Transgenerational inheritance of metabolic disease

Abstract

Metabolic disease encompasses several disorders including obesity, type 2 diabetes, and dyslipidemia. Recently, the incidence of metabolic disease has drastically increased, driven primarily by a worldwide obesity epidemic. Transgenerational inheritance remains controversial, but has been proposed to contribute to human metabolic disease risk based on a growing number of proof-of-principle studies in model organisms ranging from Caenorhabditis elegans to Mus musculus to Sus scrofa. Collectively, these studies demonstrate that heritable risk is epigenetically transmitted from parent to offspring over multiple generations in the absence of a continued exposure to the triggering stimuli. A diverse assortment of initial triggers can induce transgenerational inheritance including high-fat or high-sugar diets, low-protein diets, various toxins, and ancestral genetic variants. Although the mechanistic basis underlying the transgenerational inheritance of disease risk remains largely unknown, putative molecules mediating transmission include small RNAs, histone modifications, and DNA methylation. Due to the considerable impact of metabolic disease on human health, it is critical to better understand the role of transgenerational inheritance of metabolic disease risk to open new avenues for therapeutic intervention and improve upon the current methods for clinical diagnoses and treatment.

Keywords: Epigenetics; Epigenome; Intergenerational inheritance; Metabolism; Obesity; Transgenerational inheritance.

Figure 1. Characteristics of epigenetic and conventional inheritance patterns

The red arrow indicates a triggering event (genetic or environmental) in the F0 generation. Obesity is shown as a representative phenotype. Although the F0 mice are represented as obese, the triggering event need not induce a phenotype in the F0 generation and may instead be restricted to future offspring. Phenotypic transmission to offspring is indicated by an obese mouse in the F1-F2 generations, whereas a lean mouse in the F1-F2 generations indicates failure to transmit the phenotype. Intergenerational inheritance describes phenotypic transmission to the F1 generation. Transgenerational inheritance describes phenotypic transmission to the F2 generation.

Figure 2. Characteristics of epigenetic and conventional inheritance patterns in pregnant females

The red arrow indicates a triggering event (genetic or environmental) in the F0 generation. Obesity is shown as a representative phenotype. Although the F0 mice are represented as obese, the triggering event need not induce a phenotype in the F0 generation and may instead be restricted to future offspring. Phenotypic transmission to offspring is indicated by an obese mouse in the F1-F3 generations, whereas a lean mouse in the F1-F3 generations indicates failure to transmit the phenotype. Intergenerational inheritance describes phenotypic transmission to the F1 or F2 generation. Transgenerational inheritance describes phenotypic transmission to the F3 generation, due to the presence of germ cells in utero of the F0 female that will eventually develop in the F2 generation.