Molecular mechanisms governing offspring metabolic programming in rodent models of in utero stress

Abstract

The results of different human epidemiological datasets provided the impetus to introduce the now commonly accepted theory coined as 'developmental programming', whereby the presence of a stressor during gestation predisposes the growing fetus to develop diseases, such as metabolic dysfunction in later postnatal life. However, in a clinical setting, human lifespan and inaccessibility to tissue for analysis are major limitations to study the molecular mechanisms governing developmental programming. Subsequently, studies using animal models have proved indispensable to the identification of key molecular pathways and epigenetic mechanisms that are dysregulated in metabolic organs of the fetus and adult programmed due to an adverse gestational environment. Rodents such as mice and rats are the most used experimental animals in the study of developmental programming. This review summarises the molecular pathways and epigenetic mechanisms influencing alterations in metabolic tissues of rodent offspring exposed to in utero stress and subsequently programmed for metabolic dysfunction. By comparing molecular mechanisms in a variety of rodent models of in utero stress, we hope to summarise common themes and pathways governing later metabolic dysfunction in the offspring whilst identifying reasons for incongruencies between models so to inform future work. With the continued use and refinement of such models of developmental programming, the scientific community may gain the knowledge required for the targeted treatment of metabolic diseases that have intrauterine origins.

Maternal Exercise Mediates Hepatic Metabolic Programming via Activation of AMPK-PGC1α Axis in the Offspring of Obese Mothers

“…The paradigm that offspring metabolic health is significantly shaped by the maternal metabolic phenotype and alterations in the early life environment is known as the ‘developmental origins of health and disease‘ hypothesis (or ‘fetal metabolic programming concept‘) and was first proposed by Barker and Halles [ 25 , 26 , 27 ]. Although studies have demonstrated that adverse maternal conditions (e.g., maternal obesity) impair offspring metabolic health and that preventive interventions, such as maternal exercise during critical periods of developmental programming, seem to be able to reduce the susceptibility to and severity of metabolic dysfunction, the underlying molecular mechanisms remain poorly understood.…”

Developmental programming of offspring adipose tissue biology and obesity risk

“…This field was initiated by findings of an association between fetal malnutrition, and the development of metabolic diseases, like insulin resistance and obesity in adulthood [ 7 , 8 ]. Extensions of this work using human population and experimental animal data have shown that exposure to a diverse array of suboptimal maternal environments, including nutritionally unbalanced diets, low oxygen availability, and high body mass index (BMI) during gestation, modifies the risk of the offspring developing obesity [ 9 , 10 ]. The aim of this review is to present the findings of these studies.…”

Molecular programming in utero modulates hepatic lipid metabolism and adult metabolic risk in obese mother offspring in a sex-specific manner

“…Recent research in animal models has elucidated potential programming mechanisms that include altered hepatic function 29-32 and cellular signaling responses 33,34 . Histological analysis of the liver structure in offspring revealed the presence of marked areas of cell proliferation in female livers.…”