Nutrient fuel preference, obesity, and stem cell lineage physiology

营养燃料偏好、肥胖和干细胞谱系生理学

• 批准号: 10635071
• 负责人: Daniela Drummond-Barbosa
• 金额: $ 56.21万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10635071
• 关键词: Adipocytes; Affect; Amino Acids; Biological Process; Brain; Carbohydrates; Cell Differentiation process; Cell Lineage; Complex; Development; Diet; Disease; Drosophila genus; Drosophila melanogaster; Ecdysone; Fatty Acids; Fatty acid glycerol esters; Hormones; Human; Ketone Bodies; Knowledge; Light; Link; Lipids; Malignant Neoplasms; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Modeling; Nutrient; Nutritional Support; Obesity; Oocytes; Oogenesis; Organ; Organism; Ovary; Pathway interactions; Phosphotransferases; Physiological; Physiology; Process; Research; Signal Transduction; Sirolimus; System; Unhealthy Diet; Work; daughter cell; dietary; experience; germline stem cells; in vivo; insight; insulin-like peptide; lipid transport; lipophorin; macromolecule; metabolic abnormality assessment; nutrient metabolism; obese person; preference; response; stem cells; steroid hormone; sugar; tissue stem cells; tool; uptake

PROJECT SUMMARY Tissue stem cell lineages maintain organ function and respond to dietary and physiological factors, and they also experience intrinsic metabolic shifts as cells differentiate Metabolic/physiological alterations are also linked to a number of diseases, including obesity and cancer. The mechanisms associated with intrinsic metabolic shifts in stem cell lineages and how physiological factors affect them remain largely underexplored. The Drosophila melanogaster ovary is ideal for the study of metabolic changes and their systemic control. Oogenesis is an energy/nutrient-intensive process that precisely links oocyte development through the germline stem cell (GSC) lineage with accumulation of lipids, carbohydrates, and other macromolecules. Developmentally-controlled metabolic changes occur along differentiation of the GSC lineage. Over the past ~18 years, our work has shed light on a multi-organ network that tightly coordinates oogenesis with whole- body physiology. GSCs and their progeny grow and divide faster on nutrient-rich rather than poor diets, and brain insulin-like peptides, Target of Rapamycin, AMP-dependent kinase, the steroid hormone ecdysone, and other factors mediate this response. Other organs also support the nutritional demands of oogenesis. For example, adipocyte lipophorin-mediated transport of lipids is crucial for oocyte yolk uptake, and several other adipocyte metabolic pathways have specific effects in oogenesis. The coordination of hormones, nutrients, metabolism, and highly regulated transitions in the GSC lineage thus integrates information from the diet and other organs. It remains unclear, however, how diet-dependent pathways affect cellular metabolism as cells differentiate along stem cell lineages, and how metabolic disorders (e.g. obesity) alter this complex process. Cellular metabolism is closely tied to nutrient fuel availability and utilization. Major cellular fuels include sugars, fatty acids, amino acids, and ketone bodies, and their availability varies depending on the overall physiological and metabolic state of the organism. Over the next 5 years, we will focus on two major questions in the Drosophila model: 1) How does fuel preference shift as GSC daughters develop through various stages of differentiation and in response to diet-dependent physiological input? 2) How does obesity impact the development of the GSC lineage, its fuel preference, and response to physiological signals? These projects will provide fundamental new knowledge to significantly advance our understanding of the integration between metabolism and physiology in the control of stem cell lineages in vivo, with the potential to inform future research additional stem cell systems and how their metabolic deregulation is tied to diseased states.

项目概要 组织干细胞谱系维持器官功能并对饮食和生理因素做出反应，并且它们 当细胞分化时，也会经历内在的代谢变化 代谢/生理变化也 与许多疾病有关，包括肥胖和癌症。与内在相关的机制 干细胞谱系的代谢变化以及生理因素如何影响它们在很大程度上仍未得到充分探索。 果蝇卵巢是研究代谢变化及其系统控制的理想选择。 卵子发生是一个能量/营养密集型过程，通过 生殖干细胞 (GSC) 谱系具有脂质、碳水化合物和其他大分子的积累。 发育控制的代谢变化随着 GSC 谱系的分化而发生。过去的事 大约 18 年来，我们的工作揭示了一个多器官网络，该网络紧密协调卵子发生与整个- 身体生理学。 GSC 及其后代在营养丰富而不是营养不良的饮食中生长和分裂得更快，并且 脑胰岛素样肽、雷帕霉素靶标、AMP 依赖性激酶、类固醇激素蜕皮激素和 其他因素介导这种反应。其他器官也支持卵子发生的营养需求。为了 例如，脂肪细胞脂蛋白介导的脂质运输对于卵母细胞卵黄的摄取至关重要，而其他一些 脂肪细胞代谢途径对卵子发生有特定的影响。激素、营养素的协调， 因此，GSC 谱系中的新陈代谢和高度调控的转变整合了来自饮食和饮食的信息。 其他器官。然而，目前尚不清楚饮食依赖性途径如何影响细胞代谢 沿干细胞谱系分化，以及代谢紊乱（例如肥胖）如何改变这一复杂的过程。 细胞代谢与营养燃料的可用性和利用密切相关。主要的细胞燃料包括糖、 脂肪酸、氨基酸和酮体，其可用性根据整体生理情况而变化 和机体的代谢状态。未来5年，我们将重点解决两个重大问题： 果蝇模型：1) 随着 GSC 子代在不同阶段的发育，燃料偏好如何变化 分化和对饮食依赖性生理输入的反应？ 2）肥胖如何影响 GSC谱系的发展、其燃料偏好以及对生理信号的反应？这些项目 将提供基础的新知识，以显着增进我们对两者之间整合的理解 体内干细胞谱系控制中的代谢和生理学，有可能为未来提供信息 研究其他干细胞系统以及它们的代谢失调与疾病状态之间的关系。