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

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He, Yang 
Liu, Hesong 
Liu, Hailan 
Lawler, Katherine 


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.


Funder: National Institute for Health Research (NIHR)


Animals, Child, Female, Humans, Male, Mice, HEK293 Cells, Obesity, Obesity, Morbid, Receptor, Serotonin, 5-HT2C, Serotonin, Serotonin 5-HT2 Receptor Agonists, Adaptation, Psychological

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Nat Med

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Springer Science and Business Media LLC
NIDDK NIH HHS (R01 DK114356, P01 DK113954, R01 DK115761, K01 DK119471)
Wellcome Trust (207462/Z/17/Z, 208363/Z/17/Z)
U.S. Department of Health &amp (R01DK120858)
NCI NIH HHS (P30 CA125123, R01 CA193455)
U.S. Department of Health &amp (R01DK120858)