Interview

The organs (tissues) in our body do not engage in metabolic activity independently. Rather, they are considered to work closely with one another to achieve well-balanced metabolism for the entire body. However, not much has been revealed yet about this exchange of metabolic information between organs (interorgan network of metabolic information) and the mechanism of this network. Professor Katagiri, who has produced a host of remarkable results in his effort to discover the mechanism for the interorgan network of metabolic information, has found that the autonomic nervous system is involved in the exchange of metabolic information between organs. In recognition of his achievements, he was given the Science and Technology Award (Research Division) for fiscal 2014 by the Minister of Education, Culture, Sports, Science and Technology. In this interview, we will hear from Professor Katagiri about a number of topics from diabetes, which was the genesis for his research, to the discovery of the interorgan network of metabolic information and its significance.

– Congratulations on the reception of the Award of the Minister of Education, Culture, Sports, Science and Technology. First, could you explain about your research with the focus on the relationship between diabetes and obesity?

Katagiri:
As you know, diabetes and obesity have become very common diseases and they are now said to be national afflictions. Our ultimate goal is to find out how to treat these diseases of diabetes and obesity. In addition to this goal, we also need to know why diabetes and obesity occur, what causes these diseases to get worse and what prevents healthy people from becoming diabetic or obese. In order to do so, we are going to figure out what kinds of mechanism exist to store and consume the energy taken into the human body and how these mechanisms function to regulate the body.

– It is widely known that there is a relationship between diabetes and obesity. Do all obese people get diabetes?

Katagiri:
No, that is a wrong perception. There are obese people who do not get diabetes, while some people get diabetes even though they are not obese. It is true, however, that obese people are more likely to become diabetic. Actually, there are several types of diabetes. People who have the type of diabetes that causes the production of a hormone called insulin to reduce develop symptoms of diabetes, regardless of whether they are obese or not. By contrast, people who are capable, to a certain extent, of producing insulin often get diabetes as they become obese. On the other hand, people who can produce a high enough amount of insulin do not develop diabetes even if they become a little obese.

– Is it all right to think that patients without the ability to produce insulin can be cured to a certain extent by giving them the necessary amount of insulin?

Katagiri:
In principle, yes. But, insulin is different from other hormones such as growth hormone in that its secretion is strictly regulated all the time. To be concrete, insulin is secreted in a timely manner as you eat food. And that prevents blood sugar levels from rising. After food is processed to a certain degree, the secretion of insulin stops because blood sugar levels do not need to be lowered any more. If the secretion of insulin continues, it causes a condition called hypoglycemia. Therefore, the insulin secretion is controlled to stop so that this condition is avoided. Insulin plays an important role of controlling blood sugar levels. So, unlike other hormones, its secretion needs to be regulated in a timely manner several times a day.

– Very delicate regulation is necessary, isn’t it?

Katagiri:
Yes. So patients with a condition known as type 1 diabetes who can produce no or little insulin themselves need to take at least four, or in some cases five, insulin shots a day.

– What about non-type 1 diabetes?

Katagiri:
The other type – type 2 diabetes – has one characteristic, which is insulin resistance. I explained earlier that insulin is a hormone that reduces blood sugar levels. If insulin removes blood sugar, you may well wonder where the removed blood sugar goes. The sugar in blood goes into cells. Insulin causes sugar to move from the blood stream into cells. This property manifests itself more clearly as a person gains in weight. You eat a meal; the eaten food is digested; sugar is absorbed into the blood stream; then insulin causes the sugar to move into cells – this is how it works.

But, in cases where cells already have enough energy in them, such as when a person is obese, even if insulin tries to move sugar from the blood stream into cells, the cells reject it. They say: “We don’t need any more sugar.” We call this state “insulin resistance.” If sugar moves smoothly from the blood stream into cells, there is no problem. But, if cells refuse to receive sugar, it remains in the blood stream even when insulin is present, right?

– Is it as if cells say: “We have a full stomach”?

