Molecular mechanisms governing offspring metabolic programming in rodent models of in utero stress
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Cellular and Molecular Life Sciences
REVIEW
Molecular mechanisms governing offspring metabolic programming in rodent models of in utero stress Efthimia R. Christoforou1 · Amanda N. Sferruzzi‑Perri1 Received: 25 February 2020 / Revised: 23 May 2020 / Accepted: 27 May 2020 © The Author(s) 2020
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. Keywords Development · Programming · Metabolism · DOHAD · Fetal · Animal models
Developmental programming of metabolic disease Metabolic syndrome was characterised by the World Health Organization (WHO) in 1998 as a disease diagnosed by the presence of insulin resistance in addition to two other criteria, namely obesity, hyperlipidemia, hypertension and microalbuminuria [1]. In modern societies, this non-communicable disease has risen in prevalence, with approximately one in four people being afflicted worldwide [2, 3]. Mutations in metabolic genes, as well as life-style factors such as calorie-dense diets and sedentary lifestyle are considered as main risk factors for developing the metabolic syndrome [4–6]. However, an often-overlooked risk factor * Amanda N. Sferruzzi‑Perri [email protected] 1
Department of Physiology, Development and Neuroscience, Centre for Trophoblast Research, University of Cambridge, Downing Site, Cambridge, UK
for the development of metabolic syndrome, is the quality of one’s environment during gestation. Exposure to a suboptimal in utero environment due to a pregnancy complication or maternal nutrient deficit or surplus has
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