Nature Medicine: Serotonin 2C receptors are associated with childhood obesity

A collaborative study by Baylor College of Medicine, the University of Cambridge and the University of Exeter has revealed a new gene
linked to obesity and maladjustment.
The researchers found that rare mutations in the serotonin 2C receptor gene play a role
in the development of obesity and dysfunctional behaviors in both human and animal models.

The results, titled "Human loss-of-function variants in the serotonin 2C receptor associated with obesity and maladaptive behavior," were published this week in the journal Nature Medicine and have diagnostic and therapeutic implications
.

According to Professor Yong Xu of Baylor College of Medicine, serotonin (serotonin) is an important neurotransmitter produced in the brain, that is, it transmits information from one part of the brain to another
.
Serotonin transmits information
by binding to brain cells that carry serotonin receptors.
These brain cells are involved in a variety of functions, including mood, appetite, and some social behaviors
.

In this study, the researchers explored the role
of one of the serotonin receptors, the serotonin 2C receptor (5-HT_2CR), in weight regulation and behavior.
By combining expertise from various laboratories, the research team was able to demonstrate that the serotonin 2C receptor is an important regulator of body weight and certain
behaviors.

Initially, the researchers found that some children diagnosed with severe obesity carried a rare mutation or variation
in the serotonin 2C receptor gene.
They found 13 different variants
associated with obesity in 19 unrelated individuals.
After further identification, they found that 11 of them caused loss
of receptor function.

"People who carry the loss-of-function variant suffer from anobia (aka hyperphagia), as well as a degree of maladaptive behavior and emotional instability
.
They can quickly develop exaggerated mood changes, such as uncontrollable laughter or crying, or are particularly irritable or grumpy," Professor Xu said
.

At the same time, the researchers also found that animal models carrying human loss-of-function mutations also became obese, confirming their suspicion that loss-of-function mutations in the serotonin 2C receptor gene were associated with
obesity.

"From a diagnostic standpoint, this is an important finding," Xu said
.
"We believe that the serotonin 2C receptor gene should be included in the diagnostic gene portfolio for severe childhood obesity
.
"

In addition, the team identified the mechanism
by which this mutation leads to obesity.
"We found that the serotonin 2C receptor is required to maintain normal firing activity in hypothalamic POMC neurons," he said
.
"When the receptor undergoes loss-of-function mutations, the firing activity of POMC neurons is impaired, causing the animals to overeat and become obese
.
The normal firing activity of these neurons is necessary to
suppress overeating.
”

The researchers also used mouse models to explore associations
between loss-of-function mutations and behavior.

"We confirmed that this mutation causes reduced sociability and increased aggression in mice," Xu said
.
"Prior to these results, there was little evidence that the serotonin 2C receptor was necessary to
maintain normal behavior and prevent aggressive behavior.
We are interested in
the mechanism behind it.
”

At the transformation level, the findings suggest that patients who become obese due to loss-of-function mutations in this gene may benefit from compounds that bypass mutant receptors, such as Setmelanotide (MC4R agonist), by acting directly on downstream pathways
.
Further research is needed to test this approach
.

Original search

He, Y.
, Brouwers, B.
, Liu, H.
et al.
Human loss-of-function variants in the serotonin 2C receptor associated with obesity and maladaptive behavior.
Nat Med (2022).
https://doi.
org/10.
1038/s41591-022-02106-5