Summary: Mutations in the gene for the serotonin 2C receptor play a key role in obesity and dysfunctional behaviors in both humans 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 identifies a new gene associated with obesity and bad behavior.

The data show that rare mutations in the gene for the serotonin 2C receptor play a role in obesity and dysfunctional behaviors in humans and animal models.

The findings are published in the journal Natural medicineBoth have diagnostic and therapeutic implications.

“Serotonin is a chemical produced in the brain that acts as a neurotransmitter, sending messages from one part of the brain to another. Serotonin transmits the message by attaching to brain cells that carry serotonin receptors. These brain cells are involved in a variety of functions, including emotion, appetite, and some social behaviors, among others,” said co-author Dr. Yong Shu, professor of pediatrics-nutrition and molecular and cellular biology at Baylor.

In the current study, his lab and Dr. I. Sadaf Faruqi’s lab at the University of Cambridge collaborated to investigate the role of one type of serotonin receptor, the serotonin 2C receptor, in weight control and behavior.

By combining the individual expertise of each lab—basic and genetic animal studies in Xu’s lab and human genetics in Faruqi’s lab—the team was able to confirm that the serotonin 2C receptor is an important regulator of body weight and certain traits.

The project began with the discovery that some children diagnosed with severe obesity had a rare mutation, or mutation, of the serotonin 2C receptor gene. The researchers identified 13 different variants associated with obesity in 19 unrelated individuals. 11 of the additional features of the variables cause the loss of the receiver function.

“People who carried the non-functional variant had hyperphagia, or excessive appetite, with some degree of abnormal behavior and emotional disturbances, which included rapid, often exaggerated mood swings such as uncontrollable laughing or crying or increased anger or rage,” Xu said.

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

“This is an important finding from the point of view of investigation,” Xu said. “We suggest that the serotonin 2C receptor gene should be included in diagnostic gene panels for severe childhood-onset obesity.”

This is a graphic from the study.
Rare variants affecting 5-HT2CR in severely obese subjects. A, Abnormalities identified in 5-HT2CR protein pattern in individuals with severe early-onset obesity. ECL and ICL refer to the extra- and intracellular loops of the G-protein-coupled receptor (GPCR), the C-terminal domain of the protein. B, Weight charts for two female probands (5th and 95th percentiles based on UK population reference data as dashed lines). Credit: The researchers

The team also identified a mechanism by which such mutations may lead to obesity. “We found that the serotonin 2C receptor is required to maintain the 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, resulting in the animals overeating and becoming obese. Normal firing of these neurons is required to prevent overeating.”

The researchers also worked with a mouse model to test the relationship between loss-of-function mutations and behavior.

“We found that having the mutation reduced sociality and increased aggression in the mice,” Xu said. “Prior to these findings, there was not much evidence that the serotonin 2C receptor was required to maintain normal behavior and prevent aggression. We are interested in investigating the mechanism.”

Importantly, the findings suggest that obese patients with loss-of-function mutations in this gene may benefit from compounds that can bypass the defect in the mutant receptor by acting directly on downstream pathways, such as cetimelanotide. . Further studies should be implemented to test this approach.

So neuroscience research news

Author: Press office
Source: Baylor College of Medicine
Contact: Press Office – Baylor College of Medicine
Image: Image is credited to the researchers.

Preliminary study: Open Access.
Human differences in serotonin 2C receptor dysfunction associated with obesity and maladaptive behavior.” by Yong Shu et al Natural medicine

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This shows the pieces of the brain

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Human differences in serotonin 2C receptor dysfunction associated with obesity and maladaptive behavior.

Serotonin reuptake inhibitors and receptor agonists are used to treat obesity, anxiety and depression.

Here the serotonin 2C receptor (5-HT2cR) in weight control and behavior.

Using exome sequencing of 2,548 severely obese and 1,117 obese control individuals, we identified 13 rare variants in the 5-HT gene.2cR (HTR2C) in 19 unrelated individuals (3 males and 16 females).

Eleven variants resulted in loss of function in HEK293 cells. All individuals carrying the variants had hyperphagia and some degree of abnormal behavior.

Knockout mice that develop human dysfunction. HTR2C Differentially developed obesity and reduced social exploration behavior; Female mice heterozygous for the same variant showed similar deficits in weight loss.

using 5-HT2cThe R agonist lorcaserin attenuates depolarization of appetite-suppressing proopiomelanocortin neurons in knockout mice. In conclusion, we show that 5-HT2cR is involved in the control of human appetite, weight and behavior.

Our findings suggest that melanocortin receptor agonists may be effective in treating severe obesity in individuals who are carriers. HTR2C Alternatives. We suggest that. HTR2C Obesity should be included in diagnostic gene panels for severe childhood-onset obesity.

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