REHOVOT, Israel — For people battling obesity, it’s one thing to lose weight, but how do you stop feeling hungry? A new study is revealing how a unique “switch” in the brain controls when people feel full. Researchers say the findings may soon lead to an anti-obesity pill that turns off hunger.
Scientists from the Weizmann Institute of Science call this switch MC4 (melanocortin receptor 4). While it mostly stays active, the receptor in some can mutate and is always shut down. Individuals with this issue can pile on the pounds, even when they’re actually full.
“Our findings can help develop improved and safer anti-obesity drugs that will target MC4 with greater precision,” says lead author Dr. Moran Shalev-Benami in a media release.
Researchers note a new medication that triggers the gene received approval from the U.S. Food and Drug Administration in November. Doctors are prescribing setmelanotide to children who are genetically prone to severe obesity.
This study, appearing in the journal Science, sheds fresh light on the MC4 mechanism and is a potential “game changer” in the battle against obesity-related health issues.
Obesity can be a hereditary condition
The MC4R gene lies in a brain region called the hypothalamus. Normally, it should send out commands that cause eaters to feel full, since our default state is satiety. When energy levels drop, a “time to eat” hormone turns it off and we become hungry.
Afterwards, the brain releases a second “I’m full” hormone and turns the gene back on. Variants that permanently turn MC4 off cause people to feel constantly hungry. This makes the master switch a prime target for medication, such as setmelanotide.
Switching the gene on can stop hunger while bypassing all other energy-related signals, but scientists did not know how this process worked until now. The project was based on a severely obese family of eight in Israel, plagued by persistent hunger.
Most had a body mass index of over 70, triple the norm. Researchers traced their devastating condition to an MC4R mutation that ran in the family. Powerful microscopes determined its 3D structure in extraordinary detail, down to nucleus level.
Those images revealed setmelanotide activates the gene by entering its binding pocket. From there, it directly hits the molecular switch that signals satiety, even more potently than the natural hormone. The drug also has a surprising helper — an ion of calcium that boosts contact.
“Calcium helped the satiety hormone activate the MC4 receptor while interfering with the hunger hormone and reducing its activity,” explains co-author Dr. Peter McCormick of Queen Mary University of London.
Dr. Shalev-Benami describes the phenomenon as “truly unexpected.”
“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.”
More anti-obesity drugs on the way?
The groundbreaking analysis also reveals the drug’s entry causes structural changes in the gene. They appear to initiate the signals within the neurons that lead to the sensation of fullness. The study shows mutations interfere with these signals, leading to never-ending hunger and ultimately obesity. Moreover, the study identified hotspots that crucially distinguish MC4 from similar receptors in the same family.
“This should make it possible to design drugs that will bind only to MC4, avoiding side effects that may be caused by interactions with other receptors,” the researchers conclude.
Setmelanotide, sold under the brand name Imcivree, leads to weight loss by altering eating behavior. The latest findings open the door to drugs that treat or cure the underlying genetic problem.
SWNS writer Mark Waghorn contributed to this report.