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▎Editor of WuXi AppTec's content team The latest issue of the top academic journal "Science" published a research paper related to weight-loss drugs.
Scientists from the Weizmann Institute of Science in Israel, Queen Mary University of London, and Hebrew University of Jerusalem have collaborated to clarify a highly anticipated How innovative weight-loss drugs regulate the "hunger" switch in the brain, so as to control appetite and treat obesity.
This discovery also provides important clues for the continued development of new weight-loss drugs.
Speaking of the findings of this study, it is due to a special family: at least 8 members of this family are severely obese-the body mass index (BMI) exceeds 70, which is three times that of the average person! The family’s medical history caught the attention of Hadar Israeli, a young PhD student at the Hebrew University, who was also the first author of this study.
These obese patients are in a state where they feel hungry no matter how much they eat, and they need to eat constantly, so they are becoming more and more obese.
Israeli found that this situation is inseparable from a genetic mutation shared by the family-this mutation occurred in the melanocortin-4 (MC4) receptor gene.
Why does a single mutation in the MC4 receptor have such serious consequences? With this question in mind, the research team began to explore the structure of the MC4 receptor.
▲Always not getting enough to eat is related to the master switch in the brain that controls hunger (picture source: 123RF) Past studies have shown that the MC4 receptor is a key molecule in the hypothalamus that controls appetite, calorie intake and energy expenditure.
It is like a master switch for hunger, the default state is on, and the commands issued make us feel full.
As the body's energy decreases, certain hunger hormones will turn off MC4 receptors and make us feel "hungry"; after a full meal, another hormone can activate MC4 receptors again and let us return to a full state.
But how exactly this hunger switch works is not clear to people.
Because the MC4 receptor pathway is critical to the regulation of appetite, researchers have long regarded it as an important drug target to develop weight-loss drugs.
At the end of 2020, the US FDA approved an innovative weight-loss drug Imcivree (setmelanotide) for the treatment of obese patients with POMC, PCSK1 or LEPR gene defects.
Variations in these genes will interfere with the MC4 receptor pathway, causing patients to overeating.
As an agonist targeting MC4 receptors, setmelanotide can effectively control the weight of such patients.
▲The first new drug approved by the FDA to treat obesity caused by specific gene defects (picture source: reference [3]) In order to understand how MC4 receptors are activated, scientists isolated a large number of MC4 receptors from cell membranes and combined them with Setmelanotide was combined, and then cryo-electron microscopy (cryo-EM) technology was used to determine the structure of the composite.
Through the three-dimensional structure, the researchers found that setmelanotide enters the binding pocket of the MC4 receptor and activates the receptor.
This method hits the bullseye and directly activates the molecular switch for satiety, which is even more effective than natural hormones.
In addition, calcium ions enter the binding pocket, which can help enhance the binding of the drug to the MC4 receptor, and at the same time interfere with the effect of hunger hormone on the MC4 receptor.
"This is an unexpected discovery.
" Dr.
Moran Shalev-Benami, one of the research leaders, said, "It seems that the satiety signal can compete with the hunger signal.
Thanks to the help of calcium, the feeling of fullness can be restored after eating.
."Image source: 123RF's structural analysis of the MC4 receptor also explains the researchers' initial question, that is, how the gene mutation of the MC4 receptor can interfere with signal transduction, and ultimately lead to endless hunger pangs and constant eating.
In addition, Researchers discovered the key difference between the MC4 receptor and other similar receptors in the same family from the structure of the MC4 receptor.
Based on this result, drugs that only bind to the MC4 receptor can be designed in the future to avoid potential side effects.
"For understanding MC4 How the receptor is activated, these results fill the gap.
"The researchers concluded, "Our research will help design drugs that precisely target MC4 receptors, and help patients manage their weight better and safer in the future.
"
"References[1] Hadar Israeli et al.
, (2021) Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling.
Science Doi: 10.
1126/science.
abf7958[2] The hunger games: Uncovering the secret of the hunger switch in the brain.
Retrieved Apr.
17, 2021 from https://medicalxpress.
com/news/2021-04-hunger-games-uncovering-secret-brain.
html[3] Rhythm Pharmaceuticals Announces FDA Approval of IMCIVREE™ (setmelanotide ) as First-ever Therapy for Chronic Weight Management in Patients with Obesity Due to POMC, PCSK1 or LEPR Deficiency.
