TY - JOUR

T1 - Independent phenotypic plasticity axes define distinct obesity sub-types

AU - Yang, Chih-Hsiang

AU - Fagnocchi, Luca

AU - Apostle, Stefanos

AU - Wegert, Vanessa

AU - Casani-Galdon, Salvador

AU - Landgraf, Kathrin

AU - Panzeri, Ilaria

AU - Dror, Erez

AU - Heyne, Steffen

AU - Woerpel, Till

AU - Chandler, Darrell P.

AU - Lu, Di

AU - Yang, Tao

AU - Gibbons, Elizabeth

AU - Guerreiro, Rita

AU - Bras, Jose

AU - Thomasen, Martin

AU - Grunnet, Louise G.

AU - Vaag, Allan A.

AU - Gillberg, Linn

AU - Grundberg, Elin

AU - Conesa, Ana

AU - Korner, Antje

AU - Pospisilik, J. Andrew

AU - PERMUTE

PY - 2022/9/12

Y1 - 2022/9/12

N2 - 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 beta-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.Yang et al. show that neuronatin (NNAT) can explain part of the phenotypic variation of complex traits, independently of genetics or the environment. Such NNAT-dependent variations can stratify human cohorts into four metabolic sub-types, including two distinct types of obesity.

AB - 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 beta-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.Yang et al. show that neuronatin (NNAT) can explain part of the phenotypic variation of complex traits, independently of genetics or the environment. Such NNAT-dependent variations can stratify human cohorts into four metabolic sub-types, including two distinct types of obesity.

KW - BETA-CELL FUNCTION

KW - BODY-MASS INDEX

KW - DNA METHYLATION

KW - ADIPOSE-TISSUE

KW - MESSENGER-RNA

KW - NEURONATIN

KW - TWINS

KW - ENVIRONMENT

KW - MECHANISMS

KW - DISEASE

U2 - 10.1038/s42255-022-00629-2

DO - 10.1038/s42255-022-00629-2

M3 - Journal article

C2 - 36097183

VL - 4

SP - 1150

EP - 1165

JO - Nature Metabolism

JF - Nature Metabolism

SN - 2522-5812

ER -