Shanghai researchers gain insights into obesity control protein

Researchers at the iHuman Institute of ShanghaiTech University have made a major discovery about a protein that has a role in controlling obesity.

Their findings were published in the international journal Science on Friday.

Obesity has become a global challenge. The World Health Organization reports that, worldwide, obesity has almost tripled since 1975.

In addition to being at a higher risk of other diseases, such as Type-2 diabetes and cardiovascular diseases, obesity has been identified as an important risk factor in severe complications of COVID-19.

The Stevens’ lab of the university has been intensely focused on peptide G-protein couple receptors and those receptors involved in human obesity, diabetes and metabolism. 

Their latest discovery is a protein – the human melanocortin-4 receptor. It’s found in the hypothalamus of the brain, where it plays an important role in controlling food intake and energy expenditure, including how much energy is stored as fat. 

Therefore, the receptor is the key to regulating hunger and maintaining body weight, making it an ideal but under-exploited drug target for obesity.

Research on the structure and function of the protein as well as drug development has been full of challenges but that did not stop ShanghaiTech graduate student Yu Jing. 

Together with an international team from Roger Cone lab at the University of Michigan and University of Southern California, Yu and her team were able to determine the structure of human MC4R at a resolution of 2.8 angstrom: 10,000 times smaller than the thickness of a human hair.

Evidence suggests that certain individuals with mutations in the MC4R gene have morbid early-onset obesity syndrome. Given this, regulating MC4R can help decrease food intake for weight reduction and stimulate food intake for weight gain. Therefore, it is considered as an important drug target for controlling obesity.

Specifically, the team discovered that calcium ions bind in the MC4R binding pocket and interact with both the cell receptor and drug candidates. They observed that calcium helps to stabilize the protein-drug complex and increase the affinity and potency of the endogenous agonists.

These discoveries are very important for developing new approaches for MC4R-related obesity drug discovery.

Zhao Suwen, research associate professor at iHuman Institute and School of Life Science and Technology of ShanghaiTech University, commented: “The structure of MC4R greatly promotes our understanding of the mechanism of melanocortin signaling and designing anti-obesity drugs against this target. Obesity is a growing global problem and we need more information to understand and attack this disease, particularly for those individuals with a genetic predisposition.”