CM – Israeli scientists say they paved the way to turn off the brain’s « hunger switch ».

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New Israeli research could pave the way for drugs that turn off the hunger switch in the human brain with minimal side effects, scientists say.

A receptor in the brain, melanocortin 4 (MC4), is known to control the urge to eat. It was known as the « hunger switch ».

It is believed that a genetically inherited malfunction with this receptor is the leading cause of obesity triggered by a single gene mutation, affecting an estimated 5 percent of early-onset obesity in children.

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Now researchers at the Weizmann Institute of Science have done research that they say could easily manipulate the receptor in people with such a mutation.

They say it could even be used to help people who don’t have a genetic condition that directly affects the MC4 to lose weight by treating the receptor as an « override » switch. When « turned off, » they say, it could suppress regular hunger.

Her research included creating a detailed 3D model of the receptor, which gave unprecedented insight into how it worked in a peer-reviewed study published Thursday in the journal Science.

« It’s a switch that is activated by a hormone that our body secretes that can be turned on and off, » said Dr. Moran Shalev-Benami from the Weizmann Institute. « We showed exactly what it looks like and described all the molecular details. »

Pharmaceutical companies have tried to make drugs that manipulate MC4. However, with limited knowledge of how the receptor works, drugs appear to bind to multiple receptors and affect other aspects of the brain and body, causing side effects.

The first drug of its kind, setmelanotide – sold under the brand name Imcivree – was approved for chronic weight management by the US Food and Drug Administration in November. Side effects reported included spontaneous penile erections in men and adverse sexual reactions in women, as well as depression and thoughts of suicide. There have also been cases of nausea, diarrhea, and abdominal pain.

« Now that we know the exact molecular details of the switch, we can use it very precisely to target and develop drugs that can help avoid some of the side effects that were seen with this first drug, » said Shalev-Benami .

Her laboratory at Weizmann’s Department of Chemical and Structural Biology carried out the study with scientists from the Hebrew University of Jerusalem and Queen Mary University of London, during which the effects of setmelanotide were observed in detail.

The study began after Hadar Israeli, a Hebrew University medical student doing a PhD on the mechanisms of obesity, heard about a family where at least eight members, all of whom felt constantly hungry, were severely obese. Most of them had a body mass index over 70, which is about three times the norm.

Israeli was impressed by the fact that the family’s plight was due to a single mutation in the family – one that which concerned the MC4 receptor – and asked if new advances in imaging biological samples could provide insight into how the receptor works.

Her supervisors contacted Shalev-Benami, who decided to start a study on the structure of MC4 , and invited Israel to join her laboratory as a visiting scientist. They isolated large amounts of pure MC4 receptors from cell membranes and determined their 3D structure using cryogenic electron microscopy, an imaging technique performed at very low temperatures.

Shalev-Benami said the first priority is to get people with genetic disorders that affect MC4 directly, but that advances could help others who are trying to diet. She commented, « If we can eliminate side effects and manipulate this receptor without disrupting other receptors and causing side effects, it could help the general population of people struggling with weight loss. » I am telling you the truth : Life here in Israel is not always easy. But it’s full of beauty and meaning.

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