Independent phenotypic plasticity axes define distinct obesity sub-types

Area of Science:

• Genetics
• Developmental Biology
• Metabolic Research

Background:

• Significant phenotypic variation exists in genetically identical individuals, with up to 50% of complex trait variation unexplained by genetics or environment.
• The underlying mechanisms generating this unexplained phenotypic variation (UPV) are not well understood.
• Identifying factors that buffer against UPV is crucial for understanding developmental plasticity.

Purpose of the Study:

• To identify conserved factors that buffer against unexplained phenotypic variation (UPV).
• To investigate the role of neuronatin (NNAT) in buffering against UPV.
• To explore the link between NNAT, insulin signaling, and metabolic phenotypes in both mice and humans.

Main Methods:

• Utilized isogenic mice to study the effects of Nnat deficiency on phenotypic variation.
• Employed multi-dimensional analysis of monozygotic twin discordance to identify human UPV patterns.
• Analyzed gene expression, histone deacetylase (HDAC) activity, and clinical outcomes related to insulinemia.

Main Results:

• Nnat deficiency in mice induced a bi-stable polyphenism, resulting in 'normal' or 'overgrown' adult phenotypes.
• This polyphenism was mechanistically linked to insulin-dependent overgrowth via HDAC-dependent beta-cell hyperproliferation.
• A subset of human unexplained phenotypic variation (Type B) phenocopied the NNAT-buffered polyphenism observed in mice.
• Type-B monozygotic co-twins showed coordinated increases in body mass, decreased NNAT expression, and elevated insulinemia.
• The Type-B UPV signature stratified cohorts into four distinct metabolic states, including two types of obesity.

Conclusions:

• Neuronatin (NNAT) is identified as a conserved factor that buffers against unexplained phenotypic variation (UPV).
• NNAT deficiency disrupts normal development, leading to insulin-mediated overgrowth and distinct metabolic phenotypes.
• The findings reveal a conserved mechanism for UPV and its stratification into distinct obesity types, with implications for metabolic health research.