Katagiri:
It is not so much a full stomach but a state in which cells are well nourished. If cells refuse to receive sugar, blood sugar levels do not drop. This condition is observed in many obese people, and that is why diabetes is associated with obesity. And, as a person becomes really obese, the risk of getting diabetes increases sharply. But, even when this condition occurs and cells say they do not need any more sugar, there are cases where diabetes does not develop if insulin continues to signal cells to let in sugar, forcing them to absorb as much sugar as possible. So, the ability to produce insulin is deeply concerned with whether a person becomes diabetic.

– What kind of treatment is available for the type 2 diabetes that is associated with obesity?

Katagiri:
As Ekiken Kaibara, a Confucian scholar of the Edo period, said, effective treatments are restricted diet and exercise therapy. Eating and exercising in moderation is essential. Diabetes is often associated strongly with strict dietary therapy and restrictions. There seems to be a widespread misperception that all patients with diabetes have to give up on delicious foods and feel hungry all the time. But, these days, effective drugs such as those that help control appetite are increasing gradually, providing much more therapeutic options for diabetes than ever. So, it is now becoming increasingly possible for me to offer my patients a variety of options when choosing drugs. But, we still do not have a drug that cures obesity just by taking pills or a drug that enables a person to produce insulin without the help of insulin shots. The reality is that we are still far from finding an ultimate remedy in the true sense of the words.

– People see diabetes as a disease that is difficult to cure. Is it possible to completely cure diabetes?

Katagiri:
There has been no case of full recovery so far. Several years ago, we reported that we had discovered a method of curing a very rare type of diabetes. But the method is effective only for this really rare type of diabetes. So, unfortunately, there is no treatment at the moment that completely cures diabetes. But diabetes is a disease that can be controlled to a certain extent. Of course, there are cases where drugs need to be used to control diabetes. As for patients who have become diabetic because of obesity, however, controlling weight directly leads to a cure. But, if you lose some weight and then overeat again, you become diabetic again. In this regard, diabetes cannot be said to be a disease that can completely be cured with ease.

– Once you develop symptoms of diabetes, you will need to live with them for a long period of time.

Katagiri:
You are right. I don’t mean to cause misunderstanding, but, as a matter of fact, getting diabetes per se is not so serious. What’s worse is that diabetes may cause so-called complications that damage the eyes, nerves and kidneys. This is evident in the fact that diabetes is the leading cause of blindness in adults. The biggest problem we currently face is that a rapidly increasing number of patients are being afflicted with these diabetes-induced complications.

Another problem is arteriosclerosis. Obesity alone can cause arteriosclerosis. And, if obesity is combined with diabetes, then the risk of developing arteriosclerosis increases exponentially. Arteriosclerosis often leads to a stroke or myocardial infarction. Strokes and myocardial infarction due to arteriosclerosis are responsible for about a quarter of deaths of Japanese people. While diabetes itself is not so serious, it can lead to serious illnesses. In this situation, we are currently more focused on controlling the symptoms of diabetes to prevent complications from developing than on curing diabetes. Of course, our research is aimed at not only controlling diabetes but also preventing people from getting diabetes and curing diabetic patients.

– What made you realize that the exchange of information between organs via the brain, i.e. the interorgan network of metabolic information, is related to diabetes?

Katagiri:
The theme of our research is to treat diabetes and obesity and prevent the human body from becoming diabetic or obese. The human body is inherently supposed to have a system that protects it against obesity and diabetes. This means that obesity and diabetes can be considered to occur when that system is disrupted at a certain point of time. As our research progressed, we found out that the human body has a system for keeping a person’s physical frame and weight constant within a certain range. What is new about our research is the effort to figure out how this system is disrupted.

Now, let me explain about the researches of the past. For example, when food is digested, insulin is secreted from beta cells (β cells) in the islets of Langerhans. The secreted insulin circulates in the body and works in the individual organs. When blood sugar levels drop to a certain extent, β cells stop the secretion of insulin. The past researches on blood sugar levels claim that only β cells and insulin action are responsible for everything that happens in this process. When researches are done from this point of view, efforts are focused on to explore the mechanism of the secretion of insulin by β cells. Or, if insulin prompts muscles to accumulate fat, techniques for observing detailed molecular action in cells are used to clarify what happens in muscles.

