Not only the new coronary pneumonia, obesity has also become a global epidemic, and it has been prevalent for many years.
According to the latest data on obesity epidemiology, more than 2 billion people worldwide are suffering from obesity. It is known that overweight and obesity are important risk factors for cardiovascular disease, type 2 diabetes, hypertension, cancer, chronic kidney disease and a series of musculoskeletal diseases. Even so, it still cannot stop the growing trend of the global obese population.
It is generally believed that obesity is caused by the continuous defeat of willpower by appetite. But there are some people, no matter how much they eat, they still feel hungry, resulting in struggling to be hungry and not hungry every day, and eventually develop obesity. Because these people’s brains have genetic defects in the”master switch” that controls appetite.
Beijing time on April 16, published in a new study on”Science”, an international research team led by the Weizmann Institute of Science in Israel revealed the activation mechanism of this”master switch” and clarified How setmelanotide, a drug recently approved to treat obesity caused by genetic defects, activates this”master switch.” This discovery provides important new clues to control hunger and will help develop more effective anti-obesity drugs.
This master switch is Melanocortin Receptor 4 (MC4R). MC4R is a mysterious and interesting protein molecule. It is mainly expressed in a group of neurons in the hypothalamus. It calculates the body’s energy balance by processing various energy-related metabolic signals. Specifically, MC4R is involved in the control of food intake, energy expenditure and weight control.
When MC4R is activated, or”turned on”, it will issue commands to make us feel full. From the perspective of the brain, this should be our default state; when our energy level drops, The hypothalamic neurons will produce a kind of”it’s time to eat” hormone to inactivate or shut down MC4R, thus sending out a”hungry” signal. After we have a full meal, it releases the second”I’m full” hormone and binds to the same active site on MC4R to replace the hunger hormone and restore the receptor, that is, let us return to being full The default state of the sense. Mutations that inactivate MC4R can make people feel hungry continuously.
There are also previous experimental and clinical evidences that MC4R is the master switch and an important target for obesity drugs (such as setmelanotide). Turning it on can control hunger while bypassing all other energy-related signals. But until now, it is still elusive how this hunger transition works.
This new research starts with the plight of a”hungry” family. At least 8 members of this family suffer from constant hunger, and they are all severely obese. Most of them have a body mass index (BMI) of more than 70, which is about three times the normal level.
Their medical history attracted the attention of Hadar Israel (the first author of the study). Israel is a medical student at the Hebrew University. Under the guidance of Dr. Danny Ben-Zvi, he is pursuing a PhD in the mechanism of obesity. To Israel’s shock, the plight of this family was caused by a single mutation in the family, that is, a mutation affecting MC4R. She turned to Dr. Moran Shalev-Benami of the Department of Chemistry and Structural Biology at the Weizmann Institute to ask whether the new advances in electron microscopy could help explain why this particular mutation had such a devastating effect.
Later, Shalev-Benami initiated a study on the structure of MC4R and invited Israel to join his laboratory as a visiting scientist. Together with the researchers in the laboratory, Israel isolated a large number of MC4 receptors from the cell membrane, allowed them to bind to setmelanotide, and used cryo-electron microscopy to determine its three-dimensional structure (see the figure below).
The three-dimensional structure shows that setmelanotide activates it by entering the binding pocket of the MC4 receptor (see Figure B below), that is to say, by directly hitting the molecular switch that sends out a satiety signal, it is even better than natural satiety Sensing hormones are more effective. The study also found that this drug has a surprising auxiliary:a calcium ion binds in the MC4R orthomorphic binding pocket, thereby enhancing the binding of the drug to the receptor. In biochemical and computational experiments, researchers found that, similar to drugs, calcium also contributes to the natural satiety hormone. Calcium helps satiety hormone to activate MC4 receptors, while interfering with hunger hormone and reducing its activity.
Shalev-Benami said:“This is really an unexpected discovery. Obviously, the satiety signal can successfully compete with the hunger signal because it benefits from calcium’s “hands-on” to help the brain after eating Restore the feeling of’I’m full’.”
The structure of MC4R also shows that the entry of drugs can cause changes in the structure of the receptor; these changes seem to initiate signals in neurons, leading to a feeling of fullness.
This study explains how genetic mutations in the MC4 receptor interfere with this signaling, leading to endless hunger pangs and, ultimately, severe obesity.
In addition, the researchers also found hot spots, which are the key difference between MC4R and similar receptors in the same family. This will make it possible to design drugs that only bind to MC4 to avoid potential side effects caused by interactions with other receptors.
Shalev-Benami said:”Our research results can help develop better and safer anti-obesity drugs that can precisely target the MC4 receptor.”