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

Authors: HE, YANG - Children'S Nutrition Research Center (CNRC); BROUWERS, BAS - University Of Cambridge; LIU, HESONG - Children'S Nutrition Research Center (CNRC); LIU, HAILAN - Children'S Nutrition Research Center (CNRC); LAWLER, KATHERINE - University Of Cambridge; MENDES DE OLIVEIRA, EDSON - University Of Cambridge; LEE, DONG-KEE - Baylor College Of Medicine; YANG, YONGJIE - Children'S Nutrition Research Center (CNRC); COX, AARON - Baylor College Of Medicine; KEOGH, JULIA - University Of Cambridge; HENNING, ELANA - University Of Cambridge; BOUNDS, REBECCA - University Of Cambridge; PERDIKARI, ALIKI - University Of Cambridge; AYINAMPUDI, VIKRAM - University Of Cambridge; WANG, CHUNMEI - Children'S Nutrition Research Center (CNRC); YU, MENG - Children'S Nutrition Research Center (CNRC); TU, LONGLONG - Children'S Nutrition Research Center (CNRC); ZHANG, NAN - Children'S Nutrition Research Center (CNRC); YIN, NA - Children'S Nutrition Research Center (CNRC); HAN, JUNYING - Children'S Nutrition Research Center (CNRC); SCARCELLI, NIKOLAS - Children'S Nutrition Research Center (CNRC); YAN, ZILI - Children'S Nutrition Research Center (CNRC); CONDE, KRISTINE - Children'S Nutrition Research Center (CNRC); POTTS, CAMILLE - Children'S Nutrition Research Center (CNRC); BEAN, JONATHAN - Children'S Nutrition Research Center (CNRC); WANG, MENGJIE - Children'S Nutrition Research Center (CNRC); HARTIG, SEAN - Baylor College Of Medicine; LIAO, LAN - Baylor College Of Medicine; XU, JIANMING - Baylor College Of Medicine; BARROSO, INES - University Of Exeter; MOKROSINSKI, JACEK - University Of Cambridge; XU, YONG - Children'S Nutrition Research Center (CNRC); I SADAF, FAROOQI - University Of Cambridge

Submitted to: Nature Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/25/2022
Publication Date: 12/19/2022
Citation: He, Y., Brouwers, B., Liu, H., Liu, H., Lawler, K., Mendes De Oliveira, E., Lee, D., Yang, Y., Cox, A.R., Keogh, J.M., Henning, E., Bounds, R., Perdikari, A., Ayinampudi, V., Wang, C., Yu, M., Tu, L., Zhang, N., Yin, N., Han, J., Scarcelli, N., Yan, Z., Conde, K., Potts, C., Bean, J.C., Wang, M., Hartig, S.M., Liao, L., Xu, J., Barroso, I., Mokrosinski, J., Xu, Y., I Sadaf, F. 2022. Human loss-of-function variants in the serotonin 2C receptor associated with obesity and maladaptive behavior. Nature Medicine. 28:2537–2546. https://doi.org/10.1038/s41591-022-02106-5.
DOI: https://doi.org/10.1038/s41591-022-02106-5

Interpretive Summary: The serotonin system in our body helps regulate our mood, appetite, and weight. Scientists have found that certain drugs that affect serotonin, called serotonin reuptake inhibitors and receptor agonists, can help treat conditions like obesity, anxiety, and depression. In a recent study, scientists looked at the role of a specific serotonin receptor called 5-HT2CR in weight regulation and behavior. They examined the DNA of over 2,500 people with severe obesity and over 1,100 people without obesity and found that 19 of the obese individuals had rare genetic mutations in the gene that codes for 5-HT2CR.These genetic mutations caused a loss of function in cells, and all the people who carried them had increased appetite and some problems with behavior. When scientists engineered mice to have the same genetic mutations, they found that the mice became obese and had changes in their social behavior. The scientists also tested a drug called lorcaserin, which activates 5-HT2CR, and found that it improved appetite suppression in normal mice but not in the mice with the genetic mutations. The study shows that 5-HT2CR is important for regulating appetite, weight, and behavior in humans, and that drugs that target this receptor might be effective in treating severe obesity in individuals with these genetic mutations. The study also suggests that genetic testing for mutations in the 5-HT2CR gene could be useful for diagnosing severe childhood-onset obesity.

Technical Abstract: 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 2,548 people with severe obesity and 1,117 control individuals without obesity, we identified 13 rare variants in the gene encoding 5-HT2CR (HTR2C) in 19 unrelated people (3 males and 16 females). Eleven variants caused a loss of function in HEK293 cells. All people who carried variants had hyperphagia and some degree of maladaptive behavior. Knock-in male mice harboring a human loss-of-function HTR2C variant developed obesity and reduced social exploratory behavior; female mice heterozygous for the same variant showed similar deficits with reduced severity. Using the 5-HT2CR agonist lorcaserin, we found that depolarization of appetite-suppressing proopiomelanocortin neurons was impaired in knock-in mice. In conclusion, we demonstrate that 5-HT2CR is involved in the regulation of human appetite, weight and behavior. Our findings suggest that melanocortin receptor agonists might be effective in treating severe obesity in individuals carrying HTR2C variants. We suggest that HTR2C should be included in diagnostic gene panels for severe childhood-onset obesity.