Serotonin 2C receptor linked to obesity and maladaptive behavior

A collaborative study involving Baylor College of Medicine, the University of Cambridge and the University of Exeter Medical School reveals a new gene linked to obesity and poor behavior. The results, published in the journal nature medicine, Has 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 communicates the message by binding to brain cells that carry serotonin receptors. These brain cells regulate mood, appetite, and some social interactions among others. involved in a variety of functions, including behavior,” said co-corresponding author Dr. Yong Joo, professor of pediatric nutrition and molecular and cellular biology at Baylor.

Dr. Yong Joo
Dr. I. Sadaf Faruqi

In the current study, the Xu lab and Cambridge University Dr. I. Sadaf Farooqui’s lab 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 and genetic animal studies in the Zoo lab and human genetics in the Farooqi lab—the team was able to make the case that the serotonin 2C receptor is an important regulator of body weight and specific behaviors.

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Linking serotonin 2C receptors to obesity

The project began with the discovery that some children with severe obesity have a rare mutation or variant 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 an extreme appetite, some degree of inconsistent behavior and emotional instability, which refers to rapid, often exaggerated changes in mood such as strong emotions such as uncontrollable laughing or crying or agitated irritability or moodiness,” Xu said. .

The researchers found that animal models carrying one of the human loss-of-function mutations also became obese, which confirmed the team’s suspicion that deleterious mutations in the serotonin 2C receptor gene were involved in obesity.

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

Additionally, the team 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 receptor function is impaired, the firing activity of POMC neurons is impaired, and as a result the animals overeat and become obese. A normal firing activity of these neurons is required to suppress overeating.”

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Schematic of the serotonin 2C receptor protein. This study identified rare variants of this protein in individuals with severe early-onset obesity. Image courtesy of authors/Nature’s medicine2022.
Serotonin 2C receptors are associated with certain behaviors

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

“We confirmed that the mutation resulted in decreased sociability and increased aggression in the mice,” Xu said. “Prior to this finding, 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 results suggest that patients who develop obesity due to impaired function of this gene may benefit from compounds that can bypass the deficiency of the mutated receptor, such as cetmelanotide, acting directly downstream. Further studies need to be implemented to test this approach.

Other contributors to this work include Yang He, Bass Brouwers, Hesong Liu, Hailan Liu, Catherine Lawler, Edson Mendes de Oliveira, Dong-Ki Lee, Yongji Yang, Aaron R. Cox, Julia M. Keogh, Elana Henning, Rebecca Bounds, Aliki Perdicari. , Vikram Ayinampudi, Chunmei Wang, Meng Yu, Longlong Tu, Nan Zhang, Na Yin, Juning Han, Nicholas A. Scarcelli, Jill Ian, Christine M. Conde, Camille Potts, Jonathan C. Bin, Mengji Wang, Sean M. Hartig, Lan Liao, Jianming Xu, Ines Barroso, and Jacek Mokrosinski. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, University of Cambridge and University of Exeter Medical School.

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This research was supported by funding from Wellcome (207462/Z/17/Z and 208363/Z/17/Z), the NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, the Boettner Foundation and the Bernard Wolff Health Neuroscience Endowment. আরও সমর্থন একটি ইএমবিও দীর্ঘস্থায়ী ফেলোশিপ, এনআইএইচ গ্রান্টস (P01DK113954, R01DK115761, R01DK117281, R01DK10858, K01DK119471, R01DK119471, R01D93455, R01DK112, R0193455, R01DK112, R01DK119471, R01CA193455, R01DK12, R01DK119471, R01CA193455, R01DK112 দ্বারা সরবরাহ করা হয়েছিল কলেজ অফ মেডিসিন, আমেরিকান Diabetes Association (1-18-IBS-105), Baylor College of Medicine Bridge to Independence Award, American Heart Association, a USDA/ARS Fellowship, and Research England.

Ana María Rodríguez, Ph.D.


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