Document Type
Article
Publication Date
9-2022
Identifier
DOI: 10.1038/s42255-022-00629-2; PMCID: PMC9499872
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.
Journal Title
Nat Metab
Volume
4
Issue
9
First Page
1150
Last Page
1165
MeSH Keywords
Adaptation, Physiological; Adult; Animals; Child; Histone Deacetylases; Humans; Insulin; Membrane Proteins; Mice; Nerve Tissue Proteins; Obesity
Keywords
Physiological Adaptation; Histone Deacetylases; Insulin; Membrane Proteins; Nerve Tissue Proteins; Obesity
Recommended Citation
Yang CH, Fagnocchi L, Apostle S, et al. Independent phenotypic plasticity axes define distinct obesity sub-types. Nat Metab. 2022;4(9):1150-1165. doi:10.1038/s42255-022-00629-2
Comments
Grant support
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Publisher's Link: https://www.nature.com/articles/s42255-022-00629-2