A new study published in Science has revealed how the master switch for hunger in the brain, the melanocortin receptor 4 (MC4), works.
The research team, including scientists from the Weizmann Institute of Science, Queen Mary University of London and the Hebrew University of Jerusalem, also clarified how this switch is activated by setmelanotide (Imcivree), a drug recently approved for the treatment of severe obesity caused by certain genetic changes.
The findings shed new light on the way hunger is regulated and could help to develop improved anti-obesity medications.
The study uncovered the 3D structure of the MC4 receptor, through the use of recent advances in cryogenic electron microscopy. The 3D structure revealed that setmelanotide activates the MC4 receptor by entering its binding pocket –directly hitting the molecular switch that triggers us to feel full- even more potently than the natural satiety hormone. It also turned out that the drug has a surprising helper: an ion of calcium that enters the pocket, enhancing the drug's binding to the receptor. In biochemical and computational experiments, the scientists found that similarly to the drug, calcium also assists the natural satiety hormone.
Dr Peter McCormick, Reader in Molecular Pharmacology, said: “This is the first time this receptor has been caught in action. Interestingly, we found that calcium helped the satiety hormone activate the MC4 receptor while interfering with the hunger hormone and reducing its activity.”
"This was a truly unexpected finding," Dr Moran Shalev-Benami from the Weizmann Institute's Chemical and Structural Biology Department added. "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."
Improved anti-obesity drugs
Being constantly hungry, no matter how much you eat is a daily struggle for people with genetic defects in the brain's appetite controls, and can often lead to severe obesity.
The MC4 receptor is present in a brain region called the hypothalamus – within a cluster of neurons that compute the body's energy balance by processing a variety of energy-related metabolic signals. When the MC4 is activated, or "on" – as it normally is – it sends out commands that cause us to feel full, which means that from the brain's perspective, our default state is satiety. When our energy levels drop, the hypothalamic cluster produces a “time to eat” hormone that inactivates, or turns off the MC4 receptor, sending out a "become hungry" signal. After we eat, a second, "I'm full" hormone is released. It binds to the same active site on the MC4, replacing the hunger hormone and turning the receptor back on – bringing us back to the satiety default. Mutations that inactivate the MC4 cause people to feel constantly hungry.
MC4's structure also revealed that the drug's entry causes structural changes in the receptor; these changes appear to initiate the signals within the neurons that lead to the sensation of fullness. The study has explained how mutations in the MC4 receptor can interfere with this signaling, leading to never-ending hunger and ultimately obesity.
Moreover, the scientists have 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.
"Our findings can help develop improved and safer anti-obesity drugs that will target MC4R with greater precision," Dr Shalev-Benami said.
Dr McCormick added: “Our data will help inform which patients might respond to the current therapy, as well as laying the groundwork for more improved and more targeted medicines going forward.”
Reference: Israeli H, Degtjarik O, Fierro F, et al. Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling. Science. 2021. doi: 10.1126/science.abf7958
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