ESPEYB17 11. Obesity and Weight Regulation New Genetic Findings (2 abstracts)
11.3. Human gain-of-function MC4R variants show signaling bias and protect against obesity
Lotta LA , Mokrosinski J , Mendes de Oliveira E , Li C , Sharp SJ , Luan J , Brouwers B , Ayinampudi V , Bowker N , Kerrison N , Kaimakis V , Hoult D , Stewart ID , Wheeler E , Day FR , Perry JRB , Langenberg C , Wareham NJ & Farooqi IS
University of Cambridge MRC Epidemiology Unit, Welcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK, luca.lotta@mrc-epid.cam.ac.uk
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 variants identified in MC4R. Of these 61 variants, 12 were nonsense/frameshift variants and 49 were missense variants.
Two functional read outs were investigated in a cellular model: i) canonical Gas-mediated cAMP production and ii) the recruitment of b-arrestin to MC4R. In contrast to most previous studies of human MC4R variants, which measured the accumulation of cAMP, the majority of MC4R variants investigated here affect both cAMP production and the recruitment of b-arrestin-2 to MC4R. Interestingly, the vast majority of the variance (88%) in the association of BMI with the different MC4R variants was explained by their functional effects on b-arrestin recruitment.
Moreover, the investigators found that, in UK Biobank, ˜1 in 16 participants (6%) were carriers for gain-of-function (GoF) MC4R alleles that exhibited signaling bias, preferentially increasing b-arrestin recruitment rather than cAMP production. These GoF mutants which resulted in an increased b-arrestin recruitment showed an enhanced signaling via the MAPK pathway.
Accordingly, individuals with a GoF allele had significantly lower BMI and up to 50% lower risk of obesity, type 2 diabetes, and coronary artery disease.
To provide some illustrative data, the investigators calculated that the BMI of carriers of one GoF MC4R allele was on average 0.39 kg/m2 lower than noncarriers. Those who carried two GoF alleles had a BMI which was on average 0.88 kg/m2 lower. In an individual with a height of 1.7 m this would correspond to a body weight reduced by 2.5 kg.
In contrast to previous studies showing that the accumulation of cAMP is critical for MC4R signaling, these data demonstrate that MC4R signaling through b-arrestin is responsible for its regulation of body weight. These results may be the basis for the development of b-arrestin-biased MC4R agonists to induce weight loss as well to treat obesity-associated metabolic comorbidities. The authors make the point impressively and suggest that the clinical effects of genetic variants found in populations that exhibit natural signaling bias for a given pathway can serve as a ‘blueprint’ for modulating that pathway pharmacologically with a biased agonist.
Reference:
1. Riveros-McKay F, Mistry V, Bounds R, Hendricks A, Keogh JM, Thomas H, Henning E, Corbin LJ, Understanding Society Scientific Group, O’Rahilly S, Zeggini E, Wheeler E, Barroso I, Farooqi IS. Genetic Architecture of Human Thinness Compared to Severe Obesity. PLoS Genet 2019;15 (1):e1007603.
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ESPE Yearbook of Paediatric Endocrinology
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