Abstract
The negative impact of obesity on reproductive success is well documented but the stages at which development of the conceptus is compromised and the mechanisms responsible for the developmental failure still remain unclear. Recent findings suggest that mitochondria may be a contributing factor. However to date no studies have directly addressed the consequences of maternal obesity on mitochondria in early embryogenesis.Using an established murine model of maternal diet induced obesity and a live cell dynamic fluorescence imaging techniques coupled with molecular biology we have investigated the underlying mechanisms of obesity-induced reduced fertility. Our study is the first to show that maternal obesity prior to conception is associated with altered mitochondria in mouse oocytes and zygotes. Specifically, maternal diet-induced obesity in mice led to an increase in mitochondrial potential, mitochondrial DNA content and biogenesis. Generation of reactive oxygen species (ROS) was raised while glutathione was depleted and the redox state became more oxidised, suggestive of oxidative stress. These altered mitochondrial properties were associated with significant developmental impairment as shown by the increased number of obese mothers who failed to support blastocyst formation compared to lean dams. We propose that compromised oocyte and early embryo mitochondrial metabolism, resulting from excessive nutrient exposure prior to and during conception, may underlie poor reproductive outcomes frequently reported in obese women.
Highlights
Obesity and related metabolic disorders are a major health issue worldwide
Prolonged excitation of cells loaded with MitoTrackers may impair mitochondrial function [20] whereas the JC1 dye appears sensitive to factors other than inner mitochondrial membrane potential (Dym) [21] and may inhibit mitochondrial complex 1 [22]
Using our established model we have identified altered mitochondrial activity as one of the probable mechanisms of obesity-associated reproductive and developmental failure
Summary
Obesity and related metabolic disorders are a major health issue worldwide. With increasing prevalence in all populations and age groups, the proportion of women of reproductive age who are obese is rising [1]. It has been proposed that a high plane of nutrition might lead to excessive enrichment of the reproductive milieu [6] This in turn may induce alterations in oocyte metabolism and impede embryonic development. The central and most important function of mitochondria is the synthesis of adenosine triphosphate (ATP) by oxidative phosphorylation, a mechanism coupling the oxidation of nutrients and reducing equivalents (NAD(P)H, FADH2) with the phosphorylation of adenosine diphosphate. Both cytosolic and mitochondrial sources of NAD(P)H along with mitochondrial FADH2 stimulate the mitochondrial electron transport chain to pump H out of the mitochondrial matrix thereby hyperpolarising the inner mitochondrial membrane and generating the protonmotive force used to generate ATP. NADH oxidation in the mitochondria will produce ROS whereas NADPH oxidation (in the cytosol and mitochondria) serves to rejuvenate the antioxidant defence by reducing peroxiredoxins, thioredoxin and oxidised glutathione
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