Serotonin 2C Receptor Associated With Obesity and Maladaptive Behavior

Summary: Mutations in the serotonin 2C receptor gene play an important role in obesity and dysfunctional behavior in both human and animal models.

Source: Baylor College of Medicine

A collaborative study involving Baylor School of Medicine, the University of Cambridge and the University of Exeter Medical School reveals a new gene associated with obesity and maladaptive behavior.

Evidence suggests that rare mutations in the serotonin 2C receptor gene are involved in the development of obesity and dysfunctional behaviors in humans and animal models.

The findings were published in the journal Nature MedicineIt has both diagnostic and therapeutic implications.

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

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

By combining each lab’s individual expertise (basic and genetic animal 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 behaviors.

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The project began when some children diagnosed with severe obesity were found to carry 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 caused loss of function of the receptor.

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

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 of the serotonin 2C receptor gene are involved in obesity.

“This is an important diagnostic discovery,” Xu said. “We propose that the serotonin 2C receptor gene should be included in diagnostic gene panels for severe childhood-onset obesity.”

A diagram from this work
Rare variants affecting 5-HT2CR have been identified in people with severe obesity. a, rare variants identified in individuals with early-onset severe obesity shown in a diagram of the 5-HT2CR protein; ECL and ICL refer to the extracellular and intracellular loops of the G-protein-coupled receptor (GPCR), respectively; The C-term is the C-terminal domain of the protein. b, Weight charts of two female probands (5th and 95th percentiles based on reference data for the UK population as dashed lines). Credit: Researchers

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 the normal firing activity of POMC neurons in the hypothalamus,” said Xu. “When the receptor has a loss-of-function mutation, the firing activity of POMC neurons is disrupted, and as a result, animals overeat and become obese. A normal firing activity of these neurons is required to suppress overeating.”

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The researchers also worked with a mouse model to explore 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. “Prior to these findings, there was little evidence that the serotonin 2C receptor is necessary 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 may benefit from compounds such as cemelanotide that can bypass the deficit in the mutated receptor by acting directly downstream. . Further studies are required to test this approach.

About this neuroscience research news

Author: press office
Source: Baylor College of Medicine
To contact: Press Office – Baylor School of Medicine
Picture: Image belongs to researchers

Original research: Open Access.
“Human loss-of-function variants at the serotonin 2C receptor associated with obesity and maladaptive behavior” by Yong Xu et al. Nature Medicine

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Abstract

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Human loss-of-function variants at 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 examined the role of the serotonin 2C receptor (5-HT).2CR) in weight regulation and behavior.

Using exome sequencing from 2,548 subjects with severe obesity and 1,117 control subjects without obesity, we identified 13 rare variants in 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 people carrying the variants had hyperphagia and some degree of maladaptive behavior.

Male mice harboring a human with loss of function HTR2C variant developed obesity and reduced social exploration behavior; Female mice heterozygous for the same variant showed similar deficiencies at reduced severity.

Using 5-HT2CWe found that the R agonist lorcaserin, the depolarization of appetite-suppressing proopiomelanocortin neurons, was impaired in knock-in mice. As a result, 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 overweight individuals. HTR2C variants. We recommend this HTR2C should be included in diagnostic gene panels for severe childhood-onset obesity.

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