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drawing human brain

The discovery is expected to pave the way for revolutionary treatments for obesity.

By Yakir Benzion, United With Israel

An international team of researchers headed by Israeli scientists announced a breakthrough discovery this week. They say they have figured out how “the master switch for hunger in the brain” works and as a result may be able to produce medicines to turn it off, giving a long sought-after medical solution to obesity.

The researchers at the Weizmann Institute of Science in Rechovot and Hebrew University of Jerusalem were joined for the project by scientists at Queen Mary University of London. In scientific terms, the team discovered how to handle mutations affecting the melanocortin receptor 4, or MC4 receptor for short, the brain’s internal switch that controls whether or not you feel hungry.

When the MC4 is activated, the equivalent of being turned “on,” it sends out commands that cause us to feel full, which means that from the brain’s perspective, our default state is we are not hungry.

However, when the body’s energy levels drop, the brain produces a “time to eat” hormone that inactivates, or turns off, the MC4 receptor. That causes the brain to turn off the “feel full” mode and let you know you are now hungry.

After you eat, the brain then releases an “I’m full” hormone that binds to the MC4, replacing the hunger hormone and turning the receptor back on – returning the “feel full” mode back on so you stop eating.

One key problem is that there are people who have mutations that inactivate the MC4, which causes them to feel hungry constantly.

MC4 is known to control hunger and is a prime target for anti-obesity drugs, such as setmelanotide, because scientists have known that it can control hunger while bypassing all other energy-related signals in the body.

But until now it simply wasn’t known exactly how this hunger switch works.

The study began when PhD student Hadar Israeli came across an entire family in which eight members were plagued by persistent hunger and were all severely obese. Israeli knew that the family’s plight was due to a single mutation that ran in the family, affecting the MC4 receptor in their brains.

Israeli turned to a colleague, Dr. Moran Shalev-Benami of Weizmann’s Chemical and Structural Biology Department, and together with the scientists at Hebrew University and in London the team took samples from the family and discovered how the mutation behaves. They were surprised to find that calcium plays a role in the process.

“This was a truly unexpected finding,” Shalev-Benami said. “Apparently, the satiety signal can successfully compete with the hunger signal because it benefits from the assistance of calcium, which helps the brain restore the ‘I’m full’ sensation after we eat.”

Moreover, the scientists have identified the ways for pharmaceutical companies to design drugs that will bind only to MC4, avoiding side effects that may be caused by interactions with other receptors.

The bottom line is that a key cause of obesity has been identified, and with that knowledge, there is new hope for solving a major health conundrum.

“Our findings can help develop improved and safer anti-obesity drugs that will target MC4R with greater precision,” Shalev-Benami said.



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