Of course, it is not my intention to deny the importance of molecular level researches. However, as I have continued my research while treating patients as a doctor, I have come to this conclusion that the mechanism of metabolism that concerns the entire body cannot be understood without observing an individual as a whole, or to put it simply, a single human being, rather than just thinking at the molecular level. What kinds of information are exchanged between organs in the body? How does this exchange control blood sugar levels? And, how does the mechanism for keeping the body weight constant work in the interaction among organs? These things cannot be understood without looking at the entire body.

For example, body weight is determined by the sum of metabolism of the entire body. Blood sugar levels also change according to the sum of metabolism of the entire body. If so, we should discover how this sum is controlled. It is unlikely that the individual organs metabolize separately and freely and that the sum of metabolism by those organs happens to be constant all the time. Particularly, when we look at blood sugar levels, we can see that they are controlled in healthy people much more strictly than we think. Changes in blood sugar levels are kept within a certain range even before and after people eat. It is unthinkable that such elaborate control is accomplished by β cells alone. This leads us to suppose that not only the pancreas but various other organs know what kind of metabolism occurs in which organ and control their metabolism based on the information about it.

The question is why an organ can get to know about the metabolism occurring in other organs. If such information is exchanged between organs, in what way does that exchange take place? That was what we tried to figure out. And we concluded that there must be a part in the body that controls the metabolic information as a whole, something that plays a role similar to that of a control tower.?

For example, when a metabolic alteration suddenly occurs in an organ, the information about this alteration must be delivered throughout the body to inform other organs that metabolism has changed in that particular organ. If there is a part that monitors and controls the state of metabolism, this information must be passed to it, too. And that controlling part must send various orders to various organs in the body, causing the metabolism of those organs to change accordingly. We decided to observe these various changes taking place concurrently in the body. We presumed that the body might have homeostasis, a system for keeping the body in good condition even if something strange happens somewhere in it. We wanted to find out what it was. Also, biologically speaking, we wanted to see the exchange of information between organs in a broad context over a long span of time and space, rather than uncover the action of a single molecule and identify its cause.

– It is considered that there are two ways for organs to exchange information. One is for each organ to directly communicate with other organs on a one-to-one basis. The other is for organs to send information to a central part that acts as a control tower, and that central part relays the information to the individual organs at its discretion. Have you discovered in your research that organs communicate in the latter way?

Katagiri:
No, that’s not correct. Certainly, information can be transmitted in those two ways. Based on our findings, however, I think that the human body is not confined to the latter way of communication but has a system for enabling both ways of communication. I call these two ways of communication “gross regulation” and “fine tuning,” respectively.

There are two ways to transmit information to organs; one is via hormones, and the other is via nerves. Hormones, such as insulin mentioned earlier that is secreted to lower blood sugar levels and leptin that is concerned with body weight, are carried in the blood stream throughout the body right after they are secreted. When information is transmitted via nerves, by contrast, it is precisely delivered to a specific organ. The transmission speed is different as well. Information is transmitted more quickly via nerves. When it comes to metabolism, however, there is no significant difference between the transmission via nerves that carries information in milliseconds and the transmission via hormones that carries information in minutes. The transmission via hormones is slower, but it only takes about a minute for hormones to deliver information to the organs in the entire body once they are released into the blood stream.

These two ways, however, greatly differ in the way information is transmitted. It is considered that hormones play the part of informing the entire body of a rise in blood sugar levels at once and triggering metabolism. This is “gross regulation,” which I mentioned earlier. This is an analogy that I often use. You call out to children playing in a park to run away. Whether they listen to your warning depends on whether they can hear you. So, even if a hormone is secreted to transmit information, whether organs respond to that hormone and change metabolism depends on whether the cells in those organs have the right kind of receptor. I think that a mechanism exists that transmits information throughout the body at once and activates only those organs that are concerned.

On the other hand, control needs to be exercised to ensure that each organ remains within a certain numeric range and does not behave freely by changing metabolism at its discretion. “Fine tuning” is this kind of control. There is a part somewhere in the body that controls information and sends appropriate orders to specific organs. It is unthinkable that such elaborate orders are given at once on a one-to-many basis, as with hormones. So I think that there is a central part that sends orders precisely to the target organs. Detailed orders can be given only by a control tower that keeps everything in perspective. Such detailed orders fine-tune organs and keep them at proper numeric levels. We have been doing research with this model in mind.

