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ey0017.11-3 | New Genetic Findings | ESPEYB17

11.3. Human gain-of-function MC4R variants show signaling bias and protect against obesity

LA Lotta , J Mokrosinski , E Mendes de Oliveira , C Li , SJ Sharp , J Luan , B Brouwers , V Ayinampudi , N Bowker , N Kerrison , V Kaimakis , D Hoult , ID Stewart , E Wheeler , FR Day , JRB Perry , C Langenberg , NJ Wareham , IS Farooqi

To read the full abstract: Cell 2019;177 (3):59-607.e9. PMID 31002796.A recent GWAS showed that the heritability of thinness was comparable to that of obesity (1). Some loci showed effects across the entire BMI distribution. This is also true for variants in MC4R. The present study analyzed data on ˜0.5 million people from UK Biobank, with a focus on 61 nonsynonymous var...

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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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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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ey0015.11-7 | New Developments in Monogenic Obesity | ESPEYB15

11.7 MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency

K Clément , H Biebermann , IS Farooqi , L Van der Ploeg , B Wolters , C Poitou , L Puder , F Fiedorek , K Gottesdiener , G Kleinau , N Heyder , P Scheerer , U Blume-Peytavi , I Jahnke , S Sharma , J Mokrosinski , S Wiegand , A Müller , K Weiß , K Mai , J Spranger , A Grüters , O Blankenstein , H Krude , P Kühnen

To read the full abstract: Nat Med 2018, May;24(5):551-555[Comments on 1.1, 1.5, 1.6 and 1.7] All four here presented articles have monogenic obesity as their theme. While patients with monogenic obesity are rare, these individuals bear a heavy disease burden. Furthermore, these...

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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 gain-of-function MC4R variants show signaling bias and protect against obesity

15.3. Obesity-associated GNAS mutations and the melanocortin pathway

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

11.7 MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency

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

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