Overview: Mutations in the serotonin 2C receptor gene play a key role in obesity and dysfunctional behavior in both human and animal models.
Source: Baylor College of Medicine
A joint study involving Baylor College of Medicine, the University of Cambridge and the University of Exeter Medical School reveals a new gene linked to obesity and maladaptive behaviour.
The evidence shows that rare mutations in the serotonin 2C receptor gene play a role in the development of obesity and dysfunctional behaviors in humans and animal models.
The findings, published in the journal Naturopathyhave both diagnostic and therapeutic implications.
“Serotonin is a chemical produced in the brain that acts as a neurotransmitter, meaning it carries messages from one part of the brain to another. Serotonin communicates the message 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, 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 Dr. I. Sadaf Farooqi at the University of Cambridge to investigate the role of one of the serotonin receptors, namely the serotonin 2C receptor, in weight regulation and behaviour.
Combining each lab’s individual expertise — animal basic and genetic studies in the Xu lab and human genetics in the Farooqi lab — the team was able to argue that the serotonin 2C receptor is an important regulator of body weight and certain behaviors.
The project began 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 receptor function.
“People who carried variants of loss of function had hyperphagia, or 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 laughter or crying or increased irritability or temper ,” Xu said.
The researchers found that animal models with one of the human loss-of-function mutations also became obese, confirming the team’s suspicion that loss-of-function mutations of the serotonin 2C receptor gene were involved in obesity.
“This is an important discovery from a diagnostic standpoint,” Xu said. “We propose that the serotonin 2C receptor gene should be included in diagnostic gene panels for childhood-onset severe obesity.”
In addition, the team identified a mechanism by which such mutations can lead to obesity. “We found that the serotonin 2C receptor is necessary to maintain normal firing activity of POMC neurons in the hypothalamus,” Xu said. “When the receptor has a loss-of-function mutation, the firing activity of POMC neurons is impaired and, as a result, the animals overeat and become obese. Normal firing activity of these neurons is required to suppress overeating.”
The researchers also worked with a mouse model to investigate the link between loss-of-function mutations and behavior.
“We confirmed that having the mutation led to decreased sociability and increased aggression in mice,” Xu said. “Before these findings, there was little evidence that the serotonin 2C receptor was needed to maintain normal behavior and prevent aggression. We are interested in investigating the mechanism.”
At the translational level, the findings suggest that patients who develop obesity due to a loss-of-function mutation of this gene could benefit from compounds that can circumvent the deficit in the mutated receptor, such as setmelanotide, by acting directly on downstream pathways. . Further studies need to be conducted to test this approach.
About this neuroscience research news
Author: Press Office
Source: Baylor College of Medicine
Contact: Press Service – Baylor College of Medicine
Image: The image is credited to the researchers
Original research: Open access.
“Human loss-of-function variants in the serotonin 2C receptor associated with obesity and maladaptive behavior” by Yong Xu et al. Naturopathy
Human loss-of-function variants in the serotonin 2C receptor associated with obesity and maladaptive behavior
Serotonin reuptake inhibitors and receptor agonists are used to treat obesity, anxiety, and depression.
Here we studied the role of the serotonin 2C receptor (5-HT2CR) in weight regulation and behavior.
Using exome sequencing of 2,548 people with severe obesity and 1,117 control subjects without obesity, we identified 13 rare variants in the gene encoding 5-HT2CR (HTR2C) in 19 unrelated people (3 men and 16 women).
Eleven variants caused loss of function in HEK293 cells. All people who carried variants had hyperphagia and some degree of maladaptive behavior.
Knock-in male mice harboring a human loss of function HTR2C variant developed obesity and decreased social exploratory behavior; female mice heterozygous for the same variant showed similar deficits with reduced severity.
Using the 5-HT2CR agonist lorcaserin, we found that depolarization of appetite-suppressing proopiomelanocortin neurons was impaired in knock-in mice. In conclusion, we show that 5-HT2CR is involved in the regulation of human appetite, weight and behavior.
Our findings suggest that melanocortin receptor agonists may be effective in the treatment of severe obesity in carrier individuals HTR2C variants. We recommend that HTR2C should be included in diagnostic gene panels for childhood-onset severe obesity.