Independent phenotypic plasticity axes define distinct obesity sub-types

Nat Metab. 2022 Sep;4(9):1150-1165. doi: 10.1038/s42255-022-00629-2. Epub 2022 Sep 12.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptation, Physiological
  • Adult
  • Animals
  • Child
  • Histone Deacetylases
  • Humans
  • Insulin
  • Membrane Proteins* / metabolism
  • Mice
  • Nerve Tissue Proteins* / genetics
  • Obesity / genetics
  • Obesity / metabolism

Substances

  • Insulin
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Histone Deacetylases