"Why do you want to eat?" "Because I'm hungry." Three-year-olds can answer. So why do we feel hungry or full? Why do you feel hungry when your stomach is empty and full? Obviously, it is because we have a mechanism to regulate hunger and satiety in our bodies, and the center to control feelings must be located in the central nervous system. Biologists have long known that there is a small area under the ventral surface of the brain and thalamus-hypothalamus controls many physiological functions, including body temperature, sleep, endocrine, emotional response, reproduction, metabolism and so on. , including controlling food intake. Brain cells with similar functions gather together and are called nerve nuclei. There are many kinds of nuclei in hypothalamus, which are related to controlling food intake?
We can do two opposite experiments with animals: stimulate a nucleus or destroy a nucleus and see how the animals react. For example, in the hypothalamus, there is a group of nuclei called ventromedial nucleus (named after its orientation). If we stimulate the ventromedial nucleus of mice with weak current, mice will stop eating, even if their stomachs are empty, they will not feel hungry. However, if the current is increased and the ventromedial nucleus of the mouse is destroyed by electric shock, the mouse will always be hungry and keep eating, eating itself into a big fat man, even so fat that it can't turn around. This proves that the ventromedial hypothalamic nucleus controls the feeding of animals and is the satiety center, telling animals that they are full.
In the hypothalamus, there is also a nucleus called vestibular hypothalamus, which plays an opposite role in food intake. It is the feeding center: if stimulated, mice will start eating; If it is destroyed, the mice will start a hunger strike until they starve to death. Some people may think, what if we destroy both the ventromedial nucleus and the vestibular hypothalamic nucleus? The experimental results showed that the mice that had undergone this operation also died of hunger strike. Therefore, the ventromedial nucleus plays a role in inhibiting vestibulo-hypothalamic nucleus. If the vestibulo-hypothalamic nucleus no longer exists, it makes no difference whether there is an ventromedial nucleus or not.
The vestibulo-hypothalamic nucleus stimulates animal feeding, while the ventromedial nucleus inhibits vestibulo-hypothalamic nucleus, which is the basic mechanism of central nervous system regulating animal feeding. But the actual situation is much more complicated than this. There are other nerve nuclei involved in this process. Moreover, these nuclei are not specifically used to control food intake, but also control other physiological processes. For example, destroying the ventromedial nucleus of mice not only stimulates their eating, but also affects their sexual behavior and other behaviors (such as becoming particularly fierce). The nerve nuclei in the brain are connected by countless nerve fibers, forming an extremely complex communication network, and the signals affecting one nerve nucleus will also be transmitted to other nerve nuclei. It is difficult to clearly distinguish the specific function of each nucleus. Think about it. There are hundreds of billions of neurons in the human brain, and each neuron is connected with thousands of other neurons. What a complicated system this is. It is an impossible task to figure out the details directly.
But we can learn some details of neurophysiological activities through other methods, such as genetics and biochemistry. Genetics allows us to discover and study the consequences of gene mutation, while biochemistry allows us to study physiological mechanisms at the molecular level. 1950, it was found that one strain of mice was overeating and became very obese, and its weight was more than twice that of ordinary mice. Some people think that this is caused by a gene mutation, but at that time it was not clear where the gene was and what its specific function was. It is simply named "ob Gene" (ob is the abbreviation of English obile-obesity), and this mouse strain is called ob mouse. Later, it was found that other gene mutations could also make mice overeat, and they were named by different names, the most important of which was the db gene strain discovered by 1966 (db is the abbreviation of English diabetes).
So what makes these mutant mice overeat? It is easy to think of an experimental idea to see which chemical molecules in the hypothalamus of these mice are excessive. It is found that the hypothalamus of obese mice contains excessive neuropeptide Y, which has many physiological functions, but what we are concerned about here is whether it will affect eating. Indeed, if neuropeptide Y is injected into the brains of normal mice, they will overeat and become obese. It seems that the reason why mice are obese is because of too much neuropeptide Y. Have we solved the mystery of obesity? It's not that simple.
In the late 1960s and early 1970s, douglas coleman, an American biologist, made a conjoined experiment with two strains of obese mice, ob and db: two conjoined mice were made by connecting the blood vessels of two different mice, so that the substances in one mouse's blood could enter the other mouse and have an impact. The result of his experiment is this:
When two normal mice are conjoined, one of them will overeat, resulting in poor appetite and weight loss of the other.
Combine ob obese mice with normal mice: ob obese mice lose weight.
Combine db obese mice with normal mice: Normal mice stop eating and lose weight.
Combine ob obese mice with db obese mice: ob obese mice stop eating and lose weight, while db obese mice are not affected.
