Influence maternal aging and diet on follicular and embryo metabolism
An inability of oocyte mitochondria to meet the energy demands of maturation, fertilization, and embryo development can contribute to infertility, chromosomal abnormalities and poor assisted reproduction outcomes. This is particularly relevant in the context of maternal aging, where a loss of oocyte mitochondrial content is thought to limit oxidative phosphorylation (OXPHOS) capacity secondary to reductions in mtDNA content or replication. However, our understanding of oocyte and embryo energy metabolism during early development has been limited by inherent technical challenges, and so is currently based largely on indirect estimates of mitochondrial capacity/content, marker enzyme activities and metabolite analyses.
In collaboration with Dr. Elaine Carnevale in the Equine Reproduction Laboratory and Dr. Thomas Chen in the Department of Computer and Electrical Engineering, our team has developed the first miniaturized metabolic multi-sensor capable of real-time monitoring of mitochondrial respiration (oxygen consumption), glycolytic flux (glucose uptake and lactate release), extracellular acidification rate (ECAR, an index of anaerobic glycolysis), and H2O2 release in single equine oocytes and embryos. Using this system, we have found that oocyte OXPHOS rate declines with maternal age in mares, but mitochondrial respiratory capacity actually increases, arguing against the hypothesis that a loss of mitochondrial content impairs oocyte metabolic potential with age. In parallel studies of granulosa cell metabolism using our Oroboros O2k high-resolution respirometer in our lab, we found that aging does not impair OXPHOS capacity, but dramatically increases release of mitochondria-derived reactive oxygen species. These defects could be reversed by supplementing the maternal diet with a proprietary blend of nutrients (Platinum Performance) for 8 weeks, consistent with potential links between maternal lifestyle, the follicular environment and oocyte metabolic competence.
Current studies aim to elucidate the effects of obesity/metabolic syndrome on oocyte and embryo metabolism, and to establish new methods and instrumentation for monitoring metabolic aspects of oocyte and embryo development that facilitate scientific and therapeutic advances to optimize human reproductive fitness and IVF outcomes.
Publications:
- A multi-sensor system for measuring bovine embryo metabolism
- Design of a multi-sensor platform for integrating extracellular acidification rate with multi-metabolite flux measurement for small biological samples
- Oocyte metabolic function, lipid composition, and developmental potential are altered by diet in older mares
- Equine maternal aging affects oocyte lipid content, metabolic function and developmental potential
Effect of maternal diet and obesity on offspring metabolic programming
Childhood obesity has reached epidemic proportions in developed countries worldwide, and is closely linked to the increasing prevalence of metabolic syndrome and type 2 diabetes in these populations. It is well established that maternal obesity and overnutrition increases risk of obesity and diabetes in her offspring, but the mechanisms by which maternal diet or metabolic status “programs” the fetus in this manner are poorly understood. In collaboration with Dr. Carrie McCurdy in the Department of Human Physiology at the University of Oregon, we have found that maternal obesity shifts fetal cardiac and skeletal muscle to favor fatty acid over carbohydrate oxidation in a non-human primate (NHP) model, which may persist in the offspring to impair glucose homeostasis (studies ongoing). In collaboration with Drs. Gerrit Bouma and Quinton Winger in the Department of Biomedical Sciences, we recently modeled the effects of maternal high-fat feeding on fetal metabolism in sheep, which produced similar results. Current studies are investigation the mechanisms by with ovine maternal diet alters fetal tissue metabolism and evaluating the role of the placenta in this process.
We are also evaluating the effects of maternal obesity induced by high Fads2 expression (using our transgenic Fads2 mice) on offspring development of metabolic syndrome in adulthood, and how genotype interacts with maternal dietary PUFA composition to influence this process.
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