Serotonin 2C receptor linked to obesity and maladaptive behavior – Neuroscience News

Summary: Mutations in the serotonin 2C receptor gene play a key role in obesity and dysfunctional behaviors in human and animal models.

Source: Baylor College of Medicine

A collaborative 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 behaviors.

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 results, published in the journal natural medicinehave 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 that carry serotonin receptors. These brain cells are involved in a variety of functions, including mood, appetite, and certain social behaviors, among others,” said co-corresponding author Dr. Yong Xu, Professor of Pediatrics – Nutrition and Biology molecular and cellular at Baylor.

In the current study, Xu’s lab and Dr. I. Sadaf Farooqi’s lab at the University of Cambridge collaborated to investigate the role of one of the serotonin receptors, namely the serotonin 2C receptor, in weight regulation and behavior.

By combining the individual expertise of each lab – basic animal and genetic studies in the Xu lab and human genetics in the Farooqi lab – the team was able to demonstrate that the serotonin 2C receptor is an important regulator of body weight and certain behaviours.

The project started with the discovery 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 individuals. Further characterization of the variants revealed that 11 of them cause loss of receptor function.

“People with loss-of-function variants suffered from overeating or extreme appetite, some degree of maladaptive behavior, and emotional lability, which refers to rapid and often exaggerated mood swings, including strong emotions such as uncontrollable laughing or crying or increased irritability or temper,” Xu said.

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

“This is an important finding from a diagnostic perspective,” Xu said. “We suggest that the serotonin 2C receptor gene should be included in diagnostic gene panels for severe childhood obesity.”

Additionally, the team identified a mechanism by which such mutations can lead to obesity. “We found that the serotonin 2C receptor is required 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 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 explore the link between loss-of-function mutations and behavior.

“We confirmed that the mutation caused decreased sociability and increased aggression in mice,” Xu said. “Before these findings, there was little evidence that the serotonin 2C receptor was required to maintain normal behavior and prevent aggression. We are interested in investigating the mechanism.

At the translational level, the results suggest that patients who develop obesity due to a loss-of-function mutation in this gene could benefit from compounds able to circumvent the deficiency of the mutated receptor, such as setmelanotide, by acting directly on the pathways downstream. . Further studies should be implemented to test this approach.

About this neuroscience research news

Author: Press office
Source: Baylor College of Medicine
Contact: Press Office – Baylor College of Medicine
Image: The image is attributed to the researchers

Original research: Free access.
“Human loss-of-function variants in the serotonin 2C receptor associated with obesity and maladaptive behavior” by Yong Xu et al. natural medicine

See also

Abstract

Human variants of loss of function in 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 investigated the role of the serotonin 2C receptor (5-HT_2CR) in weight regulation and behavior.

Using exome sequencing of 2,548 individuals with severe obesity and 1,117 control individuals without obesity, we identified 13 rare variants of the gene encoding 5-HT_2CR (HTR2C) in 19 unrelated individuals (3 men and 16 women).

Eleven variants caused loss of function in HEK293 cells. All of the variant carriers suffered from overeating and some degree of maladaptive behavior.

Male knock-in mice harboring human loss of function HTR2C one variant developed obesity and reduced social exploration behavior; female mice heterozygous for the same variant showed similar deficits with reduced severity.

Use of 5-HT_2CR agonist lorcaserin, we found that depolarization of appetite-suppressing proopiomelanocortin neurons was impaired in knock-in mice. In conclusion, we demonstrate that 5-HT_2CR is involved in the regulation of human appetite, weight and behavior.

Our results suggest that melanocortin receptor agonists may be effective in treating severe obesity in carriers. HTR2C variants. We suggest that HTR2C should be included in diagnostic gene panels for severe childhood obesity.