Hormones that suppress appetite have lost their effectiveness

Putting on weight means that fat increases in the body. Why does fat increase? The reason is that people get energy by eating, but when they get more energy from food than the energy they need to live, the excess energy is stored as fat cells.

The so-called middle-aged spread was thought to be caused by a decrease in energy consumption due to a decrease in basal metabolism with age, accompanied by an increase in excess energy consumed.

However, recent studies have revealed that age-related decreases in basal metabolism do not account for so much.

So why is middle-aged spread actually occurring?

In fact, the human brain has a function to control dietary intake. For example, fat cells secrete a hormone called leptin, but when the hypothalamus, which is the appetite center of the brain, receives this leptin, it gives an order to suppress appetite.

Actually, the family line of some very overweight people has marked body weight gain because leptin does not work due to mutations in the leptin gene and the leptin receptor gene. However, it is known that administration of leptin to these people reduces appetite and body weight. That indicates that leptin is involved in maintaining normal body weight.

In other words, accumulation of fat enhances the secretion of leptin from fat cells, which reduces people’s appetite, so that body weight can be kept constant by suppressing the progression of obesity.

But in fact, although leptin is secreted, cases in which the appetite is not suppressed have occurred. It is thought that this leads to middle-aged spread.

For example, as mentioned earlier, when leptin is administered to people in families with impaired leptin action, good results may be achieved, but unfortunately it is not effective in general patients who are obese.

Actually, general patients with obesity show high blood leptin concentrations, reflecting increased fat cells, but in conditions of excess energy such as obesity, sensitivity of leptin in the hypothalamus is impaired, thereby reducing the anti-obesity actions of leptin. This is a phenomenon called leptin resistance.

The present age is said to be the age of gluttony, but in the long history of mankind, this situation has only existed in the past 100 or so years. It means modern people are taking in more energy, which exceeds their expectations, than ever before.

Excessive energy intake may hinder leptin actions to control appetite.

Negative effects derived from excess intake

Sugar intake increases blood sugar levels, which leads to insulin being secreted to promote uptake of blood sugar by muscles, the liver, the brain, etc. As a result, the blood sugar level decreases. Many people know that if insulin actions are impaired, blood sugar levels do not decrease, leading to diabetes.

It is known that prescription of a hormone called GLP1 to such patients with diabetes make the actions of insulin dramatically improve. It was found that GLP1 not only lowers blood sugar level but also suppresses appetite by reaching the brain, therefore it is also attracting great attention as a weight-loss drug.

GLP1 is a type of hormone called incretin, and the same group has a hormone called GIP. This GIP is also known to increase the actions of insulin similarly as GLP1. On the other hand, it is also known to increase body weight because it promotes the absorption of triglycerides into fat cells, in contrast to GLP1.

Our research team has revealed some parts of its mechanisms.

This is because GIP reaches the brain and induces the activation and inflammatory reaction of a molecule called Rap1 in the hypothalamus.

When Rap1 is activated and an inflammatory reaction occurs, it causes the impairment of sensitivity of leptin receptors. As a result, appetite is not suppressed and fat cells accumulate, leading to weight gain.

In fact, incretins are secreted from the small intestine, but they are secreted by absorption of sugar, fat, and proteins. In particular, GIP is excessively secreted by stimulation of fat.

In other words, it is possible that what makes people begin to take in fat excessively also makes GIP be secreted excessively and may have an effect on Rap1 in the hypothalamus, such as negative feedback.

In essence, the human body has a system to efficiently accumulate energy from less food as well as a mechanism to suppress overeating. But over the last 100 years, the intake of food has become very excessive; therefore it can said that the mechanism no longer works and, on the contrary, works negatively.

So if we said that people should return to the simple diet of more than 100 years ago, it would be correct theoretically but actually difficult. Discarding the palatability that the brain has remembered may be impossible unless something unexpected happens.

