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Independent phenotypic plasticity axes define distinct obesity sub-types

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE205741 | GEO | 2022/07/13

REPOSITORIES: GEO

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Independent phenotypic plasticity axes define mammalian metabolic and obesity sub-types [RNA-seq, mouse]

Project description:Studies in genetically identical individuals indicate that as much as 50% of complex trait variation cannot be traced to either 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 unexplained phenotypic variation. We find that Nnat deficiency in isogenic F1 mice triggers the emergence of a novel, bi-stable polyphenism, where isogenic littermates emerge into adulthood either ‘normal’ or ‘overgrown’, without intermediates. Mechanistically, emergence of these alternate phenotypic outcomes is mediated by an insulin-dependent overgrowth that arises from HDAC-dependent b-cell hyperproliferation. A multi-dimensional analysis of monozygotic twin discordance reveals the existence of two novel patterns of human UPV, one of which (Type-B UPV) phenocopies the NNAT-buffered polyphenism identified in mice. Specifically, monozygotic cotwins exhibiting Type-B UPV exhibit coordinate increases in fat and lean mass across the body; decreased NNAT expression; increased HDAC-responsive gene signatures; and clinical outcomes exceptionally linked to insulinemia. Type-B UPV accounts for approximately one third of all transcriptional variation in independent adult and childhood cohorts, indicating that this form of human phenotypic plasticity arises in early life and underpins a major dimension of observable human phenotypic variation. Critically, the Type-B UPV signature stratifies human cohorts into four metabolic sub-types, including two phenotypically and molecularly distinct types of obesity. Together, these data identify and characterize the first major axis regulating unexplained human phenotypic variation, and two major and novel forms of obesity.

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