Now, it is becoming clear that the human body exercises these two different kinds of control at the same time. It is impossible to control all metabolic activities with fine tuning alone. But, if the body tries to control metabolism only through gross regulation, values fluctuate substantially and cannot readily be stabilized to appropriate levels. That is why we think that two kinds of control are exercised. Let me use blood sugar levels as an example. When food is digested and blood sugar levels rise, insulin is secreted in response to this sudden change to deliver the order to lower blood sugar levels to all organs at once. While the organs roughly control their metabolism in line with this order, fine tuning is required at the end. So, hormones and the nervous system both engage in the transmission of information by taking advantage of their respective features. What is important is that these two kinds of control are exercised at the same time.

– Values are adjusted to appropriate levels by using both of those control mechanisms.

Katagiri:
It has been discovered that fine tuning plays a bigger role in the system for controlling blood sugar levels and keeping body weight constant than I have thought and than thought in the biologist community of the 20th century.

Take body weight, for example. Let’s suppose that a person eats 10 grams more food each day than the normal daily food consumption for ten years. If you simply assume that those extra grams add up (multiply 10 grams by 365 days and by 10 years), this person’s weight will become terribly heavy. He is supposed to gain more than 36 kilograms in weight. In reality, though, it is hardly possible that a 50-year-old person weighing 60 kilograms will increase his weight to 96 kilograms just because he keeps eating an extra 10 grams of food per day. Weight does not increase so simply. The act of eating an extra 10 grams of food a day is very common among many Japanese. The reason why body weight remains constant despite such varying daily food consumption is considered to be that fine tuning is exercised somewhere in the body to change metabolism. Several extra grams of food is very small, accounting for less than 1 percent of body weight, which is measured in kilograms. So changes resulting from such extra food can be coped with by fine tuning. If a person keeps on overeating in amounts beyond control, fine tuning may be unable to keep up, disrupting the system. But slight changes in daily food consumption do not disrupt the system, and control is exercised to keep body weight constant.

– In your research, you touch on two states of humanity – satiation and starvation. You say: “Until about 100 years ago, it was common in many countries that people were in the state of starvation. In those days, the innate instinct of human beings to consume and store as many calories as possible from eaten food as quickly as possible worked fine. Over the past several decades, however, some parts of the world, mainly developed nations, have entered the age of satiation. The calorie storing mechanism of the age of starvation still functions in the state of satiation and has become a cause of obesity.” Your theory is very convincing. Is it possible to control the instinct acquired in the age of starvation and tailor it to the modern lifestyle?

Katagiri:
Among our researches on the interorgan network, there are three researches that are central to the studies related to obesity and energy metabolism. One concerns nerve signals released from adipose tissue, which can cause and prevent a condition of appetite technically known as leptin resistance. Leptin is a hormone carried in the blood stream that suppresses appetite under normal circumstances. When a person gains in weight, an increased amount of leptin is released into the blood stream to suppress appetite and curb energy intake, thus achieving a balance. But, if a person becomes obese above a certain level, leptin does not work in the body any more. This takes the brakes off appetite, and the person keeps eating, resulting in continued excessive energy intake. This condition is called leptin resistance. It is now known that nerve signals released from nerve tissue are deeply related to these changes that concern whether leptin works or not and that the changes are controlled by those nerve signals. This was discovered in 2006. Humans have a system for keeping body weight constant. Then, why does the body exercise reverse control by making leptin ineffective and promoting obesity? We can explain how this mechanism works, but to figure out why this happens requires a lot of careful thought and conjectures. Today, leptin resistance is seen as a bad thing because it makes people obese. But it is, in my view, a mechanism that humans have acquired for survival in the course of evolution, and I think it is important that we still have that mechanism.

– In the age of satiation, that mechanism has become a cause of disease.

Katagiri:
Yes. In the past, food satiation was temporary in most cases. It was impossible that a large number of people could overeat every day. So, even if leptin resistance kicked in, it rarely made these people sick. Rather, the more common cases were ones in which a person with power in a group got most of food and overate, which often helped prevent the entire group from perishing. By contrast, in modern times when many people eat to their hearts’ content every day, leptin resistance, which disables the appetite-suppressing function, is considered to be a cause of disease.

