Brain News: Researchers uncovered how the master switch for hunger in the brain, the melanocortin receptor 4 (MC4) when activated by anti-obesity drugs like setmelanotide can cure obesity caused by genetic changes.
People with genetic defects in the brain’s appetite control suffer from uncontrolled hunger, so they eat a lot, which leads to severe obesity. The MC4 receptor – present in the brain’s hypothalamus region within a cluster of neurons – plays a key role in appetite and energy regulation.
When our body’s energy levels decrease, the hypothalamic cluster produces a “time to eat” hormone that inactivates the MC4 receptor, sending out a “become hungry” signal. After we eat, a second, “I’m full” hormone is released, which binds to the same active site on the MC4, and reactivates the receptor, it sends out commands that cause feeling full. Mutations due to pollution or any reason can inactivate the MC4, interfere with this signaling, making people to feel constantly hungry and ultimately obese.
The team isolated large quantities of pure MC4 receptors from cell membranes, let it bind with setmelanotide (Imcivree), a drug recently approved for obesity treatment, and then observed its 3D structure.
They found that setmelanotide induces structural changes and activates the MC4 receptor which leads to the sensation of fullness. The findings have important implications in developing improved anti-obesity drugs.
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Hadar Israeli, Oksana Degtjarik, Fabrizio Fierro, Vidicha Chunilal, Amandeep Kaur Gill, Nicolas J. Roth, Joaquin Botta, Vadivel Prabahar, Yoav Peleg, Li F. Chan, Danny Ben-Zvi, Peter J. McCormick, Masha Y. Niv, Moran Shalev-Benami. Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling. Science, 2021; eabf7958 DOI: 10.1126/science.abf7958