Overview: Genetic mutations in the serotonin 2C receptor play important roles in obesity and dysfunctional behaviors in both human and animal models.
sauce: Baylor College of Medicine
A collaborative study involving the Baylor College of Medicine, the University of Cambridge and the University of Exeter School of Medicine has revealed new genes associated with obesity and maladaptive behavior.
Evidence indicates that rare mutations in the gene for the serotonin 2C receptor play a role in the development of obesity and dysfunctional behaviors in humans and animal models.
Findings published in the journal natural medicinehas both diagnostic and therapeutic implications.
“Serotonin is a chemical produced in the brain that acts as a neurotransmitter, meaning it relays messages from one part of the brain to another. Serotonin binds to brain cells that have serotonin receptors. These brain cells are involved in a variety of functions, including mood, appetite, and some social behaviors, among others,” says Baylor’s Pediatrics-Nutrition and Molecular and Cell Biology. co-corresponding author Yong Xu, Ph.D., a professor at
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.
Combining the individual expertise of each lab (basic animal and genetics research in the Xu lab and human genetics in the Farooqi lab), the team discovered that serotonin 2C receptors are important for body weight and specific behaviors. could be argued to be a regulator.
The project began with the discovery that some children diagnosed with severe obesity carry a rare mutation or variant in the serotonin 2C receptor gene. The researchers identified 13 different variants associated with obesity in 19 of her unrelated individuals. Further characterization of the variants revealed that 11 of them cause receptor loss of function.
“People with the loss-of-function variant had bulimia, or extreme appetite, some degree of maladaptive behavior, and emotional lability,” Shu said.
The researchers found that an animal model with 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 play a role in obesity.
“This is an important finding from a diagnostic perspective,” said Xu. “We recommend that the serotonin 2C receptor gene should be included in diagnostic gene panels for severe childhood-onset obesity.”
In addition, the team identified mechanisms by which such mutations could lead to obesity. “We found that serotonin 2C receptors were required to maintain normal firing activity of her POMC neurons in the hypothalamus,” he said. “Loss-of-function mutations in the receptor impair the firing activity of POMC neurons, resulting in overeating and obese animals. Normal firing activity of these neurons is required to reduce overeating.” .”
Researchers have also used mouse models to investigate the relationship between loss-of-function mutations and behavior.
“We found that mice with this mutation are less sociable and more aggressive,” said Xu. “Prior to these findings, there was little evidence that serotonin 2C receptors are required to maintain normal behavior and prevent aggression.
At the translational level, this finding suggests that patients who develop obesity due to loss-of-function mutations in this gene could benefit from compounds that could circumvent defects in mutant receptors such as setmelanotide by acting directly on downstream pathways. More research needs to be done to test this approach.
About this neuroscience research news
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
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-HT).2CR) Weight control and behavior.
Using exome sequencing from 2,548 severely obese patients and 1,117 nonobese controls, we identified 13 rare variants in the gene encoding 5-HT.2CR (HTR2C) were 19 unrelated individuals (3 males, 16 females).
Eleven variants caused loss of function in HEK293 cells. All who had the variant showed binge eating and some degree of maladaptive behavior.
Knock-in male mouse harboring human loss of function HTR2C The variant developed obesity and decreased social exploratory behavior. Female mice heterozygous for the same variant showed similar impairments of reduced severity.
Use of 5-HT2CUsing the R agonist lorcaserin, we found that depolarization of anorexigenic pro-opiomelanocortin neurons was impaired in knock-in mice. In conclusion, 5-HT2CR is involved in the regulation of human appetite, weight and behavior.
Our findings suggest that melanocortin receptor agonists HTR2C variant.we suggest that HTR2C Severe childhood-onset obesity should be included in the diagnostic gene panel.