Independent phenotypic plasticity axes define distinct obesity sub-types
Chih-Hsiang Yang, Luca Fagnocchi, Stefanos Apostle, Vanessa Wegert, Salvador Casaní-Galdón, Kathrin Landgraf, Ilaria Panzeri, Erez Dror, Steffen Heyne, Till Wörpel, Darrell P. Chandler, Di Lu, Tao Yang, Elizabeth Gibbons, Rita Guerreiro, José Brás, Martin Thomasen, Louise Groth Grunnet, Allan Vaag, Linn Gillberg, Elin Grundberg, Ana Conesa, Antje Körner, PERMUTE, Timothy J. 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 W. Lary, Peter D. Gluckman, Neerja Karnani, David J. Carey, Ruth J. F. Loos, Gabriel Seifert, J. Andrew Pospisilik
Abstract
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.