Scientists may have discovered how a "switch" in the brain controls appetite, raising hopes for a new class of anti-obesity drugs.
Many people would like to lose a few pounds, with the temptation of favourite dishes and snacks often proving too much for our willpower.
For some, however, genetic defects cause them to feel famished no matter how much food they consume, resulting in severe obesity.
Scientists from the Weizmann Institute of Science in Israel studied a family of eight, all of whom endure persistent hunger and a dangerously high body mass index (BMI). This has been blamed on a single mutation in the brain's appetite switch.
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The scientists exposed the relatives' mutated switches to the obesity drug setmelanotide, which was recently approved in the US and is "proposed" for a UK sign-off.
Surprised by how the switch and drug interact, the team believes it has identified "hotspots" within the brain that could lead to new obesity treatments with fewer side effects.
The master switch – known as melanocortin receptor 4 (MC4) – resides in a region of the brain called the hypothalamus, which regulates appetite.
Writing in the journal Science, the Weizmann team described MC4 as "the crux of appetite, energy homeostasis (maintaining a consistent internal environment) and body-weight control in the central nervous system", as well as "a prime target for anti-obesity drugs".
When MC4 is "on", chemical messages are sent out telling the person they are full.
When the individual's energy level drops, MC4 is turned "off", causing the "time to eat" signal to be released.
After eating, a second "full" hormone is sent out, replacing the chemical messenger that signals hunger.
MC4 mutations are known to cause certain medical conditions where the patient feels constantly hungry.
Setmelanotide targets MC4, but it was unclear exactly how the drug triggered the "fullness" switch.
In the US, setmelanotide is approved under the brand name Imcivree for "chronic weight management" in patients with "obesity due to three rare genetic conditions".
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To learn more, the Weizmann scientists analysed the obese family, most of whom have a BMI of over 70 – around three times a healthy weight.
The relations were known to have a single MC4 mutation. To investigate this in detail, the scientists extracted large quantities of the mutated receptor from the family members' cell membranes.
Under laboratory conditions, MC4 was allowed to bind to setmelanotide.
The scientists were surprised to discover setmelanotide activates MC4 by entering its so-called binding pocket.
This means the drug hits the molecular switch that signals fullness more effectively than the natural satiety hormone, they explained.
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The binding was also enhanced by a calcium-related chemical messenger.
"This was a truly unexpected finding," said study author Dr Morgan Shalev-Benami.
"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."
Setmelanotide's entry into MC4 was also found to cause structural changes within the receptor, which may initiate the fullness signal.
The scientists believe they have identified "hotspots" that differentiate MC4 from similar receptors within its class.
This could lead to the development of drugs that bind exclusively to MC4, avoiding the side effects that can occur when other receptors are activated.
"Our findings can help develop improved and safer anti-obesity drugs that will target MC4 with greater precision," said Dr Shalev-Benami.
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