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

Autor:	Yang He, Bas Brouwers, Hesong Liu, Hailan Liu, Katherine Lawler, Edson Mendes de Oliveira, Dong-Kee Lee, Yongjie Yang, Aaron R. Cox, Julia M. Keogh, Elana Henning, Rebecca Bounds, Aliki Perdikari, Vikram Ayinampudi, Chunmei Wang, Meng Yu, Longlong Tu, Nan Zhang, Na Yin, Junying Han, Nikolas A. Scarcelli, Zili Yan, Kristine M. Conde, Camille Potts, Jonathan C. Bean, Mengjie Wang, Sean M. Hartig, Lan Liao, Jianming Xu, Inês Barroso, Jacek Mokrosinski, Yong Xu, I. Sadaf Farooqi
Přispěvatelé:	Brouwers, Bas [0000-0001-6541-4835], Mendes de Oliveira, Edson [0000-0002-7330-7826], Cox, Aaron R [0000-0002-3330-5746], Conde, Kristine M [0000-0002-9525-4606], Bean, Jonathan C [0000-0002-8007-2383], Hartig, Sean M [0000-0002-2695-2072], Xu, Jianming [0000-0002-8208-9162], Barroso, Inês [0000-0001-5800-4520], Xu, Yong [0000-0002-4908-1572], Sadaf Farooqi, I [0000-0001-7609-3504], Apollo - University of Cambridge Repository, Cox, Aaron R. [0000-0002-3330-5746], Conde, Kristine M. [0000-0002-9525-4606], Bean, Jonathan C. [0000-0002-8007-2383], Hartig, Sean M. [0000-0002-2695-2072], Sadaf Farooqi, I. [0000-0001-7609-3504]
Rok vydání:	2022
Předmět:	Male Serotonin article 631/208/1515 General Medicine General Biochemistry Genetics and Molecular Biology Obesity Morbid 631/378/340 Mice HEK293 Cells Adaptation Psychological Receptor Serotonin 5-HT2C Animals Humans Female Obesity 631/443/319 Child Serotonin 5-HT2 Receptor Agonists
Popis:	Funder: National Institute for Health Research (NIHR) 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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::18e7fcce37e71b8dfb698909029b7e74 https://www.repository.cam.ac.uk/handle/1810/344906 Zobrazit plný text záznamu