Developmental Programming and Transgenerational Transmission of Obesity

Abstract

The global obesity pandemic is often causally linked to marked changes in diet and lifestyle, namely marked increases in dietary intakes of high-energy diets and concomitant reductions in physical activity levels. However, far less attention has been paid to the role of developmental plasticity and alterations in phenotypic outcomes resulting from environmental perturbations during the early-life period. Human and animal studies have highlighted the link between alterations in the early-life environment and increased susceptibility to obesity and related metabolic disorders in later life. In particular, altered maternal nutrition, including both undernutrition and maternal obesity, has been shown to lead to transgenerational transmission of metabolic disorders. This association has been conceptualised as the developmental programming hypothesis whereby the impact of environmental influences during critical periods of developmental plasticity can elicit lifelong effects on the physiology of the offspring. Further, evidence to date suggests that this developmental programming is a transgenerational phenomenon, with a number of studies showing transmission of programming effects to subsequent generations, even in the absence of continued environmental stressors, thus perpetuating a cycle of obesity and metabolic disorders. The mechanisms responsible for these transgenerational effects remain poorly understood; evidence to date suggests a number of potential mechanisms underpinning the transgenerational transmission of the developmentally programmed phenotype through both the maternal and paternal lineage. Transgenerational phenotype transmission is often seen as a form of epigenetic inheritance with evidence showing both germline and somatic inheritance of epigenetic modifications leading to phenotype changes across generations. However, there is also evidence for non-genomic components as well as an interaction between the developing fetus with the in utero environment in the perpetuation of programmed phenotypes. A better understanding of how developmental programming effects are transmitted is essential for the implementation of initiatives aimed at curbing the current obesity crisis.

Epigenetic regulation of macrophage polarization and inflammation by DNA methylation in obesity

“…It is well documented that maternal or early-life nutrition has profound impact on the metabolic phenotypes in offspring and in later life (23,24). Alterations of DNA methylation globally or in specific genes have also been observed during the development of obesity (25,26).…”

Paternal epigenetic programming: evolving metabolic disease risk

“…Although epidemiological studies have provided evidence consistent with an independent and direct paternal programming of offspring health, it is not possible in human studies to rule out the contributions of genetic variants or lifestyle and social factors or inaccuracies arising from retrospective assessments of ancestral condition or participants' self-reports (Vickers 2014). For these reasons, the most robust evidence for paternal metabolic programming comes from studies in laboratory animals, where genetic and environmental variation can be tightly controlled.…”

Adiposopathy and epigenetics: an introduction to obesity as a transgenerational disease

“…Thus, the risk of adiposopathic disease development in an adult may be influenced by his/her perinatal environment [50][51][52] , with maternal nutrition affecting epigenetic mechanisms during development in utero, resulting in pathogenic biologic changes maintained through subsequent cell division into adulthood 33 . Importantly, not only are these epigenetic changes applicable for the first generation offspring, but also may persist for subsequent generations [64][65][66] , even in the absence of continued environmental stressors 67 . But just as unfavorable epigenetic alterations may increase disease risks, favorable epigenetic changes that occur before conception and during pregnancy may also influence the obesity risk transferred to offspring.…”