol/L (5 mmol/L), an order of magnitude higher than in people with a ketotic body type.
Some people who promote the ketogenic diet recommend 1mmol/L to 3mmol/L, but in my opinion, even 0.5mmol/L feels like a pretty strict carbohydrate restriction.
We recommend restricting carbohydrate intake so that ketone levels do not exceed 1mmol/L.
