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.
It is known that a receptor in the brain, melanocortin 4 (MC4), controls the urge to eat. This is called the ‘hunger switch’.
A genetic hereditary dysfunction with this receptor is believed to be the most common cause of obesity caused by a single gene mutation, which is estimated to account for 5 percent of obesity in children who start early.
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Now, researchers from the Weizmann Institute of Science have conducted research that they believe could effect easy manipulation of the receptor among people with such a mutation.
According to them, it can even be used to help people who do not have a genetic condition, which directly affects the MC4 in their efforts to lose weight, by considering the receptor as an “override” switch. If they are ‘turned off’, they can suppress frequent hunger.
Their research involves building a detailed 3D model of the receptor, which gives unprecedented insight into how it works, in a peer-reviewed study published Thursday in the journal Science.
“It is a switch that is activated by a hormone that our body secretes, which can switch on and off,” said dr. Moran Shalev-Benami of the Weizmann Institute said. “We showed exactly what it looked like and explained all its molecular details.”
Illustrative: on-off switches (iStock by Getty Images)
Pharmaceutical companies have rushed to manufacture drugs that manipulate MC4, but since they do so 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 by the U.S. Food and Drug Administration for chronic weight management in November, but reported side effects include spontaneous erection in men and adverse sexual reactions. women. as well as depression and suicidal thoughts. There were also cases of nausea, diarrhea and abdominal pain.
“Now that we know the exact molecular details of the switch, we can target it very precisely and design drugs that can avoid the side effects that this first drug experiences,” Shalev-Benami said.
Her laboratory at Weizmann’s Department of Chemical and Structural Biology conducted the study, which observed the impact of setmelanotide in detail, together with scientists from the Hebrew University of Jerusalem and the Queen Mary University of London.
Prof. Moran Shalev-Benami of the Weizmann Institute (thanks to the Weizmann Institute)
The study began after Hadar Israeli, a medical student at the Hebrew University who was pursuing PhD studies in the mechanisms of obesity, heard of a family in which at least eight members, all of whom were constantly hungry, were severely obese. Most of them have a body mass index of over 70, which is about the norm.
Israelis were struck by the fact that the family’s situation was due to a single mutation that took place in the family – one that affects the MC4 receptor – and asked whether new advances in the imaging of biological samples could provide insight. in how the receptor works.
Her supervisors contacted Shalev-Benami, who decided to launch a study into 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 help people with genetic conditions that directly affect MC4, but said that progress could very well help others try to diet. She said: “If we can get rid of side effects and manipulate this receptor without interfering with other receptors and causing side effects, it could help the general population of people struggling with weight loss.”
