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Independent phenotypic plasticity axes define distinct obesity sub-types

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العنوان: Independent phenotypic plasticity axes define distinct obesity sub-types
المؤلفون: Yang, C., Fagnocchi, L., Apostle, S., Wegert, V., Casaní-Galdón, S., Landgraf, K., Panzeri, I., Dror, E., Heyne, S., Wörpel, T., Chandler, D., Lu, D., Yang, T., Gibbons, E., Guerreiro, R., Bras, J., Thomasen, M., Grunnet, L., Vaag, A., Gillberg, L., Grundberg, E., Conesa, A., Körner, A., PERMUTE, Pospisilik, J.
المساهمون: European Commission, Novo Nordisk Foundation, Danish Council for Independent Research, National Institutes of Health (US), German Research Foundation, Federal Ministry of Education and Research (Germany), Kings College London, Wellcome Trust
المصدر: Nat. Metab. 4, 1150-1165 (2022)
PERMUTE 2022, ' Independent phenotypic plasticity axes define distinct obesity sub-types ', Nature Metabolism, vol. 4, pp. 1150–1165 . https://doi.org/10.1038/s42255-022-00629-2
Nature Metabolism
سنة النشر: 2022
مصطلحات موضوعية: Adult, ENVIRONMENT, Endocrinology, Diabetes and Metabolism, Membrane Proteins, Nerve Tissue Proteins, Cell Biology, Adaptation, Physiological, DISEASE, Histone Deacetylases, MECHANISMS, BODY-MASS INDEX, Mice, ADIPOSE-TISSUE, BETA-CELL FUNCTION, TWINS, Physiology (medical), Internal Medicine, Animals, Humans, Insulin, Obesity, MESSENGER-RNA, Child, DNA METHYLATION, NEURONATIN
الوصف: PERMUTE: et al.
Studies in genetically ‘identical’ individuals indicate that as much as 50% of complex trait variation cannot be traced to genetics or to the environment. The mechanisms that generate this ‘unexplained’ phenotypic variation (UPV) remain largely unknown. Here, we identify neuronatin (NNAT) as a conserved factor that buffers against UPV. We find that Nnat deficiency in isogenic mice triggers the emergence of a bi-stable polyphenism, where littermates emerge into adulthood either ‘normal’ or ‘overgrown’. Mechanistically, this is mediated by an insulin-dependent overgrowth that arises from histone deacetylase (HDAC)-dependent β-cell hyperproliferation. A multi-dimensional analysis of monozygotic twin discordance reveals the existence of two patterns of human UPV, one of which (Type B) phenocopies the NNAT-buffered polyphenism identified in mice. Specifically, Type-B monozygotic co-twins exhibit coordinated increases in fat and lean mass across the body; decreased NNAT expression; increased HDAC-responsive gene signatures; and clinical outcomes linked to insulinemia. Critically, the Type-B UPV signature stratifies both childhood and adult cohorts into four metabolic states, including two phenotypically and molecularly distinct types of obesity.
This work was supported by funding from the MPG, the VAI, the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 675610, the Novo Nordisk Foundation, European Foundation for the Study of Diabetes and the Danish Council for Independent Research and National Institutes of Health awards R21HG011964 and 1R01HG012444. The LCAT cohort was supported by grants from AK German Research Foundation CRC1052 (no. 209933838), project C05 and KO3512/3-1, the German Diabetes Association and the Federal Ministry of Education and Research, Germany, FKZ, 01EO1001 (Integrated Research and Treatment Center Adiposity Diseases). TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, Chronic Disease Research Foundation, Zoe Global Ltd. and the National Institute for Health Research-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London.
وصف الملف: application/pdf
تدمد: 2522-5812
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c996e45140a1af3154ef08668ab3cd99
https://pubmed.ncbi.nlm.nih.gov/36207625
حقوق: OPEN
رقم الأكسشن: edsair.doi.dedup.....c996e45140a1af3154ef08668ab3cd99
قاعدة البيانات: OpenAIRE
الوصف
تدمد:25225812