The gross regulation and fine tuning mechanisms that I mentioned earlier work for leptin resistance as well. When excessive food consumption is detected, the gross regulation mechanism secretes leptin. The fine tuning mechanism allows excessive energy intake in preparation for starvation. While leptin is secreted in some parts of the body, the information about how much lipid is stored in fat deposits is transmitted to the brain via nerves. Based on the received information, the brain fine-tunes the extent to which leptin works. I think that, building on this theory, we can draw up a scheme whereby appetite is controlled by regulating both hormonal stimulation and nerve signals concurrently.

There is another system that attempts to achieve a balance by burning energy in some parts of the body when fat accumulates in the liver and the person is likely to become obese. This is a good example of negative feedback. When a person stores so much energy that fat accumulates in the liver or, in other words, when a person consistently overeats, this system resolves the situation by burning the stored fat. Conversely, when nutrition is stored in the liver as carbohydrate, i.e. in the form of glycogen, the system sends information that tells the body to suppress energy consumption and heat generation in order to keep the nutrition stored. It has become known that the liver generates these two kinds of signal and that they regulate energy consumption and metabolism in the body. These signals are also transmitted via the network of nerves. The information sent by the liver is delivered via the brain to a thermogenesis organ called brown adipose tissue. Regarding energy stored as glycogen or carbohydrate, information is sent that tells the body to exert regulation so as to keep the energy stored, since food has just been taken in. If the accumulation of energy grows over time to such an extent that part of the energy comes to be stored as fat, the signal changes to one that tells the body to exert regulation so as to burn the energy and prevent the person from becoming overweight and this signal is transmitted to the brain via nerves. I think that the liver sends each of these signals as appropriate for the existing circumstances.

– Is there any negative aspect to the burning of a lot of fat?

Katagiri:
There is a nerve signal that works when fat accumulates in the liver. When this signal is transmitted, the burning of fat is activated. The fat burning mechanism works by sending the signal from the brain to the related organs and fat cells in particular. In this state, sympathetic nerves become active. We conducted experiments about the activation of sympathetic nerves, and I have realized that autonomic nerves have a much higher level of organ selectivity than I thought.

For example, there is a phenomenon we have discovered in which the neural information from the liver is delivered to the brain and the resulting signal is transmitted directly to the β cells of the pancreas, causing the β cells to start to multiply immediately. Although this mainly concerns parasympathetic nerves, it seems from our research that no change other than the multiplication of the β cells occurs in the process. In response to the information transmitted via nerves, only the β cells start to multiply in the pancreas. Neither the endocrine gland in the pancreas nor the other cells in the Langerhans islet change. No change is seen in any other organ, either, such as a change in enterokinesis due to parasympathetic hyperactivity. These results suggest that autonomic nerves have a high level of organ selectivity. The order to suppress energy consumption in brown fat in case of the accumulation of glycogen in the liver has almost no influence on organs other than brown fat. Since it does not influence other organs, its organ selectivity can be said to be extremely high.

On the other hand, it has been discovered that sympathetic nerves are activated in many parts of the body in response to those signals that are generated to burn energy, increase basal metabolism and break down fat when a lot of fat has accumulated in the liver. The most dangerous effect of the activation of sympathetic nerves is a rise in blood pressure. Blood pressure actually rises, and we have published experimental data showing that the blood pressure of an obese model mouse does not rise if by preventing fat from accumulating in the liver or nerve signals from being sent from the liver. This means that the reason why blood pressure rises in metabolic syndrome is that the mechanism that I have just described functions in the body.

As I have explained so far, it is considered that various signals are sent to the brain via nerves according to the different states of metabolism in the liver and other peripheral tissues and that the brain controls those signals and orders the organs in the entire body to maintain metabolic homeostasis dynamically on an individual basis. These orders seem to have a higher level of organ selectivity than previously thought. Given these findings, I have come to think that sending powerful information to the brain is more effective than targeting a single effector organ in coordinating the metabolic activities of the organs in the entire body and regulating metabolism at the individual level appropriately. I consider that this approach is better because it takes fine tuning into consideration as well. I am now exploring ways to develop treatments for diabetes and obesity from a new perspective.

– It’s been very interesting talking with you today. Thank you very much.