The oocyte requires glucose to resume meiosis and to be fertilized following an ovulatory gonadotropin stimulus. Glucose concentrations ranging out of a narrow concentration window to become too high or too low have profoundly negative effects on the oocyte and the resulting embryo. These can include poor rates of fertilization and for those oocytes that are fertilized, abnormal gene expression profiles in the embryo and potential birth defects. Because of the importance of oocyte health to the species, it seems unlikely that primates evolved a system in which the oocyte is dependent upon dietary sources of glucose. Rather, we hypothesize here that the somatic component of the ovarian follicle synthesizes its own glucose in response to an ovulatory stimulus as a means to provide the oocyte with a controlled amount of energy substrate. As part of this process, the somatic cells (primary mural granulosa cells) shift their own energy use from glucose to stored lipids. The breakdown of these lipids is postulated to provide both energy in form of fatty acid -oxidation, and also provide glycerol for use as the precursor of gluconeogenesis. Several pieces of preliminary data support these hypotheses. (1) Aspects of glucose uptake and metabolism by mural granulosa cells are suppressed by an ovulatory stimulus, including expression of genes in the glycolytic pathway. (2) Key markers of energy substrate use are shifted by an ovulatory stimulus from carbohydrate to lipid oxidation. (3) The mural granulosa cell expression of genes involved in gluconeogenesis increase following an ovulatory stimulus. We will test the hypothesis that mural granulosa cells undergo gluconeogenesis in response to an ovulatory stimulus with three key experiments. First, we will confirm the reduction in glucose uptake by mural granulosa cells. Second, we will determine the mechanisms regulating the shift in energy use from carbohydrates to lipids in response to an ovulatory stimulus. Third, we will demonstrate gluconeogenesis by mural granulosa cells. These experiments are critical precursors to understanding the milieu in which the oocyte develops, and how this environment can be perturbed by diet, stress, obesity, and diabetes.
The oocyte requires glucose to mature and be fertilized. However, it is exceedingly sensitive to glucose concentrations that are too high or too low. These hyper- and hypoglycemic conditions can predispose the embryo to birth defects. The goal of this proposal is to understand how glucose concentrations within the ovary are regulated during critical windows of oocyte maturation.
