Independent phenotypic plasticity axes define distinct obesity sub-types.
Nat Metab
; 4(9): 1150-1165, 2022 09.
Article
em En
| MEDLINE
| ID: mdl-36097183
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 ß-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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Membrana
/
Proteínas do Tecido Nervoso
Tipo de estudo:
Prognostic_studies
Limite:
Adult
/
Animals
/
Child
/
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article