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 C. elegans to M. musculus to S. 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.

Clinical relevance of epigenetics in the onset and management of type 2 diabetes mellitus

“…59,60 Metabolic disorders, including diabetes, can be dependent on altered epigenetic reprogramming in utero. 61 On the contrary, transgenerational effects are responsible for epigenetic changes also in later progenies that have not been exposed to the starting environmental stimulus. Interestingly, both F1 and F2 offspring of protein-restricted pregnant rats present high blood pressure and endothelial dysfunction, thus suggesting a transgenerational epigenetic inheritance from the F0 to the F2 generation.…”

Epigenetics and obesity cardiomyopathy: From pathophysiology to prevention and management

“…Using organisms encompassing from Caenorhabditis elegans to Mus musculus to Sus scrofa, transgenerational inheritance is speculated to contribute to human metabolic risk (Stegemann & Buchner, 2015). Although the basis behind transgenerational inheritance of metabolic diseases still remains elusive, the concept of "gestational programming" likely results from alterations in the epigenome (nongenomic small RNAs, histone modification, and DNA methylation) rather than in the DNA sequence (genomic) .…”

“…Malnutrition during gestation may cause intrauterine growth retardation and low birth weight, which may result in postnatal catch-up growth and consequently onset and development of obesity and type 2 diabetes. In addition, obesity and type 2 diabetes may also be programmed transgenerationally through maternal substance abuse (e.g., psychoactive substances including illicit drugs or alcohol) during gestation and lactation (Stegemann & Buchner, 2015).…”

DNA methylation in epigenetic inheritance of metabolic diseases through the male germ line

“…These studies have not yet provided an in-depth understanding of the specific mechanisms behind epigenetic inheritance or exact effect size for the disease risk in offspring. Although rodents provide convenient models for human diseases and behavioral traits, they differ notably from humans in physiological and biological processes (Nagy & Turecki 2015, Stegemann & Buchner 2015. Nevertheless, the studies presented here support the notion that environmentally induced DNA methylation changes in the father can be transmitted to offspring and operate as a risk factor for metabolic diseases in later life and eventually across several generations.…”