ESPEYB20 9. Obesity and Weight Regulation Advances in Understanding Central Weight Regulation and Behaviour (2 abstracts)
9.6. Human loss-of-function variants in the serotonin 2C receptor associated with obesity and maladaptive behavior
He Y , Brouwers B , Liu H , Lawler K , de Oliveira EM , Lee DK , Yang Y , Cox AR , Keogh JM , Henning E , Bounds R , Perdikari A , Ayinampudi V , Wang C , Yu M , Tu L , Zhang N , Yin N , Han J , Scarcelli NA , Yan Z , Conde KM , Potts C , Bean JC , Wang M , Hartig SM , Liao L , Xu J , Barroso I , Mokrosinski J , Xu Y & Farooqi IS
University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK. isf20@cam.ac.uk Nat Med 28, 2537–2546 (2022). Doi: 10.1038/s41591-022-02106-5. https://pubmed.ncbi.nlm.nih.gov/36536256/.
Brief summary: This collaborative study identified 13 monoallelic rare loss-of-function (LoF) variants in the serotonin 2C receptor (HTR2C) gene in 19 unrelated individuals with hyperphagia, severe early-onset obesity, and some degree of maladaptive behaviour. The authors used exome sequencing in 2548 individuals with severe obesity and 1117 control individuals without obesity. They found that HTR2C variants cause monogenic obesity by demonstrating the role of serotonin 2C receptors in the regulation of appetite, weight and behaviour through functional analysis of the identified variants in HEK293 cells and knock-in mice carrying a human LoF HTR2C variant.
Serotonin receptors are known to regulate body weight, mood and behaviour. Serotonin reuptake inhibitors and receptor agonists are used to treat obesity, anxiety, and depression (1,2). Previous studies in mice provided evidence that the appetite-suppressing effects are mediated specifically by serotonin receptor 2C, which is expressed in hypothalamic proopiomelanocortin (POMC) neurons (3). POMC neurons play an important role in appetite and weight regulation via the leptin-melanocortin pathway, and cause hyperphagia and severe early-childhood obesity in the complete absence of POMC due to biallelic variants.
This study is the first to identify monoallelic variants in the HTR2C gene in humans and provides evidence for the HTR2C gene as a novel cause of monogenic obesity. In addition, the study suggests a shared mechanism for obesity and anxiety, mood disorders, and maladaptive behaviour and highlights the need for a more careful assessment of anxiety and maladaptive behaviour in clinical practice in the future. As LoF HTR2C variants are likely to affect POMC signalling, affected patients may be amenable to treatment with the melanocortin 4 receptor agonist, setmelanotide, which has been approved in the UK, USA, and Europe for chronic weight management in patients with certain biallelic variants in the leptin-melanocortin pathway (4).
This well-designed study demonstrates the relevance for inclusion of the HTR2C gene to existing diagnostic gene panels for individuals with severe obesity due to its functional role in the development of obesity.
References: 1. Heisler LK, Cowley MA, Kishi T, Tecott LH, Fan W, Low MJ, u. a. Central serotonin and melanocortin pathways regulating energy homeostasis. Ann N Y Acad Sci. Juni 2003;994(1):169–74. 2. Heisler LK, Cowley MA, Tecott LH, Fan W, Low MJ, Smart JL, u. a. Activation of central melanocortin pathways by fenfluramine. Science. 26. Juli 2002;297(5581):609–11. 3. Berglund ED, Liu C, Sohn JW, Liu T, Kim MH, Lee CE, u. a. Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis. J Clin Invest. 2. Dezember 2013;123(12):5061–70. 4. Clément K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, u. a. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol. Dezember 2020;8(12):960–70.
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