Journal
NATURE MEDICINE
Volume 28, Issue 12, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41591-022-02106-5
Keywords
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Funding
- Wellcome [207462/Z/17/Z, 208363/Z/17/Z]
- National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre, a NIHR Senior Investigator Award
- Botnar Foundation
- Bernard Wolfe Health Neuroscience Endowment
- EMBO Long-term Fellowship
- National Institutes of Health (NIH) [P01DK113954, R01DK115761, R01DK117281, R01DK120858]
- US Department of Agriculture Current Research Information System [51000-064-01S]
- NIH [P30CA125123, K01DK119471, R01CA193455, R01DK126042, R01DK114356]
- Nancy Chang Award for Research Excellence at Baylor College of Medicine, American Diabetes Association [1-18-IBS-105]
- Baylor College of Medicine Bridge to Independence Award
- American Heart Association
- US Department of Agriculture Agricultural Research Service fellowship
- Research England
- Wellcome Trust [207462/Z/17/Z] Funding Source: Wellcome Trust
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Serotonin 2C receptor (5-HT2CR) plays a role in the regulation of human appetite, weight and behavior. Loss-of-function variants in the HTR2C gene are associated with obesity and maladaptive behavior. Activation of appetite-suppressing neurons is impaired in mice carrying HTR2C variants.
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.
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