Serotonin 2C Receptor Associated With Obesity and Maladaptive Behavior - Neuroscience News

Summary: Mutations successful the cistron for the serotonin 2C receptor play a cardinal relation successful obesity and dysfunctional behaviors successful some quality and carnal models.

Source: Baylor College of Medicine

A collaborative survey involving Baylor College of Medicine, the University of Cambridge and the University of Exeter Medical School reveals a caller cistron associated with obesity and maladaptive behavior.

The grounds shows that uncommon mutations successful the cistron for the serotonin 2C receptor play a relation successful the improvement of obesity and dysfunctional behaviors successful humans and carnal models.

The findings, published successful the journal Nature Medicine, person some diagnostic and therapeutic implications.

“Serotonin is simply a chemic produced successful the encephalon that acts arsenic a neurotransmitter, that is, it relays messages from 1 portion of the encephalon to another. Serotonin communicates the connection by binding to brain cells carrying serotonin receptors. These encephalon cells are progressive successful a assortment of functions, including mood, appetite and immoderate societal behaviors, among others,” said co-corresponding writer Dr. Yong Xu, prof of pediatrics—nutrition and molecular and cellular biology astatine Baylor.

In the existent study, the Xu laboratory and the laboratory of Dr. I. Sadaf Farooqi astatine the University of Cambridge, collaborated to analyse the relation of 1 of the serotonin receptors, namely serotonin 2C receptor, successful value regularisation and behavior.

By combining the idiosyncratic expertise of each lab—basic and familial carnal studies successful the Xu laboratory and human genetics in the Farooqi lab—the squad was capable to marque the lawsuit that serotonin 2C receptor is an important regulator of assemblage value and definite behaviors.

The task started with the uncovering that immoderate children diagnosed with severe obesity carried rare mutations or variants of the serotonin 2C receptor gene. The researchers identified 13 antithetic variants associated with obesity successful 19 unrelated people. Further characterization of the variants revealed that 11 of them origin loss-of-function of the receptor.

“People who carried loss-of-function variants had hyperphagia, oregon an utmost appetite, immoderate grade of maladaptive behaviour and affectional lability, which refers to rapid, often exaggerated changes successful temper including beardown emotions specified arsenic uncontrollable laughing oregon crying oregon heightened irritability oregon temper,” Xu said.

The researchers recovered that carnal models carrying 1 of the quality loss-of-function mutations also became obese, which confirmed the team’s suspicion that loss-of-function mutations of the serotonin 2C receptor cistron were progressive successful obesity.

“This is an important find from the diagnostic constituent of view,” Xu said. “We suggest that the serotonin 2C receptor cistron should beryllium included successful diagnostic cistron panels for terrible childhood-onset obesity.”

Rare variants affecting 5-HT2CR identified successful radical with terrible obesity. a, Rare variants identified successful individuals with terrible early-onset obesity shown connected a schematic of the 5-HT2CR protein; ECL and ICL notation to extra- and intracellular loops of the G-protein-coupled receptor (GPCR), respectively; C-term, C-terminal domain of the protein. b, Weight charts of 2 pistillate probands (5th and 95th percentiles based connected notation information for the UK colonisation shown arsenic dashed lines). Credit: The Researchers

In addition, the squad identified a mechanics by which specified mutations tin pb to obesity. “We recovered that the serotonin 2C receptor is required to support mean firing enactment of POMC neurons successful the hypothalamus,” Xu said. “When the receptor has a loss-of-function mutation, the firing enactment of POMC neurons is impaired and arsenic a effect the animals overeat and go obese. A mean firing enactment of these neurons is required to suppress overeating.”

The researchers besides worked with a rodent exemplary to research the transportation betwixt the loss-of-function mutations and behavior.

“We confirmed that having the mutation led to decreased sociability and accrued aggression successful mice,” Xu said. “Before these findings, determination was small grounds that the serotonin 2C receptor was required to support mean behaviour and to forestall aggression. We are funny successful investigating the mechanism.”

At the translational level, the findings suggest that patients who make obesity due to the fact that of a loss-of-function mutation of this gene, mightiness payment from compounds that tin bypass the shortage successful the mutated receptor, specified arsenic setmelanotide, by acting straight connected downstream pathways. Further studies request to beryllium implemented to trial this approach.

About this neuroscience probe news

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

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

Abstract

Human loss-of-function variants successful the serotonin 2C receptor associated with obesity and maladaptive behavior

Serotonin reuptake inhibitors and receptor agonists are utilized to dainty obesity, anxiousness and depression.

Here we studied the relation of the serotonin 2C receptor (5-HT_2CR) successful value regularisation and behavior.

Using exome sequencing of 2,548 radical with terrible obesity and 1,117 power individuals without obesity, we identified 13 uncommon variants successful the cistron encoding 5-HT_2CR (HTR2C) successful 19 unrelated radical (3 males and 16 females).

Eleven variants caused a nonaccomplishment of relation successful HEK293 cells. All radical who carried variants had hyperphagia and immoderate grade of maladaptive behavior.

Knock-in antheral mice harboring a quality loss-of-function HTR2C variant developed obesity and reduced societal exploratory behavior; pistillate mice heterozygous for the aforesaid variant showed akin deficits with reduced severity.

Using the 5-HT_2CR agonist lorcaserin, we recovered that depolarization of appetite-suppressing proopiomelanocortin neurons was impaired successful knock-in mice. In conclusion, we show that 5-HT_2CR is progressive successful the regularisation of quality appetite, value and behavior.

Our findings suggest that melanocortin receptor agonists mightiness beryllium effectual successful treating terrible obesity successful individuals carrying HTR2C variants. We suggest that HTR2C should beryllium included successful diagnostic cistron panels for terrible childhood-onset obesity.