Retrieved November 29, 2020, from 2135269/0/en/Rhythm-Pharmaceuticals-Announces-FDA-Approval-of-IMCIVREE-setmelanotide-as-First-ever-Therapy-for-Chronic-Weight-Management-in-Patients-with-Obesity-Due-to- POMC-PCSK1-or-LEPR-Defic.
html
Scientists from the Weizmann Institute of Science in Israel, Queen Mary University of London, and Hebrew University of Jerusalem have collaborated to clarify a highly anticipated How innovative weight-loss drugs regulate the "hunger" switch in the brain, so as to control appetite and treat obesity.
This discovery also provides important clues for the continued development of new weight-loss drugs.
Speaking of the findings of this study, it is due to a special family: at least 8 members of this family are severely obese-the body mass index (BMI) exceeds 70, which is three times that of the average person! The family’s medical history caught the attention of Hadar Israeli, a young PhD student at the Hebrew University, who was also the first author of this study.
These obese patients are in a state where they feel hungry no matter how much they eat, and they need to eat constantly, so they are becoming more and more obese.
Israeli found that this situation is inseparable from a genetic mutation shared by the family-this mutation occurred in the melanocortin-4 (MC4) receptor gene.
Why does a single mutation in the MC4 receptor have such serious consequences? With this question in mind, the research team began to explore the structure of the MC4 receptor.
▲Always not getting enough to eat is related to the master switch in the brain that controls hunger (picture source: 123RF) Past studies have shown that the MC4 receptor is a key molecule in the hypothalamus that controls appetite, calorie intake and energy expenditure.
It is like a master switch for hunger, the default state is on, and the commands issued make us feel full.
As the body's energy decreases, certain hunger hormones will turn off MC4 receptors and make us feel "hungry"; after a full meal, another hormone can activate MC4 receptors again and let us return to a full state.
But how exactly this hunger switch works is not clear to people.
Because the MC4 receptor pathway is critical to the regulation of appetite, researchers have long regarded it as an important drug target to develop weight-loss drugs.
At the end of 2020, the US FDA approved an innovative weight-loss drug Imcivree (setmelanotide) for the treatment of obese patients with POMC, PCSK1 or LEPR gene defects.
Variations in these genes will interfere with the MC4 receptor pathway, causing patients to overeating.
As an agonist targeting MC4 receptors, setmelanotide can effectively control the weight of such patients.
▲The first new drug approved by the FDA to treat obesity caused by specific gene defects (picture source: reference [3]) In order to understand how MC4 receptors are activated, scientists isolated a large number of MC4 receptors from cell membranes and combined them with Setmelanotide was combined, and then cryo-electron microscopy (cryo-EM) technology was used to determine the structure of the composite.
Through the three-dimensional structure, the researchers found that setmelanotide enters the binding pocket of the MC4 receptor and activates the receptor.
This method hits the bullseye and directly activates the molecular switch for satiety, which is even more effective than natural hormones.
In addition, calcium ions enter the binding pocket, which can help enhance the binding of the drug to the MC4 receptor, and at the same time interfere with the effect of hunger hormone on the MC4 receptor.
"This is an unexpected discovery.
" Dr.
Moran Shalev-Benami, one of the research leaders, said, "It seems that the satiety signal can compete with the hunger signal.
Thanks to the help of calcium, the feeling of fullness can be restored after eating.
."Image source: 123RF's structural analysis of the MC4 receptor also explains the researchers' initial question, that is, how the gene mutation of the MC4 receptor can interfere with signal transduction, and ultimately lead to endless hunger pangs and constant eating.
In addition, Researchers discovered the key difference between the MC4 receptor and other similar receptors in the same family from the structure of the MC4 receptor.
Based on this result, drugs that only bind to the MC4 receptor can be designed in the future to avoid potential side effects.
"For understanding MC4 How the receptor is activated, these results fill the gap.
"The researchers concluded, "Our research will help design drugs that precisely target MC4 receptors, and help patients manage their weight better and safer in the future.
"
"References[1] Hadar Israeli et al.
, (2021) Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling.
Science Doi: 10.
1126/science.
abf7958[2] The hunger games: Uncovering the secret of the hunger switch in the brain.
Retrieved Apr.
17, 2021 from https://medicalxpress.
com/news/2021-04-hunger-games-uncovering-secret-brain.
html[3] Rhythm Pharmaceuticals Announces FDA Approval of IMCIVREE™ (setmelanotide ) as First-ever Therapy for Chronic Weight Management in Patients with Obesity Due to POMC, PCSK1 or LEPR Deficiency.
Retrieved November 29, 2020, from 2135269/0/en/Rhythm-Pharmaceuticals-Announces-FDA-Approval-of-IMCIVREE-setmelanotide-as-First-ever-Therapy-for-Chronic-Weight-Management-in-Patients-with-Obesity-Due-to- POMC-PCSK1-or-LEPR-Defic.
html
