Gluconeogenesis and Energy Substrates: Shifting Paradigms in the Primate Ovary

糖异生和能量底物：灵长类动物卵巢范式的转变

• 批准号: 8926698
• 负责人: CHARLES L CHAFFIN
• 金额: $ 18.76万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-17 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8926698
• 关键词: Acetyl Coenzyme A; Address; Adipocytes; American diet; Animal Model; Animals; Blood Circulation; California; Carbohydrates; Cell Line; Cells; Collaborations; Complex; Congenital Abnormality; Couples; Data; Developmental Biology; Diabetes Mellitus; Diet; Embryo; Embryonic Development; Environment; Estrogens; Fatty Acids; Feedback; Fertility; Fertilization; Follicular Fluid; Food; Gene Expression; Generations; Genes; Gluconeogenesis; Glucose; Glycerol; Glycolysis; Goals; Gonadotropins; Health; Hepatocyte; Human; Human Chorionic Gonadotropin; Hyperglycemia; Hypoglycemia; Intake; Lipids; Liquid substance; Luteinizing Hormone; Macaca mulatta; Meiosis; Meiotic Prophase I; Metabolic; Metabolism; Metaphase; Modeling; Molecular Profiling; Non obese; Obesity; Oocytes; Ovarian; Ovarian Follicle; Ovary; Pathway interactions; Peripheral; Phosphoenolpyruvate Carboxylase; Physiology; Primates; Process; Progesterone; Pyruvate; Pyruvate Dehydrogenase Complex; Regulation; Reproductive Physiology; Research; Role; Signal Transduction; Somatic Cell; Source; Stimulus; Stress; Sucrose; System; Testing; Time; Tissues; Triglyceride Metabolism; Triglycerides; Woman; Work; cell type; corpus luteum; experience; fatty acid oxidation; glucose metabolism; glucose uptake; granulosa cell; innovation; non-diabetic; novel; offspring; oocyte maturation; oxidation; public health relevance; research study; response; sugar; xenoestrogen

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：卵母细胞需要葡萄糖才能恢复减数分裂并在产卵性促性腺激素刺激后受精。葡萄糖浓度从狭窄的浓度窗口变得太高或太低，对卵母细胞和所得胚胎产生了深刻的负面影响。这些可能包括受精率较差，而对于那些受精的卵母细胞，胚胎中的基因表达谱和潜在的先天缺陷。由于卵母细胞健康对该物种的重要性，灵长类动物似乎不太可能发展卵母细胞依赖葡萄糖饮食来源的系统。相反，我们在这里假设卵巢卵泡的体细胞成分响应于排卵刺激而合成其自身的葡萄糖，作为向卵母细胞提供控制量的能量底物的一种手段。作为此过程的一部分，体细胞（原代壁画颗粒细胞）将自己的能量使用从葡萄糖转移到储存的脂质。假定这些脂质的分解既可以提供脂肪酸氧化形式的能量，还提供甘油作为糖异生的前体。几个初步数据支持这些假设。 （1）壁画细胞的葡萄糖摄取和代谢方面被排卵刺激抑制，包括在糖酵解途径中的基因表达。 （2）能量底物使用的关键标记是通过排卵刺激从碳水化合物转移到脂质氧化的。 （3）在排卵刺激后，与糖异生有关的基因的壁画颗粒细胞表达增加。我们将检验以下假设：壁画细胞通过三个关键实验响应产卵刺激而经历糖异生。首先，我们将确认壁画细胞的葡萄糖摄取减少。其次，我们将确定调节碳水化合物转移到脂质的机制，以响应排卵刺激。第三，我们将通过壁画细胞来证明糖异生。这些实验是理解卵母细胞发展的环境的关键先驱，以及如何通过饮食，压力，肥胖和糖尿病来扰动这种环境。