Serotonin 2C receptor associated with obesity and maladaptive behavior

Serotonin 2C receptor associated with obesity and maladaptive behavior

Serotonin 2C receptor associated with obesity and maladaptive behavior

Abstract: Mutations in the serotonin 2C receptor gene play a key role in obesity and dysfunctional behavior in humans and animal models.

Source: Baylor School of Medicine

A joint study involving Baylor School of Medicine, the University of Cambridge and the University of Exeter School of Medicine reveals a new gene linked to obesity and maladaptive behavior.

Evidence indicates that rare mutations in the serotonin 2C receptor gene play a role in the development of obesity and dysfunctional behavior in humans and animal models.

The findings, published in the journal Natural medicinethey have both diagnostic and therapeutic implications.

“Serotonin is a chemical produced in the brain that acts as a neurotransmitter, that is, it transmits messages from one part of the brain to another. Serotonin transmits 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-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’s lab at the University of Cambridge collaborated to investigate the role of one of the serotonin receptors, 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 behaviors.

The project began 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 people. Further characterization of the variants revealed that 11 of them cause loss of receptor function.

“People who carried the loss-of-function variants had hyperphagia or extreme appetite, some degree of maladaptive behavior, and emotional lability, which refers to rapid, 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 are involved in obesity.

“This is an important finding from a diagnostic point of view,” Xu said. “We propose to include the serotonin 2C receptor gene in diagnostic gene panels for severe childhood obesity.”

Serotonin 2C receptor associated with obesity and maladaptive behavior
Rare variants affecting 5-HT2CR identified in humans with severe obesity. a, Rare variants identified in individuals with severe early-onset obesity shown in schematic of 5-HT2CR protein; ECL and ICL refer to the extracellular and intracellular loops of the G-protein coupled receptor (GPCR); C-term, C-terminal domain of the protein. b, Weight plots of two female probands (5th and 95th percentiles based on reference data for the UK population shown as dashed lines). Credit: Researchers

In addition, 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,” 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 the mutation led to reduced sociability and increased aggression in mice,” Xu said. “Prior to these discoveries, 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 findings suggest that patients who develop obesity due to a loss-of-function mutation of this gene could benefit from compounds that can bypass the deficit in the mutated receptor, such as setmelanotide, by acting directly on downstream pathways. Further studies are needed to test this approach.

About this neuroscience research news

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

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

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Abstract

Human loss-of-function variants of 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 2548 severely obese subjects and 1117 non-obese controls, we identified 13 rare variants in the gene encoding 5-HT2cR (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.

Knock-in male mice carrying human loss of function HTR2C variant of developed obesity and reduced social exploratory behavior; female mice heterozygous for the same variant showed similar defects with reduced severity.

Use of 5-HT2cR agonist lorcaserin, we found that depolarization of appetite-suppressing proopiomelanocortin neurons was attenuated 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 carriers HTR2C variants. We suggest that HTR2C should be included in diagnostic gene panels for severe childhood-onset obesity.

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