Serotonin 2C receptor associated with obesity and maladaptive behavior

A collaborative study involving Baylor College of Medicine, the University of Cambridge and the University of Exeter Medical School reveals a new gene associated with obesity and maladaptive behavior. The evidence shows that rare mutations in the gene for the serotonin 2C receptor play a role in the development of obesity and dysfunctional behaviors in humans and animal models. The findings, published in the journal Nature Medicine, have both diagnostic and therapeutic implications.

“Serotonin is a chemical produced in the brain that acts as a neurotransmitter, that is, it relays messages from one part of the brain to another. Serotonin communicates the message by binding to brain cells carrying serotonin receptors. These brain cells are involved in a variety of functions, including mood, appetite and some social behaviors, among others,” said co-corresponding author Dr. Yong Xu, professor of pediatrics- nutrition and molecular and cellular biology at Baylor.

In the current study, the Xu lab and the lab of Dr. I. Sadaf Farooqi at the University of Cambridge, collaborated to investigate the role of one of the serotonin receptors, namely serotonin 2C receptor, in weight regulation and behavior. By combining the individual expertise of each lab — basic and genetic animal studies in the Xu lab and human genetics in the Farooqi lab — the team was able to make the case that serotonin 2C receptor is an important regulator of body weight and certain behaviors.

The project started with the finding that some children diagnosed with severe obesity carried rare mutations or variants of the serotonin 2C receptor gene. The researchers identified 13 different variants associated with obesity in 19 unrelated people. Further characterization of the variants revealed that 11 of them cause loss-of-function of the receptor.

“People who carried loss-of-function variants had hyperphagia, or an extreme appetite, some degree of maladaptive behavior and emotional lability, which refers to rapid, often exaggerated changes in mood including strong emotions such as uncontrollable laughing or crying or heightened irritability or temper,” Xu said.

The researchers found that animal models carrying one of the human loss-of-function mutations also became obese, which confirmed the team’s suspicion that loss-of-function mutations of the serotonin 2C receptor gene were involved in obesity.

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