Nutrient fuel preference, obesity, and stem cell lineage physiology

项目摘要 组织干细胞谱系维持器官功能并对饮食和生理因素作出反应， 也经历内在的代谢变化，因为细胞分化代谢/生理变化也 与肥胖和癌症等多种疾病有关。与内在的相关机制 干细胞谱系中的代谢变化以及生理因素如何影响它们仍然在很大程度上未被探索。 果蝇卵巢是研究代谢变化及其系统控制的理想材料。 卵子发生是一个能量/营养密集的过程，它通过卵母细胞的发育， 生殖系干细胞（GSC）谱系，具有脂质、碳水化合物和其它大分子的积累。 发育控制的代谢变化沿着GSC谱系的分化而发生。过去 ~18年来，我们的工作揭示了一个多器官网络，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， 脑胰岛素样肽，雷帕霉素靶点，AMP依赖性激酶，类固醇激素蜕皮激素， 其它因素介导这种反应。其他器官也支持卵子发生的营养需求。为 例如，脂肪细胞载脂蛋白介导的脂质转运对于卵母细胞的卵黄摄取至关重要， 脂肪细胞代谢途径在卵子发生中具有特定的作用。荷尔蒙、营养素、 因此，GSC谱系中高度调节的代谢和转换整合了来自饮食的信息， 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， 分化沿着干细胞谱系，以及代谢紊乱（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率密切相关。主要的细胞燃料包括糖， 脂肪酸、氨基酸和酮体，它们的可用性取决于整体生理 和代谢状态。在未来五年，我们将重点关注两个主要问题， 果蝇模型：1）燃料偏好如何随着GSC子体在不同阶段的发育而变化？ 分化和响应饮食依赖的生理输入？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 将提供基本的新知识，以显着推进我们的理解之间的整合 代谢和生理学在体内干细胞谱系的控制，有可能告知未来 研究更多的干细胞系统，以及它们的代谢失调如何与疾病状态联系在一起。

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.