Children’s Nutrition Research Center Staff Publications
Publication Date
12-1-2022
Journal
Nature Medicine
DOI
10.1038/s41591-022-02106-5
PMID
36536256
PMCID
PMC9800280
PubMedCentral® Posted Date
12-19-2022
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Animals, Child, Female, Humans, Male, Mice, HEK293 Cells, Obesity, Obesity, Morbid, Receptor, Serotonin, 5-HT2C, Serotonin, Serotonin 5-HT2 Receptor Agonists, Adaptation, Psychological, Metabolism, Behavioural genetics, Molecular neuroscience
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.
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Biochemical Phenomena, Metabolism, and Nutrition Commons, Dietetics and Clinical Nutrition Commons, Medical Specialties Commons, Nutrition Commons