On the other hand, it is also true that there are many diseases caused by obesity. If so, is it possible to suppress leptin resistance and exert its original actions by eating? Thus our research team thought we could develop new functional foods.

Spinach proteins may be the savior

GIP is one of the incretin hormones secreted from the small intestine, but actually it was a completely new discovery that it reaches the brain and acts on the leptin system.

In the past, there had been no concept that hormones secreted from digestive organs act on the leptin system in the brain. However, this turned out to be a hint.

It means that there may be other substances derived from food that are absorbed in the small intestine, reach the brain and affect some of our actions.

As a result of our repeated experiments with various substances, we hit Rubisco, a protein found in spinach.

YHIEPV (green leaf peptide) is a functional peptide (two or more amino acids bounded together constitute a protein) resulting from digestion of spinach Rubisco with digestive enzyme. We have discovered that the green leaf peptide increased the sensitivity of leptin receptors in the hypothalamus.

In addition, we have also revealed that this green leaf peptide can improve leptin resistance caused by palmitic acid (one of the main fatty acids in animal fat such as beef tallow and lard), which represents a state of excessive nutrition.

In other words, we have found that green leaf peptide can regulate intracellular leptin sensitivity in the hypothalamus.

Thus far, experiments were conducted in which green leaf peptide was directly administrated to the brain. As the next step, when green leaf peptide was orally administered to obese mice, we found it actually improved leptin sensitivity in the hypothalamus, inhibited body weight gain by intake of high-fat diet, and exerted anti-obesity action.

So, we have been able to demonstrate that a peptide taken in from the mouth reaches the brain and suppresses the activation of Rap1 in the hypothalamus induced by obesity, thereby improving leptin sensitivity.

Having said that, this does not immediately help people to prevent obesity. It is still at the level of animal experiments, and further research is needed from now on.

For your information, by calculation, getting this effect on people would require eating at least 100 g of spinach each day. That is a bit difficult.

Rubisco, however, is an enzyme involved in the carbon dioxide fixation of photosynthesis in plants. It is a protein that all plants which can photosynthesize have, although there are slight differences in the primary structure of amino acids. So that means it is the most abundant protein on earth.

If this is leveraged well, it may lead to development of low-cost functional foods such as supplements that allow low environmental burdens and sustainable bulk production.

It may also present a new healthy longevity strategy by food and contribute to the achievement of SDGs.

However, I have not pursued such research having the aim of developing functional foods from the start. Scientific curiosity moved me.

I’ll be happy if you get interested or curious by hearing or reading about such research.

In particular, food provides us with nutrients and energy, and also meets our preferences. But it’s not just that, it figures in and improves everything including our activities, vigor and thought. Therefore, the kanji character for the word “food” consists of two kanji characters which mean “improvement” of “people.” In addition, we have experienced the coronavirus pandemic, and food has again been recognized as an important communication tool.

If you look at food again with such curiosity, you can feel that it holds various potentialities.

Currently, the Laboratory for Nutritional Biochemistry (Kaneko Laboratory) conducts research focusing on breast milk.

Did you know that breast milk contains a lot of fat? As mentioned earlier, a high-fat diet induces obesity in adults. However, babies who are given breast milk that is similarly high fat do not become obese. Or rather, breast milk promotes their growth and development, allowing utterances and independent ambulation during a year of breastfeeding. Why?

We discovered the interesting structure of breast milk and a new nutrition signal, which are keys to unraveling the discrepancy. We are earnestly working on research activities to introduce to you in the near future.

We would like to propose a new anti-obesity and healthy longevity strategy around the world applicable to the elderly and working generations using food, starting from the research on breast milk conducted by Kaneko Laboratory. By promoting understanding of the recognition of food structure in the living body, we hope to actively utilize food resources in new ways.

* The information contained herein is current as of November 2022.
* The contents of articles on Meiji.net are based on the personal ideas and opinions of the author and do not indicate the official opinion of Meiji University.
* I work to achieve SDGs related to the educational and research themes that I am currently engaged in.

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