Analysis of miRNAs in placental extracellular vesicles: a study of the role of metformin during obese pregnancy in mice

Abstract

Studies have shown that disrupted metabolic environments during gestation can influence fetal growth, and increase the risk to develop metabolic disease in adulthood. This has been termed the 'developmental origins of health and disease hypothesis' and proposes that nutrition during critical stages of life (such as gestation and neonatal life) permanently affects the structure and function of organs. This leads to increased risk of development of Non-Communicable Diseases (such as type 2 diabetes, cardiovascular disease obesity and non-alcoholic fatty liver disease). Evidence from the literature demonstrates that both maternal under nutrition and maternal over nutrition during gestation can lead to these programmed effects including permanent effects on the function of adipose tissue, however the underlying molecular mechanisms are not well defined. Aiming to find out possible mechanisms that explain how alterations during gestation and lactation can influence the metabolic status in adulthood, the research group headed by Professor Susan Ozanne has studied the effect of obesity during pregnancy on offspring metabolism in adulthood life. Also, considering the increase in prevalence of obesity and gestational diabetes mellitus and the control of diabetes during pregnancy with metformin, they are evaluating using their animal model as a tool to unveil the role of miRNAs on epigenetic pattern and regulation of metabolism of offspring in adulthood life. Information exchange between cells occurs in different biological systems, and is essential for life. Cell-to-cell interactions can influence the recipient cell's biology in a range of ways including its energy disposal, biosynthesis capacity and ability to survive. Although their complete function remains to be determined, there is growing evidence for a role of extracellular vesicles (EV) in transfer of information between cells with EVs being capable of delivering biomolecules and signals from one cell to cells of surrounding tissues. EV function has been associated with a range of physiological and pathological conditions, widely recognized transferring functional RNAs between cells. Many studies demonstrated the ability of EVs to transfer mRNA between cells transferring genetic code and changing cells phenotypes. Besides mRNAs, many studies have demonstrated that EVs are capable of transporting miRNAs, acting to control the metabolism of other cells in physiological or pathological conditions. There is extensive evidence of the beneficial effects of metformin treatment during glucose intolerant pregnancy. Using their mouse model of maternal diet-induced obesity, the Ozanne lab showed that although an obesogenic diet during pregnancy promoted increased fat mass, glucose intolerance, liver steatosis and reduced uterine artery compliance, all of them restored by metformin treatment. However, some placental and fetal changes like reduced fetal weight and alteration in placental efficiency associated with calcification and reduction of placental labyrinthine area were not corrected by maternal metformin treatment. It is clear that metformin is important to restore the metabolism of mother, but since it freely crosses the placenta, the long-term consequences on the offspring are uncertain. Also, they have shown in young adult life that in utero exposure to metformin let to increased adiposity in male offspring.The aim of the current study is therefore to evaluate the miRNAs profile in placental EVs of control, obese and obese mice treated with metformin. (AU)