Independent phenotypic plasticity axes define distinct obesity sub-types

• DOI: 10.1038/s42255-022-00629-2
• Publication Date: 2022-09-12T16:07:07Z
• Authors: Chih-Hsiang Yang; Luca Fagnocchi; Stefanos Apostle; Vanessa Wegert; Salvador Casaní-G...; Kathrin Landgraf; Ilaria Panzeri; Erez Dror; Steffen Heyne; Till Wörpel; Darrell P. Chandler; Di Lu; Tao Yang; Elizabeth Gibbons; Rita Guerreiro; Jose Bras; Martin Thomasen; Louise G. Grunnet; Allan A. Vaag; Linn Gillberg; Elin Grundberg; Ana Conesa; Antje Körner; ; Timothy Triche; Adelheid Lempradl; Zachary J. DeBruine; Emily Wolfrum; Zachary Madaj; Tim Gruber; Brooke Grimaldi; Andrea Parham; Mitchell J. McDonald; Joseph H. Nadeau; Ildiko Polyak; Carmen Khoo; Christine Lary; Peter D. Gluckman; Neerja Karnani; David Carey; Ruth J. F. Loos; Gabriel Seifert; J. Andrew Pospisilik
• Keywords: Trait

Studies in genetically 'identical' individuals indicate that as much 50% of complex trait variation cannot be traced to genetics or the environment. The mechanisms generate this 'unexplained' phenotypic (UPV) remain largely unknown. Here, we identify neuronatin (NNAT) a conserved factor buffers against UPV. We find Nnat deficiency isogenic mice triggers emergence bi-stable polyphenism, where littermates emerge into adulthood either 'normal' 'overgrown'. Mechanistically, is mediated by an insulin-dependent overgrowth arises from histone deacetylase (HDAC)-dependent β-cell hyperproliferation. A multi-dimensional analysis monozygotic twin discordance reveals existence two patterns human UPV, one which (Type B) phenocopies NNAT-buffered polyphenism identified mice. Specifically, Type-B co-twins exhibit coordinated increases fat and lean mass across body; decreased NNAT expression; increased HDAC-responsive gene signatures; clinical outcomes linked insulinemia. Critically, UPV signature stratifies both childhood adult cohorts four metabolic states, including phenotypically molecularly distinct types obesity.