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Yang, C.* ; Fagnocchi, L.* ; Apostle, S.* ; Wegert, V.* ; Casani-Galdon, S.* ; Landgraf, K.* ; Panzeri, I.* ; Dror, E.* ; Heyne, S.* ; Woerpel, T.* ; Chandler, D.P.* ; Lu, D.* ; Yang, T.* ; Gibbons, E.* ; Guerreiro, R.* ; Bras, J.* ; Thomasen, M.* ; Grunnet, L.G.* ; Vaag, A.A.* ; Gillberg, L.* ; Grundberg, E.* ; Conesa, A.* ; Körner, A. ; Pospisilik, J.A.*

Independent phenotypic plasticity axes define distinct obesity sub-types.

Nat. Metab. 4, 1150-1165 (2022)
Verlagsversion Forschungsdaten DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
ISSN (print) / ISBN 2522-5812
e-ISSN 2522-5812
Zeitschrift Nature metabolism
Quellenangaben Band: 4, Heft: 9, Seiten: 1150-1165 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Förderungen NHGRI NIH HHS
Wellcome Trust