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ey0018.11-3 | New hope: Increased diagnostic yield for disease causing MC4R variants and pharmacological treatment options | ESPEYB18

11.3. Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation

B Brouwers , EM de Oliveira , M Marti-Solano , FBF Monteiro , SA Laurin , JM Keogh , E Henning , R Bounds , CA Daly , S Houston , V Ayinampudi , N Wasiluk , D Clarke , B Plouffe , M Bouvier , MM Babu , IS Farooqi , J Mokrosiński

J Cell Rep. 2021 Mar 23;34(12):108862. 10.1016/j.celrep.2021.108862. https://pubmed.ncbi.nlm.nih.gov/33761344/This study demonstrates that MC4R variants found in humans affect receptor endocytosis, trafficking and dimerization and thus reveal multiple cellular mechanisms involved in weight regulation. The findings contributes to our und...

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ey0016.11-1 | New Insights into Body Weight Regulation | ESPEYB16

11.1. Genetic architecture of human thinness compared to severe obesity

F Riveros-McKay , V Mistry , R Bounds , A Hendricks , JM Keogh , H Thomas , E Henning , LJ Corbin , Understanding Society Scientific Group , S O'Rahilly , E Zeggini , E Wheeler , I Barroso , IS Farooqi

To read the full abstract: PLoS Genet. 2019; 15(1):e1007603.This genome wide association study reveals new insights into the genetic basis of thinness by investigating a large cohort of healthy persistently thin individuals. In the past, it has been speculated that inheritance of thinness may constitute a protective factor against environmental factors disposing to obesity (1). Neverthel...

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ey0019.15-3 | Obesity | ESPEYB19

15.3. Obesity-associated GNAS mutations and the melanocortin pathway

E Mendes de Oliveira , JM Keogh , F Talbot , E Henning , R Ahmed , A Perdikari , R Bounds , N Wasiluk , V Ayinampudi , I Barroso , J Mokrosinski , D Jyothish , S Lim , S Gupta , M Kershaw , C Matei , P Partha , T Randell , A McAulay , LC Wilson , T Cheetham , EC Crowne , P Clayton , IS Farooqi

N Engl J Med. 2021;385(17):1581-92. doi: 10.1056/NEJMoa2103329.PubMed ID: 34614324Brief Summary: The authors performed whole exome sequencing in 2548 children with severe obesity and identified 22 GNAS mutation carriers, almost all of which disrupted melanocortin 4 receptor (MC4R) signaling.The gene GNAS encodes the stimulatory G-protein alpha subunit pr...

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ey0016.11-3 | New Insights into Body Weight Regulation | ESPEYB16

11.3. Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis

Y Yang , AA van der Klaauw , L Zhu , TM Cacciottolo , Y He , LKJ Stadler , C Wang , P Xu , K Saito , A Jr. Hinton , X Yan , JM Keogh , E Henning , MC Banton , AE Hendricks , EG Bochukova , V Mistry , KL Lawler , L Liao , J Xu , S O'Rahilly , Q Tong , UK10K Consortium , I Barroso , BW O'Malley , IS Farooqi , Y Xu

To read the full abstract: Nat Comm 2019; 10(1): 1718Steroid receptor coactivator (SRC)-1 mediates nuclear hormone receptors and transcription factor-dependent transcription (1), and interacts with STAT3 (2) an important mediator of leptin-induced POMC expression and hence satiety (3). Src-1 knockout mice are obese (4), however, the underlying mechanism is unclear. In a...

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ey0015.11-6 | New Developments in Monogenic Obesity | ESPEYB15

11.6 Evaluation of a melanocortin-4 receptor (MC4R) agonist (setmelanotide) in MC4R deficiency

TH Collet , B Dubern , J Mokrosinski , H Connors , JM Keogh , E Mendes de Oliveira , E Henning , C Poitou-Bernert , JM Oppert , P Tounian , F Marchelli , R Alili , J Le Beyec , D Pépin , JM Lacorte , A Gottesdiener , R Bounds , S Sharma , C Folster , S Henderson B O'Rahilly , E Stoner , K Gottesdiener , BL Panaro , RD Cone , K Clément , IS Farooqi , LHT Van der Ploeg

To read the full abstract: Mol Metab. 2017 Oct; 6(10): 1321–1329See comment on 11.7...

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ey0020.9-6 | Advances in Understanding Central Weight Regulation and Behaviour | ESPEYB20

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

Y He , B Brouwers , H Liu , K Lawler , EM de Oliveira , DK Lee , Y Yang , AR Cox , JM Keogh , E Henning , R Bounds , A Perdikari , V Ayinampudi , C Wang , M Yu , L Tu , N Zhang , N Yin , J Han , NA Scarcelli , Z Yan , KM Conde , C Potts , JC Bean , M Wang , SM Hartig , L Liao , J Xu , I Barroso , J Mokrosinski , Y Xu , IS Farooqi

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 t...

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ESPE Yearbook of Paediatric Endocrinology

11.3. Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation

11.1. Genetic architecture of human thinness compared to severe obesity

15.3. Obesity-associated GNAS mutations and the melanocortin pathway

11.3. Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis

11.6 Evaluation of a melanocortin-4 receptor (MC4R) agonist (setmelanotide) in MC4R deficiency

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

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