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来恢复减数分裂并在排卵促性腺激素刺激后受精。葡萄糖浓度在狭窄的浓度窗口范围内变得过高或过低，会对卵母细胞和由此产生的胚胎产生深远的负面影响。这些可能包括受精率低、受精卵母细胞胚胎中基因表达谱异常以及潜在的出生缺陷。由于卵母细胞健康对物种的重要性，灵长类动物似乎不太可能进化出卵母细胞依赖膳食葡萄糖来源的系统。相反，我们在这里假设卵泡的体细胞成分响应排卵刺激而合成其自身的葡萄糖，作为向卵母细胞提供受控量的能量底物的手段。作为该过程的一部分，体细胞（初级壁颗粒细胞）将其自身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以脂肪酸氧化形式提供能量，并且还提供甘油用作糖异生的前体。一些初步数据支持这些假设。 (1)壁颗粒细胞的葡萄糖摄取和代谢受到排卵刺激的抑制，包括糖酵解途径中基因的表达。 (2) 能量底物利用的关键标志物因排卵刺激而从碳水化合物转变为脂质氧化。 (3)在排卵刺激后，参与糖异生的基因的壁颗粒细胞表达增加。我们将通过三个关键实验来检验壁颗粒细胞响应排卵刺激而进行糖异生的假设。首先，我们将确认壁颗粒细胞葡萄糖摄取的减少。其次，我们将确定响应排卵刺激而调节能量使用从碳水化合物到脂质的转变的机制。第三，我们将证明壁颗粒细胞的糖异生作用。这些实验是了解卵母细胞发育环境以及该环境如何受到饮食、压力、肥胖和糖尿病干扰的重要前提。