What do these experiments tell us? It can be inferred from the first experiment that once normal mice are full, satiety factors that inhibit appetite will appear in their blood. It can be inferred from the second experiment that ob obese mice lack this satiety factor, so their food intake is uncontrolled. Once the satiety factor is obtained from the blood of normal mice, their food intake becomes normal and their weight is reduced. From the third experiment, we can know that db obese mice will secrete too many satiety factors, thus inhibiting the food intake of normal mice. The fourth experiment also showed that db obese mice secreted too much satiety factor, which inhibited the feeding of ob obese mice.
Based on these experiments, we can know that the reason of overeating in ob obese mice is the lack of a satiety factor in the body, that is to say, the gene that produces satiety factor (that is, ob gene) has mutated and failed. However, there are other reasons for the excessive appetite of db fat rats. It does not lack satiety factor (that is, its satiety factor gene is normal), but satiety factor has no effect on it. We can speculate that this is because a receptor that should bind to satiety factor is defective and cannot bind to satiety factor, which makes satiety factor fail and accumulate in the body. In other words, the satiety factor receptor gene (that is, db gene) of db obese mice has been mutated.
So what is this satiety factor? If we can isolate and clone the ob gene, we can know. 1986, another American biologist Jeffrey m Friedman began to clone this gene. It took his lab eight years to clone this gene until 1994. This gene encodes a hormone, which Friedman named leptin (from Greek leptos, meaning "thin"). Leptin is a satiety factor which is deficient in ob obese mice and overproduced in db obese mice. If leptin is injected into ob obese mice every day, the times of eating and energy consumption of ob obese mice will decrease sharply after a few days, and their weight will decrease by 30% after two weeks. On the contrary, leptin has no effect on db obese mice. In 1996, the db gene was also cloned. As predicted, it does encode leptin receptor.
The human body also has leptin, which is produced and secreted by fat cells. If we eat too much food, it will be converted into fat and stored in fat cells, making fat cells bigger. Obesity is mainly the enlargement of fat cells after storing fat, not the increase of fat cells. In fact, the number of fat cells remained basically the same in our childhood. As the fat cells become larger, they begin to secrete more leptin, which reaches the hypothalamus along the blood circulation, inhibiting the synthesis of neuropeptide Y, thus inhibiting appetite. On the contrary, if people start dieting, fat cells will atrophy, leptin secretion will decrease and neuropeptide in hypothalamus will increase, which will also stimulate appetite. Leptin has other physiological functions, such as affecting sexual maturity.
Studying the mechanism of why we eat is not only of great scientific significance, but also of great practical value. In developed countries, obesity is a major social problem. For example, in the United States, about one-third of the population is obese to varying degrees, while the global obese population is estimated to be as high as 300 million. Obesity not only affects physical appearance, but also harms health, and easily leads to cardiovascular diseases, diabetes and other diseases. Therefore, the discovery of leptin has attracted the attention of the whole society. People immediately thought, can you use it as a diet pill? Leptin was discovered by 1995. Soon after, a biotechnology company in California bought the patent of leptin gene for $20 million, and began to conduct human clinical trials the next year. The results of the first clinical trial showed that injection of leptin seemed to make some people lose weight, so they entered the second clinical trial on a larger scale, but the results were not satisfactory, and its weight loss effect was not better than that of placebo. In 2002, the clinical trial was terminated. People's dream of finding a panacea for losing weight is shattered again.
Why is this? One reason is that only a few obese people are caused by leptin deficiency (only a few cases have been found in the world at present). For these people, injection of leptin has a very significant effect. However, the vast majority of obese people are not short of leptin. On the contrary, they have excessive leptin in their bodies. The reason for their overeating is not lack of leptin, but insensitivity to leptin. This may be caused by many factors, such as leptin can not enter the hypothalamus, or leptin receptor is defective like db obese mice.
We now know that besides leptin and neuropeptide Y, there are many other molecules (such as corticotropin-releasing hormone and cholecystokinin) involved in controlling food intake. The molecular mechanism of controlling food intake is actually much more complicated than what we described above, and we are just beginning to understand it. However, most researchers now agree that a person's "normal" weight is basically determined by heredity. The interaction between leptin, neuropeptide Y and other molecules establishes a set point for a person's weight and appetite, which roughly determines whether a person is fat or thin, poor appetite or strong appetite. Obesity is because this adjustment point is relatively high. In the history of human evolution, in the harsh environment of food shortage, there is actually a higher adjustment point, which has the survival advantage and can eat and store fat as much as possible to prevent famine. Only in a rich society, advantages become a burden. Obesity is a legacy of evolution.